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“When my son was diagnosed [with Type 1], I knew nothing about diabetes. I changed my research focus, thinking, as any parent would, ‘What am I going to do about this?’” says Douglas Melton.

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Breakthrough within reach for diabetes scientist and patients nearest to his heart

Harvard Correspondent

100 years after discovery of insulin, replacement therapy represents ‘a new kind of medicine,’ says Stem Cell Institute co-director Douglas Melton, whose children inspired his research

When Vertex Pharmaceuticals announced last month that its investigational stem-cell-derived replacement therapy was, in conjunction with immunosuppressive therapy, helping the first patient in a Phase 1/2 clinical trial robustly reproduce his or her own fully differentiated pancreatic islet cells, the cells that produce insulin, the news was hailed as a potential breakthrough for the treatment of Type 1 diabetes. For Harvard Stem Cell Institute Co-Director and Xander University Professor Douglas Melton, whose lab pioneered the science behind the therapy, the trial marked the most recent turning point in a decades-long effort to understand and treat the disease. In a conversation with the Gazette, Melton discussed the science behind the advance, the challenges ahead, and the personal side of his research. The interview was edited for clarity and length.

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

MELTON: The first major change in the treatment of Type 1 diabetes was probably the discovery of insulin in 1920. Now it’s 100 years later and if this works, it’s going to change the medical treatment for people with diabetes. Instead of injecting insulin, patients will get cells that will be their own insulin factories. It’s a new kind of medicine.

GAZETTE: Would you walk us through the approach?

MELTON: Nearly two decades ago we had the idea that we could use embryonic stem cells to make functional pancreatic islets for diabetics. When we first started, we had to try to figure out how the islets in a person’s pancreas replenished. Blood, for example, is replenished routinely by a blood stem cell. So, if you go give blood at a blood drive, your body makes more blood. But we showed in mice that that is not true for the pancreatic islets. Once they’re removed or killed, the adult body has no capacity to make new ones.

So the first important “a-ha” moment was to demonstrate that there was no capacity in an adult to make new islets. That moved us to another source of new material: stem cells. The next important thing, after we overcame the political issues surrounding the use of embryonic stem cells, was to ask: Can we direct the differentiation of stem cells and make them become beta cells? That problem took much longer than I expected — I told my wife it would take five years, but it took closer to 15. The project benefited enormously from undergraduates, graduate students, and postdocs. None of them were here for 15 years of course, but they all worked on different steps.

GAZETTE: What role did the Harvard Stem Cell Institute play?

MELTON: This work absolutely could not have been done using conventional support from the National Institutes of Health. First of all, NIH grants came with severe restrictions and secondly, a long-term project like this doesn’t easily map to the initial grant support they give for a one- to three-year project. I am forever grateful and feel fortunate to have been at a private institution where philanthropy, through the HSCI, wasn’t just helpful, it made all the difference.

I am exceptionally grateful as well to former Harvard President Larry Summers and Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, who supported the creation of the HSCI, which was formed specifically with the idea to explore the potential of pluripotency stem cells for discovering questions about how development works, how cells are made in our body, and hopefully for finding new treatments or cures for disease. This may be one of the first examples where it’s come to fruition. At the time, the use of embryonic stem cells was quite controversial, and Steve and Larry said that this was precisely the kind of science they wanted to support.

GAZETTE: You were fundamental in starting the Department of Stem Cell and Regenerative Biology. Can you tell us about that?

MELTON: David Scadden and I helped start the department, which lives in two Schools: Harvard Medical School and the Faculty of Arts and Science. This speaks to the unusual formation and intention of the department. I’ve talked a lot about diabetes and islets, but think about all the other tissues and diseases that people suffer from. There are faculty and students in the department working on the heart, nerves, muscle, brain, and other tissues — on all aspects of how the development of a cell and a tissue affects who we are and the course of disease. The department is an exciting one because it’s exploring experimental questions such as: How do you regenerate a limb? The department was founded with the idea that not only should you ask and answer questions about nature, but that one can do so with the intention that the results lead to new treatments for disease. It is a kind of applied biology department.

GAZETTE: This pancreatic islet work was patented by Harvard and then licensed to your biotech company, Semma, which was acquired by Vertex. Can you explain how this reflects your personal connection to the research?

MELTON: Semma is named for my two children, Sam and Emma. Both are now adults, and both have Type 1 diabetes. My son was 6 months old when he was diagnosed. And that’s when I changed my research plan. And my daughter, who’s four years older than my son, became diabetic about 10 years later, when she was 14.

When my son was diagnosed, I knew nothing about diabetes and had been working on how frogs develop. I changed my research focus, thinking, as any parent would, “What am I going to do about this?” Again, I come back to the flexibility of Harvard. Nobody said, “Why are you changing your research plan?”

GAZETTE: What’s next?

MELTON: The stem-cell-derived replacement therapy cells that have been put into this first patient were provided with a class of drugs called immunosuppressants, which depress the patient’s immune system. They have to do this because these cells were not taken from that patient, and so they are not recognized as “self.” Without immunosuppressants, they would be rejected. We want to find a way to make cells by genetic engineering that are not recognized as foreign.

I think this is a solvable problem. Why? When a woman has a baby, that baby has two sets of genes. It has genes from the egg, from the mother, which would be recognized as “self,” but it also has genes from the father, which would be “non-self.” Why does the mother’s body not reject the fetus? If we can figure that out, it will help inform our thinking about what genes to change in our stem cell-derived islets so that they could go into any person. This would be relevant not just to diabetes, but to any cells you wanted to transplant for liver or even heart transplants. It could mean no longer having to worry about immunosuppression.

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Recent Advances

ADA-funded researchers use the money from their awards to conduct critical diabetes research. In time, they publish their findings in order to inform fellow scientists of their results, which ensures that others will build upon their work. Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards!

Identification of a new player in type 1 diabetes risk

Type 1 diabetes is caused by an autoimmune attack of insulin-producing beta-cells. While genetics and the environment are known to play important roles, the underlying factors explaining why the immune system mistakenly recognize beta-cells as foreign is not known. Now, Dr. Delong has discovered a potential explanation. He found that proteins called Hybrid Insulin Peptides (HIPs) are found on beta-cells of people with type 1 diabetes and are recognized as foreign by their immune cells. Even after diabetes onset, immune cells are still present in the blood that attack these HIPs.

Next, Dr. Delong wants to determine if HIPs can serve as a biomarker or possibly even targeted to prevent or treat type 1 diabetes. Baker, R. L., Rihanek, M., Hohenstein, A. C., Nakayama, M., Michels, A., Gottlieb, P. A., Haskins, K., & Delong, T. (2019). Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes , 68 (9), 1830–1840.

Understanding the biology of body-weight regulation in children

Determining the biological mechanisms regulating body-weight is important for preventing type 2 diabetes. The rise in childhood obesity has made this even more urgent. Behavioral studies have demonstrated that responses to food consumption are altered in children with obesity, but the underlying biological mechanisms are unknown. This year, Dr. Schur tested changes in brain and hormonal responses to a meal in normal-weight and obese children. Results from her study show that hormonal responses in obese children are normal following a meal, but responses within the brain are reduced. The lack of response within the brain may predispose them to overconsumption of food or difficulty with weight-loss.

With this information at hand, Dr. Schur wants to investigate how this information can be used to treat obesity in children and reduce diabetes.

Roth, C. L., Melhorn, S. J., Elfers, C. T., Scholz, K., De Leon, M. R. B., Rowland, M., Kearns, S., Aylward, E., Grabowski, T. J., Saelens, B. E., & Schur, E. A. (2019). Central Nervous System and Peripheral Hormone Responses to a Meal in Children. The Journal of Clinical Endocrinology and Metabolism , 104 (5), 1471–1483.

A novel molecule to improve continuous glucose monitoring

To create a fully automated artificial pancreas, it is critical to be able to quantify blood glucose in an accurate and stable manner. Current ways of continuously monitoring glucose are dependent on the activity of an enzyme which can change over time, meaning the potential for inaccurate readings and need for frequent replacement or calibration. Dr. Wang has developed a novel molecule that uses a different, non-enzymatic approach to continuously monitor glucose levels in the blood. This new molecule is stable over long periods of time and can be easily integrated into miniaturized systems.

Now, Dr. Wang is in the process of patenting his invention and intends to continue research on this new molecule so that it can eventually benefit people living with diabetes.

Wang, B. , Chou, K.-H., Queenan, B. N., Pennathur, S., & Bazan, G. C. (2019). Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose. Angewandte Chemie (International Ed. in English) , 58 (31), 10612–10615.

Addressing the legacy effect of diabetes

Several large clinical trials have demonstrated the importance of tight glucose control for reducing diabetes complications. However, few studies to date have tested this in the real-world, outside of a controlled clinical setting. In a study published this year, Dr. Laiteerapong found that indeed in a real-world setting, people with lower hemoglobin A1C levels after diagnosis had significantly lower vascular complications later on, a phenomenon known as the ‘legacy effect’ of glucose control. Her research noted the importance of early intervention for the best outcomes, as those with the low A1C levels just one-year after diagnosis had significantly lower vascular disease risk compared to people with higher A1C levels.

With these findings in hand, physicians and policymakers will have more material to debate and determine the best course of action for improving outcomes in people newly diagnosed with diabetes.

Laiteerapong, N. , Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care , 42 (3), 416–426.

A new way to prevent immune cells from attacking insulin-producing beta-cells

Replacing insulin-producing beta-cells that have been lost in people with type 1 diabetes is a promising strategy to restore control of glucose levels. However, because the autoimmune disease is a continuous process, replacing beta-cells results in another immune attack if immunosorbent drugs are not used, which carry significant side-effects. This year, Dr. Song reported on the potential of an immunotherapy he developed that prevents immune cells from attacking beta-cells and reduces inflammatory processes. This immunotherapy offers several potential benefits, including eliminating the need for immunosuppression, long-lasting effects, and the ability to customize the treatment to each patient.

The ability to suppress autoimmunity has implications for both prevention of type 1 diabetes and improving success rates of islet transplantation.

Haque, M., Lei, F., Xiong, X., Das, J. K., Ren, X., Fang, D., Salek-Ardakani, S., Yang, J.-M., & Song, J . (2019). Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight , 4 (7).

A new target to improve insulin sensitivity

The hormone insulin normally acts like a ‘key’, traveling through the blood and opening the cellular ‘lock’ to enable the entry of glucose into muscle and fat cells. However, in people with type 2 diabetes, the lock on the cellular door has, in effect, been changed, meaning insulin isn’t as effective. This phenomenon is called insulin resistance. Scientists have long sought to understand what causes insulin resistance and develop therapies to enable insulin to work correctly again. This year, Dr. Summers determined an essential role for a molecule called ceramides as a driver of insulin resistance in mice. He also presented a new therapeutic strategy for lowering ceramides and reversing insulin resistance. His findings were published in one of the most prestigious scientific journals, Science .

Soon, Dr. Summers and his team will attempt to validate these findings in humans, with the ultimate goal of developing a new medication to help improve outcomes in people with diabetes.

Chaurasia, B., Tippetts, T. S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., … Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science (New York, N.Y.) , 365 (6451), 386–392.

Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A. , Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society , 3 (3), 643–654.

Investigating the loss of postmenopausal protection from cardiovascular disease in women with type 1 diabetes

On average, women have a lower risk of developing heart disease compared to men. However, research has shown that this protection is lost in women with type 1 diabetes. The process of menopause increases rates of heart disease in women, but it is not known how menopause affects women with type 1 diabetes in regard to risk for developing heart disease. In a study published this year, Dr. Snell-Bergeon found that menopause increased risk markers for heart disease in women with type 1 diabetes more than women without diabetes.

Research has led to improved treatments and significant gains in life expectancy for people with diabetes and, as a result, many more women are reaching the age of menopause. Future research is needed to address prevention and treatment options.

Keshawarz, A., Pyle, L., Alman, A., Sassano, C., Westfeldt, E., Sippl, R., & Snell-Bergeon, J. (2019). Type 1 Diabetes Accelerates Progression of Coronary Artery Calcium Over the Menopausal Transition: The CACTI Study. Diabetes Care , 42 (12), 2315–2321.

Identification of a potential therapy for diabetic neuropathy related to type 1 and type 2 diabetes

Diabetic neuropathy is a type of nerve damage that is one of the most common complications affecting people with diabetes. For some, neuropathy can be mild, but for others, it can be painful and debilitating. Additionally, neuropathy can affect the spinal cord and the brain. Effective clinical treatments for neuropathy are currently lacking. Recently, Dr. Calcutt reported results of a new potential therapy that could bring hope to the millions of people living with diabetic neuropathy. His study found that a molecule currently in clinical trials for the treatment of depression may be valuable for diabetic neuropathy, particularly the type affecting the brain.

Because the molecule is already in clinical trials, there is the potential that it can benefit patients sooner than later.

Jolivalt, C. G., Marquez, A., Quach, D., Navarro Diaz, M. C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D. R., Fernyhough, P., Johe, K., & Calcutt, N. A. (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes , 68 (11), 2143–2154.

ADA-funded researcher studying link between ageing and type 2 diabetes

One of the most important risk factors for developing type 2 diabetes is age. As a person gets older, their risk for developing type 2 diabetes increases. Scientists want to better understand the relationship between ageing and diabetes in order to determine out how to best prevent and treat type 2 diabetes. ADA-funded researcher Rafael Arrojo e Drigo, PhD, from the Salk Institute for Biological Studies, is one of those scientists working hard to solve this puzzle.

Recently, Dr. Arrojo e Drigo published results from his research in the journal Cell Metabolism . The goal of this specific study was to use high-powered microscopes and novel cellular imaging tools to determine the ‘age’ of different cells that reside in organs that control glucose levels, including the brain, liver and pancreas. He found that, in mice, the cells that make insulin in the pancreas – called beta-cells – were a mosaic of both old and young cells. Some beta-cells appeared to be as old as the animal itself, and some were determined to be much younger, indicating they recently underwent cell division.

Insufficient insulin production by beta-cells is known to be a cause of type 2 diabetes. One reason for this is thought to be fewer numbers of functional beta-cells. Dr. Arrojo e Drigo believes that people with or at risk for diabetes may have fewer ‘young’ beta-cells, which are likely to function better than old ones. Alternatively, if we can figure out how to induce the production of younger, high-functioning beta-cells in the pancreas, it could be a potential treatment for people with diabetes.

In the near future, Dr. Arrojo e Drigo’s wants to figure out how to apply this research to humans. “The next step is to look for molecular or morphological features that would allow us to distinguish a young cell from and old cell,” Dr. Arrojo e Drigo said.

The results from this research are expected to provide a unique insight into the life-cycle of beta-cells and pave the way to novel therapeutic avenues for type 2 diabetes.

Watch a video of Dr. Arrojo e Drigo explaining his research!

Arrojo E Drigo, R. , Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., … Hetzer, M. W. (2019). Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism , 30 (2), 343-351.e3.

Researcher identifies potential underlying cause of type 1 diabetes

Type 1 diabetes occurs when the immune system mistakenly recognizes insulin-producing beta-cells as foreign and attacks them. The result is insulin deficiency due to the destruction of the beta-cells. Thankfully, this previously life-threatening condition can be managed through glucose monitoring and insulin administration. Still, therapies designed to address the underlying immunological cause of type 1 diabetes remain unavailable.

Conventional approaches have focused on suppressing the immune system, which has serious side effects and has been mostly unsuccessful. The American Diabetes Association recently awarded a grant to Dr. Kenneth Brayman, who proposed to take a different approach. What if instead of suppressing the whole immune system, we boost regulatory aspects that already exist in the system, thereby reigning in inappropriate immune cell activation and preventing beta-cell destruction? His idea focused on a molecule called immunoglobulin M (IgM), which is responsible for limiting inflammation and regulating immune cell development.

In a paper published in the journal Diabetes , Dr. Brayman and a team of researchers reported exciting findings related to this approach. They found that supplementing IgM obtained from healthy mice into mice with type 1 diabetes selectively reduced the amount of autoreactive immune cells known to target beta-cells for destruction. Amazingly, this resulted in reversal of new-onset diabetes. Importantly, the authors of the study determined this therapy is translatable to humans. IgM isolated from healthy human donors also prevented the development of type 1 diabetes in a humanized mouse model of type 1 diabetes.

The scientists tweaked the original experiment by isolating IgM from mice prone to developing type 1 diabetes, but before it actually occurred. When mice with newly onset diabetes were supplemented with this IgM, their diabetes was not reversed. This finding suggests that in type 1 diabetes, IgM loses its capacity to serve as a regulator of immune cells, which may be contribute to the underlying cause of the disease.

Future studies will determine exactly how IgM changes its regulatory properties to enable diabetes development. Identification of the most biologically optimal IgM will facilitate transition to clinical applications of IgM as a potential therapeutic for people with type 1 diabetes.    Wilson, C. S., Chhabra, P., Marshall, A. F., Morr, C. V., Stocks, B. T., Hoopes, E. M., Bonami, R.H., Poffenberger, G., Brayman, K.L. , Moore, D. J. (2018). Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice. Diabetes .

ADA-funded researcher designs community program to help all people tackle diabetes

Diabetes self-management and support programs are important adjuncts to traditional physician directed treatment. These community-based programs aim to give people with diabetes the knowledge and skills necessary to effectively self-manage their condition. While several clinical trials have demonstrated the value of diabetes self-management programs in terms of improving glucose control and reducing health-care costs, whether this also occurs in implemented programs outside a controlled setting is unclear, particularly in socially and economically disadvantaged groups.

Lack of infrastructure and manpower are often cited as barriers to implementation of these programs in socioeconomically disadvantaged communities. ADA-funded researcher Dr. Briana Mezuk addressed this challenge in a study recently published in The Diabetes Educator . Dr. Mezuk partnered with the YMCA to evaluate the impact of the Diabetes Control Program in Richmond, Virginia. This community-academic partnership enabled both implementation and evaluation of the Diabetes Control Program in socially disadvantaged communities, who are at higher risk for developing diabetes and the complications that accompany it.

Dr. Mezuk had two primary research questions: (1) What is the geographic and demographic reach of the program? and (2) Is the program effective at improving diabetes management and health outcomes in participants? Over a 12-week study period, Dr. Mezuk found that there was broad geographic and demographic participation in the program. The program had participants from urban, suburban and rural areas, most of which came from lower-income zip codes. HbA1C, mental health and self-management behaviors all improved in people taking part in the Greater Richmond Diabetes Control Program. Results from this study demonstrate the value of diabetes self-management programs and their potential to broadly improve health outcomes in socioeconomically diverse communities. Potential exists for community-based programs to address the widespread issue of outcome disparities related to diabetes.  Mezuk, B. , Thornton, W., Sealy-Jefferson, S., Montgomery, J., Smith, J., Lexima, E., … Concha, J. B. (2018). Successfully Managing Diabetes in a Community Setting: Evidence from the YMCA of Greater Richmond Diabetes Control Program. The Diabetes Educator , 44 (4), 383–394.

Using incentives to stimulate behavior changes in youth at risk for developing diabetes

Once referred to as ‘adult-onset diabetes’, incidence of type 2 diabetes is now rapidly increasing in America’s youth. Unfortunately, children often do not have the ability to understand how everyday choices impact their health. Could there be a way to change a child’s eating behaviors? Davene Wright, PhD, of Seattle Children’s Hospital was granted an Innovative Clinical or Translational Science award to determine whether using incentives, directed by parents, can improve behaviors related to diabetes risk. A study published this year in Preventive Medicine Reports outlined what incentives were most desirable and feasible to implement. A key finding was that incentives should be tied to behavior changes and not to changes in body-weight.

With this information in hand, Dr. Wright now wants to see if incentives do indeed change a child’s eating habits and risk for developing type 2 diabetes. She is also planning to test whether an incentive program can improve behavior related to diabetes management in youth with type 1 diabetes. Jacob-Files, E., Powell, J., & Wright, D. R. (2018). Exploring parent attitudes around using incentives to promote engagement in family-based weight management programs. Preventive Medicine Reports , 10 , 278–284.

Determining the genetic risk for gestational diabetes

Research has identified more than 100 genetic variants linked to risk for developing type 2 diabetes in humans. However, the extent to which these same genetic variants might affect a woman’s probability for getting gestational diabetes has not been investigated.

Pathway to Stop Diabetes ® Accelerator awardee Marie-France Hivert, MD, of Harvard University set out to answer this critical question. Dr. Hivert found that indeed genetic determinants of type 2 diabetes outside of pregnancy are also strong risk factors for gestational diabetes. This study was published in the journal Diabetes .

The implications? Because of this finding, doctors in the clinic may soon be able to identify women at risk for getting gestational diabetes and take proactive steps to prevent it. Powe, C. E., Nodzenski, M., Talbot, O., Allard, C., Briggs, C., Leya, M. V., … Hivert, M.-F. (2018). Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus. Diabetes , 67 (12), 2703–2709.

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Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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New Research Sheds Light on Cause of Type 2 Diabetes

St. Petersburg, Fla. – September 12, 2023 – Scientists at Johns Hopkins All Children’s Hospital, along with an international team of researchers, are shedding new light on the causes of Type 2 diabetes. The new research, published in the journal Nature Communications , offers a potential strategy for developing new therapies that could restore dysfunctional pancreatic beta-cells or, perhaps, even prevent Type 2 diabetes from developing.

The new study shows that the beta-cells of Type 2 diabetes patients are deficient in a cell trafficking protein called “phosphatidylinositol transfer protein alpha” (or PITPNA), which can promote the formation of “little packages,” or intracellular granules containing insulin. These structures facilitate processing and maturation of insulin “cargo.” By restoring PITPNA in the Type 2 deficient beta-cells, production of insulin granule is restored and this reverses many of the deficiencies associated with beta-cell failure and Type 2 diabetes.

Researchers say it’s important to understand how specific genes regulate pancreatic beta-cell function, including those that mediate insulin granule production and maturation like PITPNA to provide therapeutic options for people.

Matthew Poy, Ph.D. , an associate professor of Medicine and Biological Chemistry in the Johns Hopkins University School of Medicine and leader of the Johns Hopkins All Children’s team within the  Institute for Fundamental Biomedical Research , was lead researcher on the study. He adds that follow-up work is now focused on whether PITPNA can enhance the functionality of stem-cell-derived pancreatic beta-cells. Since stem cell-based therapies are still in their relatively early stages of clinical development, it appears a great deal of the potential of this approach remains untapped. Poy believes that increasing levels of PITPNA in stem cell-derived beta-cells is an approach that could enhance the ability to produce and release mature insulin prior to transplantation in diabetic subjects.

“Our dream is that increasing PITPNA could improve the efficacy and potency of beta-like stem cells,” Poy says. “This is where our research is heading, but we have to discover whether the capacity of these undifferentiated stem cells that can be converted into many different cell types can be optimized — and to what level — to be converted into healthy insulin producing beta-cells. The goal would be to find a cure for type 2 diabetes.”

Read more about this groundbreaking research.

This study was funded through grants from the  Johns Hopkins All Children’s Foundation , the  National Institute of Health, the Robert A. Welch Foundation, the Helmholtz Gemeinschaft , the European Foundation for the Study of Diabetes, the  Swedish Science Council , the  NovoNordisk Foundation  and the  Deutsche Forschungsgemeinschaft .     About Johns Hopkins All Children’s Hospital Johns Hopkins All Children’s Hospital in St. Petersburg is a leader in children’s health care, combining a legacy of compassionate care focused solely on children since 1926 with the innovation and experience of one of the world’s leading health care systems. The 259-bed teaching hospital, stands at the forefront of discovery, leading innovative research to cure and prevent childhood diseases while training the next generation of pediatric experts. With a network of Johns Hopkins All Children’s Outpatient Care centers and collaborative care provided by All Children’s Specialty Physicians at regional hospitals, Johns Hopkins All Children’s brings care closer to home. Johns Hopkins All Children’s Hospital consistently keeps the patient and family at the center of care while continuing to expand its mission in treatment, research, education and advocacy. For more information, visit HopkinsAllChildrens.org .

Clinical Trials

Displaying 175 studies

The purpose of this study is to identify immune mediated diabetes in patients treated with PD 1 inhibitors, and characterizing its clinical course, laboratory features and possible risk factors. 

The purpose of this study is to determine the longitudinal effect of diabetes-associated variation in TCF7L2 on a-cell function and the contribution of a-cell function to longitudinal glucose tolerance and EGP in non-diabetic subjects.  

The purpose of this study is to identify potentially modifiable barriers to hyperglycemia management in hospitalized diabetic patients. Both general hospitalized diabetic patients and first time renal transplant patients will be studied.

The purpose of this study is to establish a biobank of blood samples to study the relationship between diabetes mellitus and other pancreatic conditions.

The objective of this study is to gain understanding of how patients with diabetes mellitus (DM) dispose of hazardous waste items (e.g., needles, used glucometer strips, unused insulin) with the goal of providing education regarding safe practices

The goal of this study is to understand how and why insulin resistant individuals respond differently to exercise as compared with insulin sensitive individuals at the skeletal muscle and gene expression level.

The purpose of this study is to compare the effectiveness and safety of an automated insulin delivery (AID) study system using a Model Predictive Control (MPC) algorithm versus Sensor Augmented Pump (SAP) (which may or may not include PLGS; to be referred to as SAP) therapy in people with type 1 diabetes. A Pilot Phase involving up to 7 participants using the study system for 10-14 days will be conducted prior to the crossover trial.

The purpose of this study is to determine if a 6 month supply (1 meal//day) of healthy food choices readily available in the patients home and self management training including understanding how foods impact diabetes, improved food choices and how to prepare those foods, will improve glucose control, and if there will be lasting behavior change modification after the program.

The objectives of this study are to determine whether the InPen® alters the glycemic control and variability in adolescents and emerging adults with type 1 diabetes, and to determine if InPen® use alters the perceived burden of diabetes cares, diabetes distress scores, transition readiness scores, and parental experience of child illness scale (11-13).

The goal of this study is to determine the role of postprandial glucagon suppression and insulin secretion in the progression of glucose intolerance in people with diabetes-associated variation in TCF7L2.

The purpose of this study is to use the well-characterized Diabetes Control and Complications Trial (DCCT) cohort of 1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro- and macrovascular outcomes.

The purpose of this study is to establish a cohort of new onset diabetes patients.

Patients age 25 to 75 who are in the care of one of the primary care physicians at Mayo Clinic in Jacksonville, Florida or Montage Health in Monterey, California and have a recent HbA1c in the range of 7.5% to 13% will be prospectively identified and eligible for participation in this randomized, crossover clinical trial examining the effect of medically tailored meal delivery on glycemic control. Eligible patients who sign informed consent will be randomized in a 1:1 fashion to treatment sequence AB or treatment sequence BA.  In the first study phase, participants randomized to sequence AB will receive 3 ...

The purpose of this study is to determine if patient’s own Continuous Glucose Monitoring (CGMs) worn in the non-ICU hospital setting have adequate accuracy for blood glucose monitoring when compared to point-of-care capillary glucose measurement, and to determine if alerts given by CGMs worn in the non-ICU hospital would prevent episodes of hyperglycemia and hypoglycemia.

The obectives of this study are to identify insulin resistance (IR)-specific chromatin signatures in mature adipocytes and myotubes, and to identify IR-specific chromatin signatures in progenitor cells from adipose tissue (AT) and skeletal muscle (SM).

The purpose of this study is to demonstrate that a morning injection of Toujeo compared to Lantus will provide better glycemic control, as shown  by Continuous Glucose Monitoring (CGM), in adult patients with type 1 diabetes mellitus.

The purpose of this study is to identify changes to the metabolome (range of chemicals produced in the body) and microbiome (intestine microbe environment) that are unique to Roux-en-Y gastric bypass surgery and assess the associated effect on the metabolism of patients with type 2 diabetes.

The primary aim of this study is to compare the outcome measures of adult ECH type 2 diabetes patients who were referred to onsite pharmacist services for management of their diabetes to similar patients who were not referred for pharmacy service management of their diabetes. A secondary aim of the study is to assess the Kasson providers’ satisfaction level and estimated pharmacy service referral frequency to their patients. A tertiary aim of the study is to compare the hospitalization rates of type 2 diabetes rates who were referred to onsite pharmacist services for management of their diabetes to similar patients ...

To explore the feasibility of conducting a family centered wellness coaching program for patients at high risk for developing diabetes, in a primary care setting.

To determine engagement patterns.

To describe characteristics of families who are likely to participate.

To identify barriers/limitations to family centered wellness coaching.

To assess whether a family centered 8 week wellness coaching intervention for primary care patients at high risk for diabetes will improve self-care behaviors as measured by self-reported changes in physical activity level and food choices.

This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.

The purpose of this study is to assess the effectiveness of Revita® DMR for improving HbA1c to ≤ 7% without the need of insulin in subjects with T2D compared to sham and to assess the effectiveness of DMR versus Sham on improvement in Glycemic, Hepatic and Cardiovascular endpoints.

The purpose of this study is to identify risk factors for ICI associated diabetes mellitus and to assess the severity and natural course of this immune related adverse effect.

The purpose of this study is to evaluate the impact of a digital storytelling intervention derived through a community-based participatory research (CBPR) approach on type 2 diabetes mellitus (T2D) outcomes among Hispanic adults with poorly controlled type 2 diabetes mellitus (T2D) in primary care settings through a randomized clinical trial.

The purpose of this study is to assess the impact of a whole food plant-based diet on blood sugar control in diabetic patients versus a control group on the American Diabetics Association diet before having a total hip, knee, or shoulder replacement surgery.

The purpose of  this study is to learn more about if the medication, Entresto, could help the function of the heart and kidneys.

The purpose of this study is to evaluate 6 weeks of home use of the Control-IQ automated insulin delivery system in individuals with type 2 diabetes.

This study will evaluate whether bile acids are able to increase insulin sensitivity and enhance glycemic control in T2DM patients, as well as exploring the mechanisms that enhance glycemic control. These observations will provide the preliminary data for proposing future therapeutic as well as further mechanistic studies of the role of bile acids in the control of glycemia in T2DM.

The purpose of this study is to determine if Inpatient Stress Hyperglycemia is an indicator of future risk of developing type 2 Diabetes Mellitus.

The purpose of this study is to collect blood samples for biomarker assessment in type 1 diabetes prior to and at specific time points during closed loop control.

The purpose of this study is to assess the effectiveness of a digital storytelling intervention derived through a community based participatory research (CBPR) approach on self-management of type 2 diabetes (T2D) among Somali adults. 

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

Hypothesis: Increased contact with the diabetes care team throughout pregnancy will lead to improved glucose control during pregnancy.

The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion ...

The purpose of this study is to test the hypothesis that patients with T2DM will have greater deterioration in BMSi and in cortical porosity over 3 yrs as compared to sex- and age-matched non-diabetic controls; and identify the circulating hormonal (e.g., estradiol [E2], testosterone [T]) and biochemical (e.g., bone turnover markers, AGEs) determinants of changes in these key parameters of bone quality, and evaluate the possible relationship between existing diabetic complications and skeletal deterioration over time in the T2DM patients.

The purpose of this study is to serve as a comparator group to a group of patients that will be managed with AP for varying periods of time during pregnancy.

The purpose of this study is to determine the effect of endogenous GLP-1 secretion on islet function in people with Typr 2 Diabetes Mellitus (T2DM).

GLP-1 is a hormone made by the body that promotes the production of insulin in response to eating. However, there is increasing evidence that this hormone might help support the body’s ability to produce insulin when diabetes develops. 

The purpose of this study is to assess whether psyllium is more effective in lowering fasting blood sugar and HbA1c, and to evaluate the effect of psyllium compared to wheat dextrin on the following laboratory markers:  LDL-C, inflammatory markers such as ceramides and hsCRP, and branch chain amino acids which predict Diabetes Mellitus (DM).

The purpose of this study is to evaluate glucose variability in patients with type 1 diabetes (T1D) and insulin antibodies, to evaluate the clinical significance of insulin antibodies, and to establish an in vitro assay that would detect antibodies to insulin and insulin analogs.

This clinical trial will identify exercise-related and emotional stress related effects on glycemic control in patients with type 1 diabetes using sensor-augmented pump (SAP) therapy.

This study will test the efficacy of BKR-017 (colon-targeted 500 mg butyrate tablets) on insulin sensitivity, glucose control and triglycerides in type-1 diabetes subjects.

This observational study is conducted to determine how the duodenal layer thicknesses (mucosa, submucosa, and muscularis) vary with several factors in patients with and without type 2 diabetes.

The purpose of this research is to test the safety and effectiveness of the interoperable Artificial Pancreas System Smartphone App (iAPS) in managing blood sugars in pregnant patients with type 1 diabetes.

This mixed methods study aims to answer the question: "What is the work of being a patient with type 2 diabetes mellitus?" .

The objective of this study is to evaluate the EWIS in patients with type 1 diabetes on insulin pump therapy.

This study is a multi-center, non-randomized, prospective single arm study with type 1 patients with diabetes on insulin pump therapy with Continuous Glucose Monitoring (CGM).

A total of up to 300 subjects will be enrolled at up to 20 investigational centers in the US in order to have 240 subjects meeting eligibility criteria. Each subject will wear their own MiniMed™ 670G insulin system. Each subject will be given 12 infusion sets to wear (each infusion set for at least 174 hours, or ...

The purpose of this study is to use the USS Virginia Closed-Loop system for overnight insulin delivery in adults with Type 1 Diabetes (T1DM) in an outpatient setting to evaluate the system's ability to significantly improve blood glucose levels. This protocol will test the feasibility of "bedside" closed-loop control - an approach comprised of standard sensor-augmented pump therapy during the day using off-the-shelf devices and overnight closed-loop control using experimental devices in an outpatient setting. The rationale for this study is as follows: we anticipate that closed-loop control may ultimately be adopted by patients with T1DM in a selective manner. ...

The purpose of this study is to assess penile length pre- and post-completion of RestoreX® traction therapy compared to control groups (no treatment) among men with type II diabetes.

The overall objective of this study is to perform baseline and repeat assessments over time of the metabolic and immunologic status of individuals at risk for type 1 diabetes (T1D) to:

• characterize their risk for developing T1D and identify subjects eligible for prevention trials;
• describe the pathogenic evolution of T1D; and
• increase the understanding of the pathogenic factors involved in the development of T1D.

This trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, phase 2 study in subjects with Type 2 Diabetes Mellitus to evaluate the effect of TTP399 on HbA1c following administration for 6 months.

The purpose of this study is to find the inheritable changes in genetic makeup that are related to the development of type 2 diabetes in Latino families.

Our goal in this pilot study is to test and develop a novel method that will accurately measure, in vivo, glucagon kinetics in healthy humans and generate preliminary data in type 1 diabetes (T1DM) subjects under overnight fasted conditions.

The objective of this early feasibility study is to assess the feasibility and preliminary safety of the Endogenex Divice for endoscopic duodenal mucosal regeneration in patients with type 2 diabetes (T2D) inadequately controlled on 2-3 non-insulin glucose-lowering medications. 

The study purpose is to understand patients’ with the diagnosis of Diabetes Mellitus type 1 or 2 perception of the care they receive in the Diabetes clinic or Diabetes technology clinic at Mayo Clinic and to explore and to identify the healthcare system components patients consider important to be part of the comprehensive regenerative care in the clinical setting.

However, before we can implement structural changes or design interventions to promote comprehensive regenerative care in clinical practice, we first need to characterize those regenerative practices occurring today, patients expectations, perceptions and experiences about comprehensive regenerative care and determine the ...

The purpose of this study is to determine the impact of patient decision aids compared to usual care on measures of patient involvement in decision-making, diabetes care processes, medication adherence, glycemic and cardiovascular risk factor control, and use of resources in nonurban practices in the Midwestern United States.

The purpose of this study is to evaluate if breathing pure oxygen overnight affects insulin sensitivity in participants with diabetes.   

The purpose of this study is to assess a novel informatics approach that incorporates the use of patient’s diabetes self-care data into the design and delivery of individualized education interventions to improve diabetes control.

The purpose of this study is to assess the glycemic variability in patients with complex diabetes admitted in the hospital using a glycemic sensor.

The purpose of this research is to create a single registry for type 1 and type 2 diabetes at Mayo Rochester and affiliated Mayo sites.

The purpose of this study is to estimate the risk of diabetes related complications after total pancreatectomy.  We will contact long term survivors after total pancreatectomy to obtain data regarding diabetes related end organ complications.

The multi-purpose of this study is to examine the effectiveness of “InsulisiteGuider” in patients with type 1 diabetes (T1D) through a two-group randomized controlled trial, to characterize the RNA biomarkers in skin epithelial cells isolated from the continuous subcutaneous insulin infusion (CSII) cannulas from T1D patients, and to characterize RNA biomarkers in the blood and saliva of TID patients.

The purpose of this study is to understand nighttime glucose regulation in humans and find if the pattern is different in people with Type 2 diabetes

Can QBSAfe be implemented in a clinical practice setting and improve quality of life, reduce treatment burden and hypoglycemia among older, complex patients with type 2 diabetes?

Questionnaire administered to diabetic patients in primary care practice (La Crosse Mayo Family Medicine Residency /Family Health Clinic) to assess patient’s diabetic knowledge. Retrospective chart review will also be done to assess objective diabetic control based on most recent hemoglobin A1c.    

Exendin-(9,39) has been shown to have effects on beta-cell function, and after gastric bypass, to accelerate gastrointestinal transit. - infused at rates of 300pmol/kg/min. Given that gastrointestinal transit is typically delayed by Glucagon-Like Peptide-1 (GLP-1) and also that this hormone causes decreased food intake through increased satiation, it is reasonable to expect an effect of Exendin-9,39 on appetite. This may help explain the effects of gastric bypass on food intake. To examine the effect of Exendin on food intake we propose a dose-response study to determine whether the compound has effects in a dose-dependent fashion. We will examine the presence ...

This study is being done to determine the roles that several molecules play in the repair of injured cells that line your blood vessels.

This purpose of this study is to determine if activation of a person's immune system in the small intestine could be a contributing cause of Type 1 Diabetes.

The purpose of this project is to collect data over the first year of clinical use of the FDA approved 670G closed loop insulin delivery system among patients with type 1 diabetes. The goal is to evaluate how this newly approved system impacts both clinical and patient-reported outcomes.

It is unknown how patient preferences and values impact the comparative effectiveness of second-line medications for Type 2 diabetes (T2D). The purpose of this study is to elicit patient preferences toward various treatment outcomes (e.g., hospitalization, kidney disease) using a participatory ranking exercise, use these rankings to generate individually weighted composite outcomes, and estimate patient-centered treatment effects of four different second-line T2D medications that reflect the patient's value for each outcome. 

The purpose of this mixed-methods study is to deploy the tenets of Health and Wellness Coaching (HWC) through a program called BeWell360 model , tailored to the needs of Healthcare Workers (HCWs) as patients living with poorly-controlled Type 2 Diabetes (T2D). The objective of this study is to pilot-test this novel, scalable, and sustainable BeWell360 model that is embedded and integrated as part of primary care for Mayo Clinic Employees within Mayo Clinic Florida who are identified as patients li)ving with poorly-controlled T2D. 

The purpose of this study is to evaluate the dose-dependent effects of TAK-954 on gastric emptying time of solids in participants with diabetic or idiopathic gastroparesis assessed by scintigraphy.

The study is being done to find out if low blood sugar (hypoglycemia) can be reduced in people with type 1 diabetes (T1D) 65 years and older with use of automated insulin delivery (AID) system.

The device systems used in this study are approved by the Food and Drug Administration (FDA) for diabetes management. We will be collecting data about how they are used, how well they work, and how safe they are.

This study aims to identify an early stage biomarker for type 1 diabetes. In vitro evidence identified a significant enrichment of the chemokine CXCL10 in β-cell derived EXO upon exposure to diabetogenic pro-inflammatory cytokines. The study also aims to test protocols for efficient isolation of plasma-derived EXO from small volumes of sample, develop an assay for the sensitive detection of CXCL10 in plasma-derived EXO, and characterization of plasma-derived EXO through assessment of concentration, size, and content (proteomics).

The study is designed to understand the confidence and competence level of patients with type 1 diabetes mellitus in their ability to make changes to their insulin pump.

The primary goal of this study protocol is to determine the candidate ratio of pramlintide and insulin co-infusion in individuals with type 1 diabetes (T1DM) to enable stable glucose control during the overnight post-absorptive and in the postprandial periods.

The investigators will determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat /high glycemic diet and thus exhibit elevated cellular oxidative damage. The investigators previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and the investigators hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. The investigators will ...

The purpose of this trial is to assess the performance of an Artificial Pancreas (AP) device using the Portable Artificial Pancreas System (pAPS) platform for subjects with type 1 diabetes using an insulin pump and rapid acting insulin. This proposed study is designed to compare closed-loop control with or without optimization of initialization parameters related to basal insulin infusion rates and insulin to carbohydrate (I:C) ratios for meals and snacks. The study consists of an evaluation of the Artificial Pancreas device system during two 24-27.5-hour closed-loop phases in an outpatient/hotel environment. Prior to the closed-loop phases, each subject will undergo ...

The purpose of this study is to gather preliminary data to better understand acute effects of exercise on glucose metabolism. We will address if subjects with Type 1 Diabetes (T1D) are more insulin sensitive during and following a short bout of exercise compared to healthy controls. We will also determine insulin dependent and insulin independent effects on exercise in people with and without type 1 diabetes.

The purpose of this study is to retrospectively and prospectively compare maternal and fetal/newborn clinical outcomes in age-matched pregnant patients with T1D and healthy controls and to assess the relationship between glycemic variability and pregnancy outcomes in the current era.

The objective for thisstudy is to characterize the impact of glycemic excursions on cognition in Type 1 Diabetes (T1D) and determine mediators and moderators of this relationship. This study will allow us to determine how glycemic excursions impact cognition, as well as to identify mediators and moderators of this relationship that could lead to novel interventions.

The purpose of this research is to find out how genetic variations in GLP1R, alters insulin secretion, in the fasting state and when blood sugars levels are elevated. Results from this study may help us identify therapies to prevent or reverse type 2 diabetes mellitus.

The purpose of this study is to compare the effectiveness and safety of an automated insulin delivery (AID) system using a model predictive control (MPC) algorithm versus Sensor-Augmented Pump/Predictive Low Glucose Suspend (SAP/PLGS) therapy with different stress assessments over a 4-week period.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for muscle insulin resistance, although it has been shown that raising FFA with Intralipid can cause muscle insulin resistance within 4 hours. We do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We propose to alter the profile and concentrations of FFA of healthy, non-obese adults using an overnight, intra-duodenal palm oil infusion vs. ...

The objectives of this study are to identify circulating extracellular vesicle (EV)-derived protein and RNA signatures associated with Type 2 Diabetes (T2D), and to identify changes in circulating EV cargo in patients whose T2D resolves after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB).

The purpose of this study is to assess the effectiveness and safety of treatment with various dose levels of TAK-906 in adult participants with gastroparesis compared with placebo during 12 weeks of treatment.

This research study is being done to develop educational materials that will help patients and clinicians talk about diabetes treatment and management options.

The purpose of this study is to evaluate whether or not a 6 month supply (1 meal//day) of healthy food choices readily available in the patient's home and self management training including understanding of how foods impact diabetes, improved food choices and how to prepare those foods, improve glucose control.  In addition, it will evaluate whether or not there will be lasting behavior change modification after the program.

To understand why patients with indigestion with or without diabetes have gastrointestinal symptoms and in particular to understand where the symptoms are related to increased sensitivity to nutrients.

To determine if the EndoBarrier safely and effectively improves glycemic control in obese subjects with type 2 diabetes.

The primary objective of this study is to determine if continuous glucose monitoring (CGM) can reduce hypoglycemia and improve quality of life in older adults with type 1 diabetes (T1D).

The purpose of this study is to compare the rate of progression from prediabetes at 4 months to frank diabetes at 12 months (as defined by increase in HbA1C or fasting BS to diabetic range based on the ADA criteria) after transplantation in kidney transplant recipients on Exenatide SR + SOC vs. standard-of-care alone.

The purpose of this study evaluates a subset of people with isolated Impaired Fasting Glucose with Normal Glucose Tolerance (i.e., IFG/NGT) believed to have normal β-cell function in response to a glucose challenge, suggesting that – at least in this subset of prediabetes – fasting glucose is regulated independently of glucose in the postprandial period. To some extent this is borne out by genetic association studies which have identified loci that affect fasting glucose but not glucose tolerance and vice-versa.

Increased accumulation of fat into the muscles is associated with what is called insulin-resistant state, which is a pre-diabetic state. The purpose of this research is to find out how fat circulating in the blood following fat consumption is taken up by the muscles in healthy people as well as people that are insulin-resistant. The investigators are specifically interested in how a hormone called insulin is involved in this process. Findings from this research will contribute to our understanding of why insulin-resistant people have increased accumulation of fat in their muscles, and ultimately help to design appropriate interventions to prevent ...

The purpose of this study is to learn more about how the body stores dietary fat. Medical research has shown that fat stored in different parts of the body can affect the risk for diabetes, heart disease and other major health conditions.

The purpose of this study is to see why the ability of fat cells to respond to insulin is different depending on body shape and how fat tissue inflammation is involved.

The purpose of this study is to determine the mechanism(s) by which common bariatric surgical procedures alter carbohydrate metabolism. Understanding these mechanisms may ultimately lead to the development of new interventions for the prevention and treatment of type 2 diabetes and obesity.

The purpose of this study is to evaluate the effects of improving glycemic control, and/or reducing glycemic variability on gastric emptying, intestinal barrier function, autonomic nerve functions, and epigenetic changes in subjects with type 1 diabetes mellitus (T1DM) and  type 2 diabetes mellitus (T2DM) who are switched to intensive insulin therapy as part of clinical practice.

This study is designed to compare an intensive lifestyle and activity coaching program ("Sessions") to usual care for diabetic patients who are sedentary. The question to be answered is whether the Sessions program improves clinical or patient centric outcomes. Recruitment is through invitiation only.

The purpose of this study is to determine the metabolic effects of Colesevelam, particularly for the ability to lower blood sugar after a meal in type 2 diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.

The purpose of this study is to test whether markers of cellular aging and the SASP are elevated in subjects with obesity and further increased in patients with obesity and Type 2 Diabetes Mellitus (T2DM) and to relate markers of cellular aging (senescence) and the SASP to skeletal parameters (DXA, HRpQCT, bone turnover markers) in each of these groups.

Integration of Diabetes Prevention Program (DPP) and Diabetes Self Management Program (DSMP) into WellConnect.

The purpose of this study is to investigate if a blood test measuring copeptin within 24 hours following pituitary surgery could predict development of diabetes insipidus (increased urination and thirst with fluid balance problems) as opposed to the clinical methods we currently use.

This is a study to evaluate a new Point of Care test for blood glucose monitoring.

Women with gestational diabetes mellitus (GDM) are likely to have insulin resistance that persists long after pregnancy, resulting in greater risk of developing type 2 diabetes mellitus (T2DM). The study will compare women with and without a previous diagnosis of GDM to determine if women with a history of GDM have abnormal fatty acid metabolism, specifically impaired adipose tissue lipolysis. The study will aim to determine whether women with a history of GDM have impaired pancreatic β-cell function. The study will determine whether women with a history of GDM have tissue specific defects in insulin action, and also identify the effect of a ...

The purpose of this study is to determine the changes in tissue function that occur in the first year postpartum in women with and without gestational diabetes mellitus.

The Early Detection Initiative for pancreatic cancer is a multi-center randomized controlled trial to determine if algorithm-based screening in patients with new onset hyperglycemia and diabetes can result in earlier detection of pancreatic ductal adenocarcinoma.

The purpose of this study is assess the feasibility, effectiveness, and acceptability of Diabetes-REM (Rescue, Engagement, and Management), a comprehensive community paramedic (CP) program to improve diabetes self-management among adults in Southeast Minnesota (SEMN) treated for servere hypoglycemia by the Mayo Clinic Ambulance Services (MCAS).

The purpose of this study is to improve our understanding of why gastrointestinal symptoms occur in diabetes mellitus patients and identify new treatment(s) in the future.  

These symptoms are often distressing and may impair glycemic control. We do not understand how diabetes mellitus affects the GI tracy. In 45 patients undergoing sleeve gastrectomy, we plan to compare the cellular composition of circulating peripheral mononuclear cells, stomach immune cells, and interstitial cells of Cajal in the stomach. 

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM), whereas lower body obesity (LBO) is characterized by near-normal insulin sensitivity. It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking differs between different obesity phenotypes. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. By measuring muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates we will provide the first integrated examination ...

The goal of this study is to evaluate the presence of podocytes (special cells in the kidney that prevent protein loss) in the urine in patients with diabetes or glomerulonephritis (inflammation in the kidneys). Loss of podocyte in the urine may be an earlier sign of kidney injury (before protein loss) and the goal of this study is to evaluate the association between protein in the urine and podocytes in the urine.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for the abnormal response to insulin. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We will measure muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates under both saline control (high overnight FFA) and after an overnight infusion of intravenous ...

Using stem cell derived intestinal epithelial cultures (enteroids) derived from obese (BMI> 30) patients and non-obese and metabolically normal patients (either post-bariatric surgery (BS) or BS-naïve with BMI < 25), dietary glucose absorption was measured. We identified that enteroids from obese patients were characterized by glucose hyper-absorption (~ 5 fold) compared to non-obese patients. Significant upregulation of major intestinal sugar transporters, including SGLT1, GLU2 and GLUT5 was responsible for hyper-absorptive phenotype and their pharmacologic inhibition significantly decreased glucose absorption. Importantly, we observed that enteroids from post-BS non-obese patients exhibited low dietary glucose absorption, indicating that altered glucose absorption ...

The objective of the study is to assess efficacy and safety of a closed loop system (t:slim X2 with Control-IQ Technology) in a large randomized controlled trial.

The purpose of this study is to determine if a blood test called "pancreatic polypeptide" can help distinguish between patients with diabetes mellitus with and without pancreatic cancer.

The purpose of this study is to evaluate the effectiveness and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

The purpose of this study is to create a prospective cohort of subjects with increased probability of being diagnosed with pancreatic cancer and then screen this cohort for pancreatic cancer

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research ...

The purpose of this study is to demonstrate feasibility of dynamic 11C-ER176 PET imaging to identify macrophage-driven immune dysregulation in gastric muscle of patients with DG. Non-invasive quantitative assessment with PET can significantly add to our diagnostic armamentarium for patients with diabetic gastroenteropathy.

What are the effects of transient insulin deprivation on brain structure, blood flow, mitochondrial function, and cognitive function in T1DM patients? What are the effects of transient insulin deprivation on circulating exosomes and metabolites in T1DM patients?

The purpose of this study is to develop a better blood test to diagnose early kidney injury in type 1 diabetes.

The purpose of this study is to evaluate the effects of multiple dose regimens of RM-131 on vomiting episodes, stomach emptying and stomach paralysis symptoms in patients with Type 1 and Type 2 diabetes and gastroparesis.

The purpose of this study is to demonstrate the safety and effectiveness of the Hybrid Closed Loop system (HCL) in adult and pediatric patients with type 1 diabetes in the home setting. A diverse population of patients with type 1 diabetes will be studied. The study population will have a large range for duration of diabetes and glycemic control, as measured by glycosylated hemoglobin (A1C). They will be enrolled in the study regardless of their prior diabetes regimen, including using Multiple Daily Injections (MDI), Continuous Subcutaneous Insulin Infusion (CSII) or Sensor-Augmented Pump therapy (SAP)

The purpose of this study is to identify novel genetic variants that predispose to Type 1 Diabetes.

The purpose of this study is to evaluate the safety of utilizing insulin lispro-aabc in the MiniMed™ 780G System to support product and system labeling.

The objective of the study is to assess the efficacy and safety of home use of a Control-to-Range (CTR) closed-loop (CL) system.

The purpose of this 3-month extension study (DCLP3 Extension) following a primary trial (DCLP3 or NCT03563313) to assess effectiveness and safety of a closed loop system (t:slim X2 with Control-IQ Technology) in a large randomized controlled trial.

The goal of this work is to identify an early stage biomarker for type 1 diabetes. In vitro evidence using rodent models has identified a significant enrichment of the chemokine CXCL10 in β-cell derived sEV upon exposure to diabetogenic pro-inflammatory cytokines. The aims of this project will focus on 1) testing protocols for efficient isolation of plasma-derived sEV from small volumes of sample, 2) development of an assay for the sensitive detection of CXCL10 in plasma-derived sEV, and 3) characterization of plasma-derived sEV through assessment of concentration, size, and content (proteomics). The study plans to include children that ...

The purpose of this study is to assess key characteristics of bone quality, specifically material strength and porosity, in patients who have type 2 diabetes. These patients are at an unexplained increased risk for fractures and there is an urgent need to refine clinical assessment for this risk.

The purpose of this study is to look at how participants' daily life is affected by their heart failure. The study will also look at the change in participants' body weight. This study will compare the effect of semaglutide (a new medicine) compared to "dummy" medicine on body weight and heart failure symptoms. Participants will either get semaglutide or "dummy" medicine, which treatment participants get is decided by chance. Participants will need to take 1 injection once a week. 

This study aims to measure the percentage of time spent in hyperglycemia in patients on insulin therapy and evaluate diabetes related patient reported outcomes in kidney transplant recipients with type 2 diabetes. It also aimes to evaluate immunosuppression related patient reported outcomes in kidney transplant recipients with type 2 diabetes.

The objectives of this study are to evaluate the safety of IW-9179 in patients with diabetic gastroparesis (DGP) and the effect of treatment on the cardinal symptoms of DGP.

The purpose of this study is to understand why patients with indigestion, with or without diabetes, have gastrointestinal symptoms and, in particular, to understand where the symptoms are related to increased sensitivity to nutrients.Subsequently, look at the effects of Ondansetron on these patients' symptoms.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and exploratory effectiveness of nimacimab in patients with diabetic gastroparesis.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of this study is to prospectively assemble a cohort of subjects >50 and ≤85 years of age with New-onset Diabetes (NOD):

• Estimate the probability of pancreatic ductal adenocarcinoma (PDAC) in the NOD Cohort;
• Establish a biobank of clinically annotated biospecimens including a reference set of biospecimens from pre-symptomatic PDAC and control new-onset type 2 diabetes mellitus (DM) subjects;
• Facilitate validation of emerging tests for identifying NOD subjects at high risk for having PDAC using the reference set; and
• Provide a platform for development of an interventional protocol for early detection of sporadic PDAC ...

The purpose of this study is to evaluate whether or not semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will receive semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when ...

The study is being undertaken to understand how a gastric bypass can affect a subject's diabetes even prior to their losing significant amounts of weight. The hypothesis of this study is that increased glucagon-like peptide-1 (GLP-1) secretion explains the amelioration in insulin secretion after Roux-en-Y Gastric Bypass (RYGB) surgery.

The purpose of this study is to assess the effectiveness and safety of D-PLEX administered concomitantly over a period of 90 days (3 months)with the standard of care (SOC) IV prophylactic antibiotic treatment vs. SOC in prevention of post-cardiac surgery sternal infections.

Diabetics are at risk for invasive pneumococcal infections and are more likely to have severe outcomes with infection compared to the general population. The pneumococcal (PPSV23) vaccination is recommended for all people with type 1 diabetes, but whether the vaccine is beneficial for this population has not been established.  The purpose of this study is to determine if children with type 1 diabetes have adequate immune response to the PPSV23 vaccination and to assess factors affecting immune response through a pre and post vaccination blood sample.

The primary purpose of this study is to prospectively assess symptoms of bloating (severity, prevalence) in patients with diabetic gastroparesis.

The purpose of this study is to track the treatment burden experienced by patients living with Type 2 Diabetes Mellitus (T2DM) experience as they work to manage their illness in the context of social distancing measures. 

To promote social distancing during the COVID-19 pandemic, health care institutions around the world have rapidly expanded their use of telemedicine to replace in-office appointments where possible.1 For patients with diabetes, who spend considerable time and energy engaging with various components of the health care system,2,3 this unexpected and abrupt transition to virtual health care may signal significant changes to ...

The purpose of this study is to collect device data to assist in the development of a Personalized Closed Loop (PCL) system.

Assessment of glucose metabolism and liver fat after 12 week dietary intervention in pre diabetes subjects. Subjects will be randomized to either high fat (olive oil supplemented),high carb/high fiber (beans supplemented) and high carb/low fiber diets. Glucose metabolism will be assessed by labeled oral glucose tolerance test and liver fat by magnetic resonance spectroscopy pre randomization and at 8 and 12 week after starting dietary intervention.

To study the effect of an ileocolonic formulation of ox bile extract on insulin sensitivity, postprandial glycemia and incretin levels, gastric emptying, body weight and fasting serum FGF-19 (fibroblast growth factor) levels in overweight or obese type 2 diabetic subjects on therapy with DPP4 (dipeptidyl peptidase-4) inhibitors (e.g. sitagliptin) alone or in combination with metformin.

The objectives of this study are to evaluate the effectiveness and safety of PB in the treatment of patients with hereditary nephrogenic diabetes insipidus, to evaluate the effectiveness and safety of PB in polyuric patients with autosomal dominant polycystic kidney disease treated with tolvaptan, and to evaluate the effectiveness and safety of PB in polyuric patients previously treated with lithium.

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with type 2 diabetes or prediabetes and chronic heart failure with preserved systolic function.

The purpose of this study is to look at the relationship of patient-centered education, the Electronic Medical Record (patient portal) and the use of digital photography to improve the practice of routine foot care and reduce the number of foot ulcers/wounds in patients with diabetes.

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels. This is a frequent problem that is most commonly due to type 2 diabetes. However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as chronic pancreatitis or pancreatic cancer, as the cause of their diabetes. Currently, there is no test to identify the small number of patients who have diabetes caused by a primary problem with their pancreas.

The goal of this study is to develop a test to distinguish these ...

A research study to enhance clinical discussion between patients and pharmacists using a shared decision making tool for type 2 diabetes or usual care.

While the potential clinical uses of pulsed electromagnetic field therapy (PEMF) are extensive, we are focusing on the potential benefits of PEMF on vascular health. We are targeting, the pre diabetic - metabolic syndrome population, a group with high prevalence in the American population. This population tends to be overweight, low fitness, high blood pressure, high triglycerides and borderline high blood glucose.

The purpose of this study is to compare incidence rates of complete hard-to-heal diabetic foot ulcer healing in Medicare beneficiaries following application of the 3C Patch® plus usual care (i.e., care consistent with the International Working Group on the Diabetic Foot guidelines), tested against a historical control group of similar patients that received usual care during a randomized controlled trial.

The purpose of this study is to measure and characterize specific immune cell abnormalities found in patients who have type 1 diabetes and may or may not be on the waiting list for either a pancreas alone or a pancreas and kidney transplant.

The MADIT S-ICD trial is designed to evaluate if subjects with a prior myocardial infarction, diabetes mellitus and a relatively preserved ejection fraction of 36-50% will have a survival benefit from receiving a subcutaneous implantable cardioverter defibrillator (S-ICD) when compared to those receiving conventional medical therapy.

The purpose of this study is to assess the effects of a nighttime rise in cortisol on the body's glucose production in type 2 diabetes.

As the global epidemic of obesity and diabetes mellitus spreads, an exponential rise in incident chronic kidney disease (CKD) complicated by end stage renal disease (ESRD) is predicted, leaving healthcare systems overwhelmed worldwide. Hence, there is urgent need for novel therapies to slow the progression of DKD and optimize the health of this patient population. The purpose of this study is to examine the effect of a supplement on mesenchymal stem cells, physical body function (or frailty), kidney function, and total clearance of senescent cells in individuals with CKD. At present, we are enrolling participants with CKD, with a subset ...

The goal of this study is to evaluate a new format for delivery of a culturally tailored digital storytelling intervention by incorporating a facilitated group discussion following the videos, for management of type II diabetes in Latino communities.

The purpose of this study is to evaluate the safety and efficacy of oral Pyridorin 300 mg BID in reducing the rate of progression of nephropathy due to type 2 diabetes mellitus.

The purpose of this study is to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease (fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes).

To compare the effect of senolytic drugs on cellular senescence, physical ability or frailty, and adipose tissue-derived MSC functionality in patients with chronic kidney disease. Primary Objectives: To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on clearing senescent adipose-derived MSC in patients with CKD. To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on improving adipose-derived MSC functionality in patients with CKD. Secondary Objective: To assess the short-term effect of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on ...

This protocol is being conducted to determine the mechanisms responsible for insulin resistance, obesity and type 2 diabetes.

The purpose of this study is to evaluate the ability of appropriately-trained family physicians to screen for and identify Diabetic Retinopathy using retinal camera and, secondarily, to describe patients’ perception of the convenience and cost-effectiveness of retinal imaging.

The purpose of this study is to develop a blood test to distinguish various causes of diabetes by evaluating patients who have developed diabetes within the last 3 years, but we will also enroll a small number of patients with long-term diabetes and normal blood sugars for comparison. 

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels.  This is a frequent problem that is most commonly due to type 2 diabetes.  However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as ...

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients who have type 2 diabetes and chronic heart failure with reduced systolic function.

Hypothesis: We hypothesize that patients from the Family Medicine Department at Mayo Clinic Florida who participate in RPM will have significantly reduced emergency room visits, hospitalizations, and hospital contacts.  

Aims, purpose, or objectives: In this study, we will compare the RPM group to a control group that does not receive RPM. The primary objective is to determine if there are significant group differences in emergency room visits, hospitalizations, outpatient primary care visits, outpatient specialty care visits, and hospital contacts (inbound patient portal messages and phone calls). The secondary objective is to determine if there are ...

The purpose of this research is to determine if CGM (continuous glucose monitors) used in the hospital in patients with COVID-19 and diabetes treated with insulin will be as accurate as POC (point of care) glucose monitors. Also if found to be accurate, CGM reading data will be used together with POC glucometers to dose insulin therapy.

The purpose of this study is to evaluate the effect of fenofibrate compared with placebo for prevention of diabetic retinopathy (DR) worsening or center-involved diabetic macular edema (CI-DME) with vision loss through 4 years of follow-up in participants with mild to moderately severe non-proliferative DR (NPDR) and no CI-DME at baseline.

The purpose of this study is to use multiple devices to measure blood sugar changes and the reasons for these changes in healthy and diabetic children.

The purpose of this study is gain the adolescent perspective on living with type 1 diabetes.

The purpose of this study is to assess painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation.

The purpose of this study is to see if there is a connection between bad experiences in the patient's childhood, either by the patient or the parent, and poor blood sugar control, obesity, poor blood lipid levels, and depression in patients with type 1 diabetes.

The purpose of this study is to examine the evolution of diabetic kindey injury over an extended period in a group of subjects who previously completed a clinical trial which assessed the ability of losartan to protect the kidney from injury in early diabetic kidney disease. We will also explore the relationship between diabetic kidney disease and other diabetes complications, including neuropathy and retinopathy.

The objectives of this study are to determine if the 1-year graft success rate following DMEK performed with corneas from donors without diabetes is superior to the graft success rate with cornea donors with diabetes, to determine if the 1-year central endothelial cell loss (ECL) following DMEK performed with corneas from donors without diabetes is superior to the central ECL when corneas from donors with diabetes are used, nd to explore the relationship of severity of diabetes in the donor, as measured by eye bank-determined diabetes risk categorization scores, post-mortem hemoglobin A1c (HbA1c), and skin advanced glycation endproducts (AGE) and ...

The purpose of this study is to understand the day-to-day variability in stomach emptying and gastrointestinal (GI) transit in patients with digestive symptoms. This information will be useful for interpreting the results of stomach emptying studies in future.

The purpose of this study is to evaluate the effietiveness of remdesivir (RDV) in reducing the rate of of all-cause medically attended visits (MAVs; medical visits attended in person by the participant and a health care professional) or death in non-hospitalized participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting.

The purpose of this study is to determine whether short-term treatment with Fisetin reduces the rate of death and long term complications related to COVID-19.

This study (SE2030) will establish a platform of data to build the perfect stress echo test, suitable for all patients, anywhere, anytime, also quantitative and operator independent.

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• Published: 08 May 2024

Advances and challenges of the cell-based therapies among diabetic patients

• Ramin Raoufinia 1 , 2 ,
• Hamid Reza Rahimi 2 ,
• Ehsan Saburi 2 &
• Meysam Moghbeli   ORCID: orcid.org/0000-0001-9680-0309 2  

Journal of Translational Medicine volume  22 , Article number:  435 ( 2024 ) Cite this article

361 Accesses

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Diabetes mellitus is a significant global public health challenge, with a rising prevalence and associated morbidity and mortality. Cell therapy has evolved over time and holds great potential in diabetes treatment. In the present review, we discussed the recent progresses in cell-based therapies for diabetes that provides an overview of islet and stem cell transplantation technologies used in clinical settings, highlighting their strengths and limitations. We also discussed immunomodulatory strategies employed in cell therapies. Therefore, this review highlights key progresses that pave the way to design transformative treatments to improve the life quality among diabetic patients.

Diabetes mellitus poses a formidable global public health challenge due to its rapid growing prevalence and associated morbidity, disability, and mortality [ 1 ]. According to the International Diabetes Federation, over 537 million adults aged 20–79 had diabetes worldwide in 2021 that is expected to rise to around 783 million cases by 2045 [ 2 ]. Obesity, unhealthy diets, physical inactivity as well as genetic and epigenetic predispositions are important risk factors of diabetes [ 3 , 4 , 5 ]. Diabetes is typically classified into type 1 diabetes mellitus (T1DM), gestational diabetes mellitus (GDM), and type 2 diabetes mellitus (T2DM) [ 2 ]. T1DM primarily arises from autoimmune-related damage of insulin-secreting beta cells, resulting in severe hyperglycemia and ketoacidosis [ 6 ]. In contrast, T2DM generally has a more gradual onset characterized by insulin resistance along with diminished compensatory insulin secretion from pancreatic beta cell dysfunction [ 7 ]. Diabetes is associated with macrovascular complications such as heart disease and stroke, as well as microvascular issues in eyes, kidneys, and nervous system [ 8 ]. Cancer is also a leading cause of diabetes-related death, and dementia-associated mortality has risen in recent decades [ 9 , 10 , 11 , 12 ]. Cell therapy involves transferring autologous or allogenic cellular material into patients [ 13 ]. The global market size of cell therapy is estimated to grow from $9.5 billion in 2021 to $23 billion by 2028 [ 14 ]. It combines stem and non-stem cell therapies consisting of unicellular or multicellular preparations. Cell therapies typically use autologous or allogenic cells via injection and infusion [ 15 ]. In the present review, we discussed the recent advances in cell-based therapy of diabetes, from foundational islet transplantation to regenerative strategies to highlight key developments that improve the effective treatments for diabetic patients.

Cell replacement therapy for diabetes

Pancreatic transplantation was firstly used in 1966 to treat type 1 diabetes using whole organ transplants. During the 1970s–80s, segmental pancreatic grafts were combined with techniques to divert digestive secretions away from transplanted cells. Three main techniques emerged; simultaneous pancreas-kidney transplants, pancreas transplants following kidney transplants, and pancreatic transplants. International collaboration on tracking outcomes began in 1980 with the formation of several pancreatic transplant registries and associations. However, whole organ transplantation was faced with several challenges including organ rejection, vascular complications, limited organ availability, and the effects of lifelong immunosuppression [ 16 , 17 ]. Islet cell transplantation was explored as an alternative, however isolating and transplanting pancreatic islets proved difficult due to donor availability, rejection, and immunosuppression side effects. Recent research has focused on stem cell sources that could reconstitute immune tolerance and preserve beta cell function such as mesenchymal stem cells, bone marrow cells, and embryonic stem cells [ 18 ]. A novel stem cell therapy called VX-880 was developed using proprietary technology to grow insulin-producing beta cells from allogeneic stem cells. Clinical trials began in 2021 after FDA approval to deliver the cells intrahepatically under immune suppression. A second approach called VX-264 encapsulates the same cells, avoiding immunosuppression but requiring surgical implantation [ 17 ]. In 2023, FDA approved the first allogeneic pancreatic islet cell therapy called Lantidra for adults with type 1 diabetes experiencing severe hypoglycemia. Approval was based on two studies where 21–30% of participants no longer required insulin one year post-treatment, with benefits lasting over five years in some cases. However, this treatment have mild and serious adverse events that are associated with treatment dose and the methods of islet cell infusion [ 19 , 20 ].

Emerging strategies for cell delivery via microencapsulation and biological devices in clinical trials

Alginate capsules as cell delivery systems.

A seminal investigation conducted in 1994 demonstrated the successful transplantation of alginate-encapsulated islets into the peritoneum of kidney transplant patients who were receiving immunosuppression therapy. Remarkably, these patients achieved insulin independence for up to nine months [ 21 ]. However, subsequent trials conducted without immunosuppression yielded inconsistent outcomes. In a study conducted in 2006, islets were encapsulated in triple-layer alginate capsules and implanted intraperitoneally in type 1 diabetes (T1D) patients. There was a positive correlation between the encapsulation and insulin production that reduced exogenous insulin requirements during one year. Despite this progress, the entry of cytokines remained a potential concern [ 22 ]. Another study employed the single-layer barium-alginate capsules that sustained insulin production for up to 2.5 years [ 23 ]. It has been reported that the microneedle, comprising a calcium alginate frame with polydopamine-coated poly-lactic-co-glycolic acid microspheres encapsulating insulin, enables light-triggered insulin release. Microneedle provided a suitable insulin dose to maintain blood glucose levels in line with daily fluctuations. These results established the efficacy and safety of the developed microneedle for diabetes treatment [ 24 ]. Another therapeutic approach explored the encapsulation of pancreatic islets with mesenchymal stem cells (MSCs) and decellularized pancreatic extracellular matrix (ECM). ECM derived from the pancreas supported islet cell growth and maintenance to enhance insulin expression [ 25 ]. Sodium alginate and hyaluronic acid were incorporated due to their roles in collagen production, wound healing, and physical crosslinking. The 3D porous membranes allowed optimal water and oxygen transfer while diverting excess exudate from diabetic wounds. Hydrogel accelerated re-epithelization, while decreased inflammation, indicating potential as the diabetic wound dressings [ 26 ]. Additionally, the incorporation of specific ECM components, such as collagen IV and RGD, into alginate-based microcapsules significantly improved the survival, insulin secretion, and longevity of microencapsulated islets [ 27 ].

Encaptra® device from ViaCyte

In contrast to microencapsulation techniques, ViaCyte developed a semipermeable pouch method named Encaptra, which contains pancreatic precursor cells derived from the embryonic stem cells [ 28 ]. In the initial trial conducted in 2014, the “VC-01” device was implanted in T1D individuals without the use of immunosuppression [ 29 ]. The trial confirmed the safety of the device; however, the occurrence of hypoxia induced cellular necrosis [ 30 ]. The device was modified as “VC-02” with larger pores, and two trials (NCT03162926, NCT03163511) demonstrated promising outcomes, including increased fasting C-peptide levels and a 20% reduction in insulin requirements during one year in the majority of participants [ 31 ]. In order to eliminate the necessity for immunosuppressants, ViaCyte collaborated with Gore to develop an expanded polytetrafluoroethylene (ePTFE) device with both immuno-isolating and pro-angiogenic properties [ 32 ]. This device (NCT04678557) aimed to prevent immune cell attachment and T-cell activation [ 33 ]. Additionally, ViaCyte is exploring the integration of CRISPR technology to modify stem cells, specifically by eliminating β2-microglobulin expression and PD-L1 up regulation. It is hypothesized that these genetic modifications will further hinder immune cell attachment and T-cell activation [ 30 , 34 ].

Semipermeable device from Semma therapeutics

Semma Therapeutics, which has been acquired by Vertex, pioneered the utilization of differentiated stem cell-derived islet cell clusters in clinical trials. Semma houses these cells between two semipermeable polyvinylidene fluoride membranes and is designed for subcutaneous implantation (NCT04786262) [ 31 , 35 ]. Vertex reported a significant breakthrough by infusing differentiated beta cells via the portal vein in a participant who was receiving immunosuppressants. This approach led to substantial C-peptide production and improved glycemic control during 90 days [ 36 ].

βAir device from Beta O2

Beta O2’s innovative βAir device utilizes an alginate-PTFE membrane complex to encapsulate islets, providing partial immunoisolation while ensuring a continuous supply of oxygen, which is crucial for optimal islet function [ 37 , 38 ]. The βAir device that was seeded with human islets was subcutaneously implanted in T1D individuals (NCT02064309). Although, low insulin levels were produced for up to eight weeks, there was not any reduction in the required exogenous insulin [ 37 ]. While, increasing the number of islets could potentially enhance their function, it is important to note that the continuous reliance on oxygen poses a risk of infection, despite efforts to optimize the survival of encapsulated islets [ 39 , 40 ].

Cell pouch™ device from Sernova

Sernova has developed the Cell Pouch device, which offers pre-vascularized polypropylene chambers for islet transplantation without the need for immunoprotection. The device consists of multiple cylindrical chambers that are prefilled with PTFE plugs, which are then removed after implantation to create the empty space [ 41 ]. In a 2012 trial (NCT01652911), islets were placed in the vascularized pouches of three recipients who were also receiving immunosuppression that resulted in a transient increase in C-peptide levels [ 41 ]. In a 2018 trial (NCT03513939), immunosuppression was administered after implantation and islet introduction. This trial reported sustained C-peptide production for up to nine months in two recipients, along with improved glycemic control [ 42 ]. Regarding the limitations of immunosuppression, Sernova is exploring the possibility of encapsulating islets in hydrogel as an alternative approach [ 43 ].

Shielded living therapeutics™ from Sigilon Therapeutics

Sigilon has developed the Shielded Living Therapeutics sphere, which consists of cell clusters enclosed within an alginate-TMTD coating [ 44 ]. Preclinical studies demonstrated that murine islet transplants encapsulated within these spheres maintained normoglycemia for a period of six months [ 45 ]. In a 2020 trial conducted for hemophilia (NCT04541628), the spheres were evaluated for their ability to express Factor VIII [ 46 ]. However, the trial was paused due to the development of antibodies in the third recipient receiving the highest cell doses. While, preclinical studies have shown promising efficacy, there are safety concerns regarding the TMTD coating that need to be addressed before these spheres can be used for human islet transplantation as a treatment for diabetes [ 31 ]. Emerging technologies have been investigated in clinical trials for delivering insulin-producing islets or stem cell-derived beta cells via microencapsulation or use of implantable biological devices (Table 1). Optimizing encapsulation and developing alternative implantable devices moves the field toward delivering safe and effective islet replacement without chronic immunosuppression dependency that represented an important new frontier for the cell-based treatment of diabetes. However, continued refining will be required to fully realize this promising vision and using these preclinical concepts in clinic.

Immunoengineering strategies: biomaterials for modulating immune responses

Islet encapsulation aims to prevent immune responses toward transplant antigens. However, foreign body response (FBR) against biomaterials induces inflammation around encapsulated islets that obstructs oxygen/nutrient access and causes graft failure [ 31 ]. Extensive research revealed biomaterial properties profoundly influence FBR severity, with high purity/biocompatibility moderating inflammation [ 47 ]. Deeper understanding of biomaterial immunobiology enabled developing immune-modulating constructs to steer host interactions. By altering topology/chemistry to hinder nonspecific binding and cell adhesion, these “immune-evasive biomaterials” intended to attenuate xenograft rejection at inception [ 44 ]. Both innate and adaptive immune responses have crucial roles in the context of pancreatic islet transplantation. These responses encompass the activation of tissue macrophages and neutrophils following injury, leading to the release of inflammatory cytokines that subsequently activate antigen-presenting cells (APCs), CD8 + T cells, CD4 + T cells, and cytotoxic T lymphocytes (Fig.  1 ). Zwitterionic polymers conferred anti-fouling attributes but crosslinking limitations constrained their application [ 48 ]. Novel mild zwitterionization introduced alginate modifications that prolonged prevention of fibrotic overgrowth by mitigating initial responses [ 49 , 50 , 51 ]. The prevention of graft rejection following islet cell transplantation necessitates the systemic administration of immunosuppressive agents. While, these agents effectively suppress immune responses, their continuous use exposes patients to an increased risk of infection and cancer. To mitigate these concerns, an alternative approach involving the localized delivery of immunosuppressants at the transplantation site has emerged. This localized delivery system offers several advantages, including targeted drug delivery, reduced systemic exposure, and potentially reduces the immunosuppressants doses [ 52 ]. Polymeric carriers dispersed cyclosporine A continuously at the graft site to dynamically tamp down proinflammatory cascades and T-cell activation [ 53 , 54 ]. TGF-β/IL-10 co-delivery at the microencapsulation interface hindered innate antigen presentation, obstructing adaptive response priming [ 55 , 56 ]. Regulatory T-cells emerged as the potent immunomodulators when coated on islets to improve insulin production in vitro [ 57 ]. Similarly, recombinant Jagged-1 surface patterning increased regulatory lymphocytes in vitro while enhancing glycemic oversight in vivo [ 58 ]. Targeting proinflammatory effector T-cells or presenting their Fas ligand death receptor improved long-term viability when combined with rapamycin prophylaxis [ 52 , 59 ]. Immobilizing thrombomodulin or urokinase mitigated local inflammation, with the latter conferring lifelong xenotransplant survival [ 60 ]. Peptides recognizing IL-1 receptors provided robust protection from destabilizing proinflammatory cytokines [ 61 ]. Leukemia inhibiting factor improved islet performance over polyethylene glycol encapsulation alone by inducing regulatory T-cell lineages [ 62 ]. Silk scaffolds facilitated IL-4/dexamethasone emancipation that meaningfully decreased immune reactions to grafts [ 63 ]. Therefore, the localized delivery of immunosuppressants at the transplantation site represents a promising strategy for islet cell transplantation. Compared to systemic administration, local delivery can achieve targeted immune modulation only at the graft location while reducing drug exposure throughout the body. This localized approach aims to sufficiently suppress the immune response to prevent rejection, while limiting negative side effects that may occur from systemic immunosuppression. A variety of biomaterials and surface modification strategies have been developed and investigated for the local delivery of immunosuppressive agents and immunomodulatory cytokines [ 64 , 65 , 66 ]. Understanding how biomaterial properties influence the immune response is critical to design biomaterials that can modulate inflammation and improve islet graft survival through localized immunomodulation.

Cell-based therapy through the integration of additive manufacturing techniques

Additive manufacturing utilizes computer modeling to fabricate complex 3D structures on-site with minimal post-processing. Common methods for the biomedical application are fused filament fabrication (FFF), stereolithography (SLA), and bioprinting [ 67 ]. FFF is a layer-by-layer technique that extrudes heated thermoplastics [ 68 ]. Commonly used feedstocks include acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA). Other thermoplastics that have been utilized with FDM include thermoplastic polyurethane (TPU), polycarbonate (PC), polystyrene (PS), polyetherimide (PEI), polycaprolactone (PCL), polyaryletherketone (PAEK), and polyetheretherketone (PEEK), with the latter demonstrating high strength and heat tolerance. A major advantage of FDM is its ability to fabricate multi-material objects through continuous printing and alteration of the build material. In addition to typical polymers like PC and polystyrene (PS), FDM can print composites reinforced with glass, metals, ceramics, and bioresorbable polymers via integration of the constituent powders with a binding matrix. This enables enhanced control over the experimental component fabrication. While, ceramic and metal filaments traditionally contain the corresponding powder mixed with a binder, FDM provides versatility in the functional prototype construction from a wide range of thermoplastic feedstocks using precise and additive layer manufacture [ 68 , 69 , 70 , 71 , 72 ]. It provides geometric reproducibility and reduced variability compared to traditional techniques. FFF prints served as scaffolds for the transplanted cells [ 67 ]. However, minimum feature size is limited to ? ∼  250 μm by nozzle diameter [ 68 ]. SLA employs light-curable liquid resins and achieves higher 50–150 μm resolution than FFF but with restricted material choices. Bone grafts and surgical guides are common applications [ 67 ]. Incorporating biomaterials like hydroxyapatite has expanded utility, though processing is required to mitigate cytotoxicity. Additive manufacturing can address limitations in oxygen transport, cell/material placement control and vasculature formation, and clinically translatable insulin-secreting implants [ 67 ]. Therefore, additive manufacturing technologies have the potential to enhance various aspects of the cell-based transplant design, from improving nutrient transport through optimized implant geometry to achieving precision integration of therapeutic agents (Table 2).

Enhancing nutrient transport through optimization of implant geometry

Tissue engineering for the islet transplantation requires maximizing nutrient transport [ 73 , 74 ]. Traditional scaffold fabrication introduces macroporosity but lacks precision that results in inflammation [ 67 ]. Cell encapsulation provides immunoprotection by limiting interactions between transplanted cells and the host immune system. However, this protective barrier also poses challenges for the efficient transport of essential nutrients, including oxygen, to the encapsulated cells. Modifying the geometries of encapsulation devices using conventional methods to enhance oxygen delivery has proven to be inconsistently challenging [ 67 ], so that novel approaches are required to address these challenges. Additive manufacturing allows customizing biomaterial scaffolds with defined geometries and micropore sizes to improve transport [ 75 , 76 , 77 , 78 , 79 ]. The 3D printed PLA scaffolds with islets have successful vascularization and cellular survival after subcutaneous transplantation [ 80 , 81 ]. Interlocking toroidal hydrogel-elastomer constructs also increased surface area and cell viability [ 82 , 83 , 84 ].

Enhancing vascularization and engraftment

Rich host vascularization of transplant devices is essential to support long-term islet survival through efficient nutrient delivery and insulin kinetics. Early platforms modified bulk material properties to promote vessel infiltration and anastomoses [ 85 , 86 , 87 , 88 , 89 ]. Additive manufacturing can further optimize microscale geometry to both accelerate host vessel connections and control intra-device vasculature homogeneity beyond traditional fabrication. Initial work reproduced macroscale vessels but scales were diverged from cell-based therapies [ 73 , 90 , 91 , 92 ]. Leveraging Additive manufacturing designed structures guided vessel formation in vitro and in vivo [ 80 , 89 , 93 ]. Shifting to bioprinting complex branching conduits in supportive hydrogels facilitated clinical translation for diverse cell therapies [ 94 , 95 , 96 , 97 , 98 ]. Researchers focused on developing a 3D scaffold platform to improve the transplantation outcomes of islet cells in T1D. The scaffold featured a heparinized surface and immobilized vascular endothelial growth factor (VEGF) to enhance vascularization. Scaffold effectively promoted angiogenesis and facilitated the growth of new blood vessels. Additionally, encapsulated islets within the scaffold had functional responses to glucose stimuli. These findings suggested that the developed scaffold platform holds potential for successful extra-hepatic islet transplantation, offering new possibilities for T1D treatment [ 99 ]. Research on vascularization of islets via additive manufacturing techniques has primarily focused on the fundamental discoveries. In one study, engineered pseudo islets (EPIs) were created by combining the mouse insulin-secreting beta cells with rat heart microvascular endothelial cells. EPIs demonstrated extensive outgrowth of capillaries into the surrounding matrix. Although, EPIs containing both cell types that underwent capillarization maintained viability and function over time in culture, non-vascularized EPIs lacking endothelial cells could not sustain viability or functionality long-term. This supported the potential for inducing angiogenesis within bioengineered islet constructs. Future work may combine patient-specific stem cell-derived human beta cells with endothelial cells using this approach to promote long-term graft survival for treating type 1 diabetes [ 98 ]. While, large-scale 3D printed vascularized structures are currently limited for the islet transplantation, advancements in leveraging additive manufacturing for the optimization vascularization conditions through the pore sizes and material choices, may facilitate translation to β-cell therapy in type 1 diabetes.

Precision placement of cells and matrix for enhanced control

Beyond distributing biomaterials, additive manufacturing enables micro-level cell and protein control. For islet transplantation, optimal cellular distribution and supportive extracellular matrix niche reduce rapid dysfunction and apoptosis [ 100 , 101 , 102 ]. Traditional techniques heterogeneously load cells after fabrication or struggle with incomplete encapsulation [ 103 , 104 ]. Bioprinting allows in situ encapsulation and printing of multiple cell types and matrix components while dictating 3D placement and dimensions [ 105 , 106 ]. Islet transplant research prints hydrogel-encapsulated clusters surrounded by supportive cells and doped with immune modulators to improve the transplant environment [ 107 ]. Progress in bioprinting offers consistency and defines physical/chemical graft properties beyond traditional fabrication.

Achieving controlled integration of therapeutic agents for enhanced efficacy

In addition to the cell and matrix placement, additive manufacturing enables precision therapeutic integration. Incorporating therapeutics aims to recapitulate the in vivo environment through angiogenesis, islet health promotion, and immunomodulation [ 67 , 108 ]. Growth factors promote vessel formation and insulin secretion while decrease apoptosis [ 108 , 109 , 110 , 111 ]. Local immunomodulators regulate the immune system in a specific site of the body. They decrease inflammation and promote the successful integration of transplanted cells or tissues by minimizing the need for widespread immune suppression in whole body [ 67 ]. Traditional homogeneous delivery methods restrict the ability to customize the spatial distribution of substances and pose a risk of harmful effects on transplants or hosts [ 112 ]. The use of discreet gradients in bioprinting can offer precise physiological signals. By combining traditional drug release methods with AM, it becomes possible to create tissues that exhibit distinct therapeutic localization. Bioprinted composites have the ability to release factors with gradients throughout the entire construct that enables a more comprehensive and targeted approach in tissue engineering [ 112 , 113 , 114 ].

Cell based gene therapy

Gene therapy holds great promise for diabetes management, offering innovative approaches to deliver and manipulate the insulin gene in various tissues. Viral methods, such as lentivirus, adenovirus, and adeno-associated virus (AAV), along with non-viral techniques like liposomes and naked DNA, have been utilized to deliver the insulin gene to target tissues [ 115 ]. This section aims to provide an overview of important studies in the field of gene therapy for diabetes management, emphasizing advancements in insulin gene delivery and manipulation (Table 3).

Enteroendocrine K-cells and pancreatic β-cells

Enteroendocrine K-cells in the intestines and pancreatic β-cells share similarities in their production of glucose-dependent insulinotropic polypeptide (GIP) and their regulatory mechanisms. Understanding these similarities offers insights into T2D management and improving glucose homeostasis. However, attempts to reverse diabetes effectively through K-cell transplantation have been unsuccessful. Nevertheless, research on gene editing techniques has shown promising results in management of the diabetes mellitus [ 116 , 117 ]. AAV vectors have been employed to co-express insulin and glucokinase genes in skeletal muscles, demonstrating long-term effectiveness in achieving normo-glycemia without exogenous insulin [ 118 , 119 ].

Gene editing techniques

Gene editing techniques using AAV vectors effectively improved normo-glycemia in animal models. Co-expression of insulin and glucokinase in transgenic mice increased glucose absorption and regulated insulin production. Duodenal homeobox 1 (PDX1) gene transfer via AAV2 in a humanized liver mouse model also led to insulin secretion and glycemic control [ 120 ]. Adenovirus-mediated transfection of hepatic cells with neurogenin 3 (NGN3) resulted in insulin production and trans-differentiation of oval cell populations [ 121 , 122 ]. Targeting specific promoters in liver cells such as phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), albumin, and insulin-like growth factor binding protein-1 (IGFBP-1) enhanced hepatic insulin gene therapy [ 123 , 124 ]. AAV-mediated overexpression of SIRT1 reduced inflammation, hypoxia, apoptosis and improved neural function in the retina of diabetic db/db mice [ 125 ]. Another study developed a plasmid expressing a single-strand insulin analogue for intramuscular injection using a specialized gene delivery technique. A single administration provided sustained insulin expression for 1.5 months and effectively regulated blood glucose levels without immune responses or tissue damage in diabetic mice.

Non-viral gene delivery methods

Non-viral approaches have also key roles in achieving glycemic control. The combination of insulin fragments with DNA plasmid, administered via intravenous injection improved normo-glycemia for extended periods. DNA transposon facilitated gene integration into the host chromosome that addressed the short-term liver expression. Additionally, the co-injection of DNA plasmid containing insulin with furin significantly enhanced insulin production within muscles [ 126 ]. Non-viral plasmids were engineered to carry proinsulin and pancreatic regenerating genes to ameliorate streptozotocin-induced T1DM [ 127 ]. The pVAX plasmid vectors prolonged therapeutic effects in achieving normo-glycemia without the need for further treatment [ 127 ]. Bioreducible cationic polymers, such as poly-(cystamine bisacrylamide-diamino hexane) (p(CBA-DAH)), have been employed to deliver RAE-1 to pancreatic islets, resulting in improved insulin levels [ 128 ]. Furthermore, ex vivo gene transfer and autologous grafts have shown promising outcomes in animal models. The introduction of the human insulin gene into pancreatic or liver cells followed by autologous grafts improved insulin secretion, glycemic control, and alleviated the diabetic complications in pigs. However, gene silencing eventually occurred, necessitating a deeper understanding of the underlying mechanisms [ 128 , 129 ].

Stem cell based therapy in diabetes

Efforts are ongoing to develop standardized processes for donor and recipient selection/allocation to increase pancreas utilization [ 130 , 131 , 132 , 133 ]. Techniques for isolating pancreatic islets are being optimized to become more standardized and consistent. Noninvasive imaging technologies allow the monitoring of the transplanted islets without surgery [ 134 , 135 ]. Biomarkers could also evaluate how immunomodulation strategies are working [ 136 , 137 , 138 ]. Researchers are also exploring alternative transplant sites in the body beyond just the liver, to see if the other locations may better support islet graft survival and function. Together, these areas of refinement aim to improve the safety and reliability of islet transplantation procedures as a potential therapy for diabetes [ 139 ]. Bioengineering approaches are being developed to optimize the islet transplantation microenvironment using biomaterials which enhance islet engraftment and function through engineered extracellular niches [ 140 , 141 ]. For example, encapsulation techniques aim to protect pancreatic islets against immune reponse by enclosing them within semipermeable hydrogel polymer capsules [ 142 , 143 ]. This localized immunoisolation strategy utilizes biomaterials like alginate to create a physical barrier preventing immune cell contact while still allowing nutrient and oxygen diffusion. Researchers concurrently seek alternative unlimited cellular sources to address limited islet availability. Mesenchymal stem cells possess immunomodulatory properties and their adjuvant delivery, either early in disease onset or simultaneously with islet transplantation, has shown promising signs of improving outcomes in preclinical investigations. By dampening inflammatory responses and favoring regenerative processes, stem cells may help to establish a more tolerogenic transplant environment. These bioengineering and cell therapy approaches offer potential pathways towards eliminating the exogenous insulin requirement [ 144 , 145 ]. A variety of stem cell types have therapeutic potential for diabetes (Fig.  2 ). Pluripotent stem cells possess immense promise for overcoming the limitations of islet transplantation. Human embryonic stem cells and induced pluripotent stem cells are especially attractive candidates due to their unique ability to both self-renew indefinitely and differentiate into any cell type. This makes them an ideal source of replacement pancreatic beta cells. Significant research effort across academic and industrial laboratories has led to advancement in differentiation protocols that can convert pluripotent stem cells into functional beta-like cells in vitro. However, establishing consistent, well-characterized cellular production methods that comply with stringent safety and efficacy standards remains a priority for clinical translation. Ongoing work aims to generate therapeutic stem cell-derived beta cell replacements exhibiting stable, glucose-responsive insulin secretion comparable to primary islets. Although, technological and regulatory hurdles still must be cleared, pluripotent stem cells have the greatest potential to finally solve the problem of limited cell availability and provide an unlimited source of transplantable tissue suitable for widespread treatment of diabetes [ 145 , 146 , 147 , 148 ]. There are currently six registered clinical trials evaluating the use of human pluripotent stem cells for the T1D treatment. All trials except one use PEC-01 cells, which consist of a mixture of pancreatic endoderm and polyhormonal cell population derived from CyT49 stem cells that are fully committed to endocrine differentiation upon implantation [ 149 ]. The initial trial implanted PEC-01 cells within an encapsulation device, hypothesizing no need for immunosuppression. While, well-tolerated with minor adverse effects, insufficient engraftment occurred due to foreign body responses that eliminated the cells [ 150 ]. The trial transitioned in 2017 to use an open encapsulation device that required immunosuppression. Subcutaneous engraftment, differentiation of cells into islet-like clusters, and glucose-responsive insulin production provided the first evidence that pancreatic progenitor cells can survive, mature, and function as the endocrine cells in humans. Potential benefits on stimulated C-peptide levels and glycemic control were observed in one patient [ 151 , 152 ]. Two reports in late 2021 described results in 17 patients receiving PEC-01 cells in an open device. Engraftment and insulin expression occurred in the majority, glucose-responsive secretion in over one-third, and various glycemic improvements were observed at six months. Explanted tissues contained heterogeneous pancreatic compositions including mature beta cells, with no teratoma formation and mild adverse effects related to surgery/immunosuppression. VX-880 uses fully differentiated insulin-producing stem cell-derived islet cells in phase 1/2 trial evaluating portal infusion and different doses requiring immunosuppression. Preliminary results suggest early engraftment and insulin secretion. The manin challenge was controlling immune rejection without systemic immunosuppression [ 149 ]. Several strategies are being explored to address the challenges of immune rejection in stem cell therapies for diabetes. They include generating stem cell lines that are universally compatible through HLA silencing, developing milder regimens of immunosuppression, and refining encapsulation and containment approaches to protect transplanted cells toward immune response. Establishing standardized stem cell banks is also an area of investigation [ 153 , 154 ]. Xenotransplantation using gene-edited porcine islets remains an exciting avenue of research given advances to improve engraftment and reduce immunogenicity in preclinical studies [ 155 ]. Novel approaches continue to emerge as well, such as decellularization techniques, 3D bioprinting of tissue constructs, and creating interspecies chimeras. Rapid evolution of cell-based therapies across both academic and commercial sectors is promising to restore normoglycemic control in diabetic cases. Refinement of existing methods and development of new strategies hold potential to perform a safe and effective cell replacement without reliance on systemic immunosuppression. Stem cell and regenerative therapies may ultimately manage diabetes through restored endogenous insulin production [ 156 ]. Recently a meta analysis evaluated the safety and efficacy of MSC-based therapy for diabetes in humans. This comprehensive analysis was conducted on 262 patients across six trials that met the inclusion criteria within the last five years. The results reveal that treatment with MSCs significantly reduced the dosage of anti-diabetic drugs over a 12-months. Following treatment, HbAc1 levels decreased by an average of 32%, fasting blood glucose levels decreased by an average of 45%, and C-peptide levels showed a decrease of 38% in two trials and an increase of 36% in four trials. Notably, no severe adverse events were reported across all trials. Therefore, it can be concluded that MSC therapy for type 2 diabetes is safe and effective [ 157 ].

Advances in islet transplantation and stem cell-derived Beta cells

Limited number of the islet transplantation donors highlights the importance of cell therapy in diabetes. Although, higher islet numbers from multiple donors increase the success, limited pancreas availability restricts widespread use [ 158 ]. Using multiple donors also increases rejection risk, while isolation of the islets can cause tissue damage [ 159 ]. To overcome these challenges, researchers have explored the differentiation of stem cells into beta cells in vitro to generate an unlimited supply of insulin-producing cells with standardized and characterized products. Genetic engineering techniques have also been investigated to confer advantages such as stress resistance or immune evasion [ 158 ]. ViaCyte has developed a stem cell-derived pancreatic progenitor called PEC-01, which has the ability to mature into endocrine cells in rodent models. To protect the transplanted cells from immune response, retrieval encapsulation devices were also created [ 160 , 161 , 162 ]. In an initial human clinical trial conducted in 2014 (NCT02239354), the Encaptra device was utilized with the aim of providing complete immunoprotection of transplanted cells through the use of a cell-impermeable membrane. Although, the PEC-Encap product showed reliable tolerance and minimal adverse effects, the trial was stopped due to the inadequate engraftment of functional products. While, a few endocrine cells were observed, fibrosis around the capsule led to graft loss and supression of the insulin secretion. To address this challenge, a more recent development called the PEC-Direct device was introduced, which featured openings in the membrane to facilitate vascularization, thereby improving nutrient exchange and supporting cell viability. However, since host cells could infiltrate the device, immunosuppression was necessary following the transplantation [ 163 , 164 , 165 ]. Protocols were developed to generate clusters of stem cell-derived beta cells that secreted glucose-responsive insulin. These clusters, referred to SC-islets, also contained other endocrine cells, including glucagon-producing cells. SC-islets improved glycemic control in diabetic mice and nonhuman primates [ 146 , 166 , 167 , 168 ]. In a trial conducted in 2017 (NCT03163511), the transplantation of progenitor cells resulted in the maturation of endocrine cells, and glucose-responsive C-peptide secretion was observed 6–9 months post-transplantation. Notably, the majority of these mature endocrine cells exhibited glucagon-positive characteristics. The porous regions housing the endocrine cells allowed for the infiltration of host vessels to facilitate vascularization. However, non-cellular regions were isolated by the presence of fibrosis [ 164 , 165 ]. Although, there was not a sufficient levels of circulating C-peptide in these trials, the findings underscored the significance of promoting vascularization and minimizing fibrotic reactions [ 164 , 169 ]. Vertex conducted a human trial in 2021 (NCT04786262) involving the transplantation of half-dose VX-880 cells (SC-islets) without a device to avoid previous problems, which necessitated immunosuppression. Preliminary results reported improved glycemic control, although it took longer to achieve the same outcome compared to rodent models [ 158 ]. Overall, progresses in islet transplantation and stem cell-derived beta cells pave the way for overcoming the limitations of traditional approaches. Further research and refinements are also required to achieve consistent and clinically significant outcomes in the treatment of diabetes.

Chalenges and limitations

Cell-based therapies have been significantly progressed for diabetes; however, there are still several challenges that need to be overcome. Clinical trials investigating encapsulation devices and islet transplantation techniques have provided valuable insights but face several obstacles including oxygenation, host immune responses, and insufficient long-term engraftment success. Immunoengineering of biomaterials and additive manufacturing for the development of 3D islet structures aim to modulate inflammation and promote graft revascularization. Nevertheless, achieving consistent normalization of blood glucose levels without exogenous insulin remains a challenge in human studies. In the field of gene therapy and stem cell differentiation, research focuses on genetically-modified or progenitor-derived insulin-secreting β-like cells to optimize protocols that ensure safety and functionality. The main challenge is to establish stable and functional cells capable of permanently restoring normoglycemia without the need for external intervention. One major barrier is the immune response, which targets allogeneic and xenogeneic islet grafts. Although, local immunotherapy minimizes the systemic effects, evading graft destruction through biomaterials without the requirement of immune suppression remains a significant challenge. The translation of precision 3D islet constructs and genetically reprogrammed cells also necessitates scalable manufacturing processes to ensure consistent function and long-term safety across batches. When critically appraising progress in the field of cell-based diabetes treatments, it is imperative to consider the regulatory, ethical, economic, and safety factors that shape translational applications. At the regulatory level, oversight bodies play a pivotal role in establishing standards to ensure patient welfare while enabling therapeutic innovation. FDA oversees clinical trials and product approvals in the United States (US), while in Europe the EMA provides parallel regulatory guidance. Within the US, organizations like the United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) govern organ and cell allocation protocols [ 17 , 170 ]. However, as regenerative approaches diverge from traditional organ transplantation, regulatory pathways require ongoing harmonization between the agencies and jurisdictions. Continual dialogue between researchers, oversight boards, and policymakers will be crucial to streamline guidelines in a patient-centric manner that balances safety, efficacy, and timely access to cutting-edge therapies. For instance, as stem cell-derived beta cells and 3D bioprinted tissue constructs emerge, traditional drug and device frameworks may not adequately address product characterization and manufacturing complexities for these advanced therapeutic products [ 67 ]. Within clinics, maintaining compliance with evolving regulations impacts research directives and ultimately patients’ access to the novel treatments. Addressing informed consent, clinical trial design, and privacy protections for sensitive health data are also paramount from an ethical perspective [ 128 , 129 ]. Autonomy and agency of research participants in decision-making related to experimental therapies demand prudency. Equitable accessibility of new treatment options also warrants attention to avoid certain populations facing undue barriers. Cell sourcing presents ethical issues depending on derivation from embryonic, fetal or adult tissues. Logistical matters like shipping and processing stem cell-derived islets prior to transplantation necessitate scrutiny. Tumorigenic potential of the undifferentiated pluripotent stem cells should be optimized through rigorous preclinical testing. Transitioning therapies between animal and early human investigations necessitates well-characterized cellular products showing consistent safety and glucose-responsive insulin secretion profiles comparable to pancreatic islets. Long-term animal model data substantiating lack of malignant transformation following transplantation aids allaying ethical safety concerns as the therapies progress clinically. Researchers carefully screen new concepts to prevent side effects in participants while pursuing curative goals. In terms of economic costs, islet and stem cell transplant procedures remain prohibitively expensive for broad applicability despite promising clinical signals. The field requires sustained study to validate techniques, track long-term outcomes, assess healthcare costs offsets from mitigating diabetes’ debilitating complications, and establish cost-benefit ratios for national reimbursement paradigms. Public-private partnerships may accelerate large, interventional trials and longitudinal research to precisely quantify the cellular therapies’ safety profiles and real-world efficacies compared to intensive management versus costs of intensive diabetes care. Ongoing developments like 3D bioprinting offer catalytic manufacturing potential fundamentally recalibrating economics by enhancing yields, standardizing procedures, and reducing costs through scale. By thoroughly and sensitively examining regulatory frameworks, informed consent processes, risks and benefits, as well as financial considerations at both micro and macro levels, researchers, oversight boards and broader stakeholder networks can advance cell-based therapies towards delivering life-changing benefits for all communities. A multidisciplinary, conscientious approach balances progress against patient welfare. A combination of multiple strategies may help to overcome these limitations. For instance, gene-modified islets integrated within vascularized biomaterial implants or sequenced therapies have promising results to prime grafts in pro-regenerative environments before transplantation. Collaboration across disciplines offers hope that refined individualized therapies may eventually achieve durable insulin independence through functional pancreatic cell or tissue engraftment, not only for diabetes but also for chronic pancreatitis. Regarding, ongoing progresses in unraveling these barriers, cell replacement approaches have the potential to improve diabetes management.

Conclusions

This review provides a comprehensive overview of the advances, challenges, and future directions in various cell-based therapeutic approaches for the treatment of diabetes. Significant progresses have been achieved in microencapsulation design, immunomodulation, tissue constructs, genetic and cellular reprogramming techniques, as well as initial clinical translation. However, the complete restoration of normoglycemia without the need for lifelong immunosuppression is still considered as a significant therapeutic challenge. Therefore, addressing the transplant environment of the hostile nature, developing minimally invasive delivery methods, and overcoming limitations in engraftment efficiency and longevity are crucial issues for the future researches. Through the sustained multidisciplinary efforts for the improvement of existing strategies and establishing novel paradigms, achieving durable insulin independence can be a realistic goal for all diabetic cases through the personalized cell replacement or regeneration.

Immune Responses toward pancreatic islets following transplantation. This figure illustrates the immune responses, including the innate and adaptive immunity that are triggered upon pancreatic islet transplantation. Immune response begins with the activation of tissue macrophages and neutrophils in response to injury. Subsequent, release of inflammatory cytokines stimulates antigen-presenting cells (APCs), CD4 + T cells, CD8 + T cells, and cytotoxic T lymphocytes to orchestrate the immune response

Potential stem cell sources for the treatment of diabetes

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Acrylonitrile butadiene styrene

Activate antigen-presenting cells

Adeno-associated virus

Duodenal homeobox 1

Engineered pseudo islets

Expanded polytetrafluoroethylene

Extracellular matrix

Foreign body response

Fused filament fabrication

Gestational diabetes mellitus

Glucose 6-phosphatase

Insulin-like growth factor binding protein-1

Mesenchymal stem cells

Neurogenin 3

Organ Procurement and Transplantation Network

Phosphoenolpyruvate carboxykinase

Polyaryletherketone

Polycaprolactone

Polycarbonate

Polyetheretherketone

Polyetherimide

Poly-lactic acid

Polystyrene

Stereolithography

Thermoplastic polyurethane

Type 1 diabetes

Type 1 diabetes mellitus

Type 2 diabetes mellitus

United Network for Organ Sharing

United States

Vascular endothelial growth factor

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Prevalence and factors associated with diabetes-related distress in type 2 diabetes patients: a study in Hong Kong primary care setting

• Man Ho Wong 1 ,
• Sin Man Kwan 1 ,
• Man Chi Dao 1 ,
• Sau Nga Fu 1 &
• Wan Luk 1  

Scientific Reports volume  14 , Article number:  10688 ( 2024 ) Cite this article

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• Endocrine system and metabolic diseases

Diabetes-related distress (DRD) refers to the psychological distress specific to living with diabetes. DRD can lead to negative clinical consequences such as poor self-management. By knowing the local prevalence and severity of DRD, primary care teams can improve the DRD evaluation in our daily practice. This was a cross-sectional study conducted in 3 General Out-patient Clinics (GOPCs) from 1 December 2021 to 31 May 2022. A random sample of adult Chinese subjects with T2DM, who regularly followed up in the selected clinic in the past 12 months, were included. DRD was measured by the validated 15-item Chinese version of the Diabetes Distress Scale (CDDS-15). An overall mean score ≥ 2.0 was considered clinically significant. The association of DRD with selected clinical and personal factors was investigated. The study recruited 362 subjects (mean age 64.2 years old, S.D. 9.5) with a variable duration of living with T2DM (median duration 7.0 years, IQR 10.0). The response rate was 90.6%. The median HbA1c was 6.9% (IQR 0.9). More than half (59.4%) of the subjects reported a clinically significant DRD. Younger subjects were more likely to have DRD (odds ratio of 0.965, 95% CI 0.937–0.994, p  = 0.017). Patients with T2DM in GOPCs commonly experience clinically significant DRD, particularly in the younger age group. The primary care clinicians could consider integrating the evaluation of DRD as a part of comprehensive diabetes care.

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Introduction.

It is estimated that the prevalence of type 2 diabetes mellitus (T2DM) in adults in Hong Kong (HK) is approximately 10% of the population 1 . The Hospital Authority of Hong Kong provides public healthcare services to around 400,000 diabetic patients, with the General Out-patient Clinics (GOPCs) offering primary care to over 60% of these individuals 2 . People living with T2DM are affected by this chronic and progressive condition not only physically, but also emotionally. Diabetes-related distress (DRD) refers to the psychological distress specific to living with diabetes. It includes a wide range of emotions, such as feeling overwhelmed by the demands of self-management and restrictions. People with T2DM have to control diet, regularly do exercise and take medications 3 . Many of them may have fears of existing or future diabetes complications, concerns about hypoglycaemia and frustration with care providers 4 .

DRD involves emotional symptoms that may overlap with some psychological conditions, such as depression. However, a previous literature has demonstrated that DRD and depression are different constructs that need different assessment and management approaches 5 . Compared to depression, DRD is peculiar to the emotional distress caused by relentless self-management of diabetes and it does not imply underlying psychopathology. Also, DRD is more closely associated with diabetes-related behavioural and biomedical outcomes than depression. Particularly, it has been shown that DRD influences glycaemic control whereas the impact of depression appears to be equivocal 5 , 6 , 7 . Compared to depression, DRD is highly responsive to clinical intervention 4 . A systemic review has shown that interventions delivered by primary care clinicians, psychoeducation and motivational interviewing resulted in significant DRD reduction 8 .

DRD is prevalent among patients with T2DM, in which a meta-analysis demonstrated the overall prevalence of DRD was 36% 2 . Also, studies in China found that 42.5–77.2% of Chinese people with T2DM experienced DRD 9 , 10 , 11 , 12 . The occurrence of DRD may be influenced by age, gender, culture, type of diabetes, use of insulin, number of complications and duration of diabetes 13 . DRD can lead to negative clinical consequences as studies have shown that a high level of DRD was associated with poor self-management, suboptimal glycaemic control and poor quality of life 14 , 15 , 16 , 17 . The American Diabetes Association recommended that DRD should be routinely monitored, particularly when treatment targets are not met and/or at the onset of diabetes complications 18 . However, DRD is not assessed or recognized in most of the primary care practices in Hong Kong. Since the local prevalence and severity of DRD remain unknown, it is difficult to determine whether DRD assessment should be routinely included in local DM care.

The primary objective of this study was to study the proportion of clinically significant DRD among patients with T2DM in GOPCs in HK. The secondary objective was to identify the associated factors of DRD.

There are 2 hypotheses in this study. (1) The proportion of clinically significant DRD among patients with T2DM in GOPC in HK is common, which is at least 36%, according to existing literature. (2) There is a significant association of DRD with demographic and clinical parameters.

Methodology

Study design.

This was a cross-sectional and prospective study conducted in three GOPCs in HK from 1 December 2021 to 31 May 2022. The three GOPCs include South Kwai Chung Jockey Club GOPC, Ha Kwai Chung GOPC and Cheung Sha Wan Jockey Club GOPC. The inclusion criteria were all adult Chinese patients, who had known diagnosis of T2DM and had at least two regular follow-ups for T2DM in the selected clinic in the past 12 months.

The exclusion criteria were patients diagnosed with type 1 diabetes, patients who had active follow-up of T2DM or were prescribed DM medications in Medicine Department specialist out-patient clinic, patients with known psychiatric illnesses who had active follow-up in either Psychiatry specialists or mental health services, patients who did not have diabetes related blood tests in the past 12 months from the study period, pregnant women, patients who did not understand written Chinese and mentally incapacitated persons.

A list of patients assigned with the International Classification of Primary Care (ICPC) code T90 (Diabetes; non-insulin-dependent) in the selected clinic was drawn from the Hospital Authority’s Clinical Data Analysis and Reporting System (CDARS) 2 weeks prior to the scheduled follow-up appointment with a corresponding appointment number. Up to 5 patients were selected from the list using random number table each day during the study period. A reminder was set in the computer system to identify those selected patients. The patients were invited and asked for consent to participate the study by the attending doctors. Information sheets about the study were given. Patients would complete the questionnaire individually and return it to the healthcare assistant in the clinic. Patients who refused to participate or give consent in this study were regarded as non-responders. Patients who had incomplete questionnaires or missing data were excluded from the statistical analysis. This study follows the principles of Declaration of Helsinki.

Sample size

The sample size was calculated by using the sample size formula:

where the desired precision was taken to be within 5% at 95% confidence interval.

Z = value from standard normal distribution corresponding to desired confidence level (Z = 1.96 for 95% CI)

P is expected true proportion

e is desired precision (margin of error).

The expected proportion in the study population was set to be 36% based on the overall prevalence in the previous meta-analysis study 2 .

Assuming the response rate was 90%, the sample size was estimated to be 355/0.9 = 395 patients, which would round up to 400 patients. Thus, we would aim at recruiting at least 400 patients.

Measurement

Diabetes Distress Scale (DDS) is one of the most commonly used and validated self-report measures to evaluate DRD internationally. The DDS is specific to patients with T2DM and provides a more comprehensive assessment to overcome the psychometric limitations of other measures such as Problems Areas in Diabetes (PAID) scale 2 . Another strength is that DDS also allows healthcare providers to identify the key sources of DRD 4 . The Chinese version of the Diabetes Distress Scale (CDDS-15) was validated in Hong Kong with consistent factor structure and good internal reliability (Cronbach’s alpha 0.902), which is specific for clinical use in Hong Kong Chinese type 2 diabetic patients 19 . There are 3 categories of CDDS-15, consisting of emotional burden (6 items), regimen- and social support- related distress (6 items), and physician-related distress (3 items) 19 . Each item was rated by patients using a 6-point Likert scale from 1 for “not a problem” to 6 for “a very serious problem.” The total mean item score was determined by adding the responses for all items and dividing by 15. Each subscale mean score was calculated by summing item responses in that subscale and dividing by the corresponding number of items. As reported by the study “When is diabetes distress clinically meaningful?: establishing cut points for the Diabetes Distress Scale”, an overall mean score ≥ 2.0 is considered clinically significant 17 . DRD was regarded as a dichotomous variable in this study, with subjects considered to have clinically significant DRD if CDDS-15 mean score ≥ 2.0.

We collected the data by using a printout questionnaire, consisting of three components: (1) The score of the CDDS-15; (2) demographic characteristics such as age, gender, education level, employment status, need of financial assistance to support basic living with Comprehensive Social Security Assistance (CSSA), living arrangement, and smoking status; (3) clinical parameters were obtained by reviewing participants’ medical records, including duration of T2DM, number of oral hypoglycaemic agent, use of insulin, latest Haemoglobin A1c (HbA1c) level, body mass index (BMI), diabetes complications and frequency of hypoglycaemic episodes in the past month. (see Appendix).

The primary outcome was the proportion of DRD among patients with T2DM in the selected study centres. The secondary outcome was the associated factors of DRD including demographic characteristics and clinical parameters as mentioned above.

Statistical analysis

The collected data was analyzed using the IBM Statistical Product and Service Solutions (SPSS) version 25 software. Qualitative variables were presented as frequencies and percentages. Quantitative variables were described as mean and standard deviation (SD), or median and interquartile range (IQR), as appropriate.

Pearson’s Chi-squared test was performed to compare the qualitative variables between participants without clinically significant DRD (DDS < 2) and participants with clinically significant DRD (DDS ≥ 2). Student’s t- test and Mann–Whitney U test was applied for quantitative variables with normal and non-normal distribution, respectively. When variables showed a p -value < 0.2 in the univariate analysis, they would be incorporated into the multivariate analysis. It was done to assure that all potentially associated variables were studied. Logistic regression analysis was used to adjust the confounding effect between variables and to identify the associated factors of DRD in those participants. Findings were considered statistically significant when the p -value < 0.05.

Ethics approval and consent to participate

Informed consent in written form was obtained from all patients. The study was approved by the Hospital Authority Kowloon West Cluster Research Ethics Committee (KWC REC Reference: KW/EX-21-121(162-06)). The CDDS-15 questionnaire was granted permission for use in this study by American Diabetes Association (Permission Request Number: KL072021-MHW). This study follows the principles of Declaration of Helsinki.

Patients’ demographic and clinical characteristics

We distributed 408 questionnaires, thirty-eight patients refused to participate in the study and the response rate was 90.6%. Eight questionnaires were found to have incomplete data and were discarded. Therefore, the total number of questionnaires included in the statistical analysis was 362.

Among the 362 participants, the mean age was 64.2 years old (SD 9.5) and male to female ratio was approximately 1:1. Fewer than 8% of participants (n = 27) had attained tertiary education. Approximately 40% of the participants (n = 146) were retired. The median HbA1c was 6.9% (IQR 0.9). The median duration of living with T2DM since diagnosis was 7.0 years (IQR 10.0). The mean BMI was 26.0 (SD 3.9). For the regimen type, approximately 90% of the participants (n = 324) were taking oral hypoglycaemic agents with or without insulin. The participants’ demographic and clinical characteristics were presented in Table 1 .

Proportion of DRD

A total of 59.4% of the study participants were found to have clinically significant DRD according to the total mean item score (DDS ≥ 2). Among the 3 subscales of DRD, emotional burden was observed in 64.9% of participants, followed by regimen- and social support-related distress (64.1%). Physician-related distress (33.7%) was relatively less affected. This is illustrated in Fig.  1 .

The proportion of clinically significant DRD among patients with T2DM in different subscales (n = 362).

Factors associated with DRD

In the univariate analysis, age and employment status were found to be significantly associated with DRD (unadjusted p  < 0.05). These factors, together with other variables with unadjusted p  < 0.2 including BMI, HbA1c level and regimen type, were further analyzed in the multivariate logistic regression, as shown in Table 2 . Only age was significantly associated with the occurrence of DRD among patients with T2DM, in which the adjusted odds ratio was 0.965 (95% CI 0.937–0.994, adjusted p  = 0.017).

In our study, 59.4% of patients with T2DM in the GOPC setting in HK suffered from clinically significant DRD. It is comparable to the studies in China with a reported prevalence 42.5–77.2% 9 , 10 , 11 , 12 . However, it is much higher than the overall prevalence 36% in the meta-analysis, in which the majority of the studies involved were from Western countries 2 . In Asia, the prevalence of DRD was reported to be 32%, 49%, and 53% in Singapore, Malaysia, and India, respectively 20 , 21 , 22 . The prevalence varies substantially across countries. This could be explained by the difference in the healthcare system, demographics, and cultural background.

Among the 3 subscales of DRD, the proportion of physician-related distress was the lowest in this study, which is similar to the findings in other studies 17 , 23 . Participants might not attribute their distress to physicians if they could obtain sufficient expertise and direction from physicians regarding their T2DM management. Nonetheless, healthcare professionals should pay more attention to the emotional side of diabetes care as more than 60% of subjects in this study had clinically significant emotional burden and regimen- and social support-related distress.

Our study showed that older age was associated with lower odds of DRD (OR 0.965). This is consistent with the results of other studies 24 , 25 , 26 . One study showed that the relation of DRD to psychological and behavioral outcomes is attenuated in older adults, regardless of the duration of T2DM 27 . One hypothesis is that older adults react less to stress because their previous experiences in coping with stress have led to better emotion regulation strategies 28 . On the other hand, younger patients usually have more responsibilities at work and family such as supporting their children and elderly family members 26 . These stressors can worsen the burden associated with the self-management of T2DM.

The HbA1c level was not significantly associated with DRD in our study. This is in line with the results of various international studies 2 , 16 , 23 . In contrast, a study conducted in a specialist clinic in HK using the CDDS-15 questionnaire showed that DRD had a positive relationship with HbA1c level 29 . The disparity may be explained by the difference in the healthcare setting and patients’ demographics. Also, only a minority of patients (7.5%) were prescribed insulin in the GOPC setting in our study, whereas 48% of the subjects were prescribed insulin in the specialist clinic in that study. In fact, there is mixed evidence in the literature regarding the relationship between glycaemic control and DRD 4 . Although DRD is modestly associated with poor glycaemic control, patients with good glycaemic control can also experience high DRD 4 , 16 . Achieving the HbA1c target may require intensive efforts that are potentially impacting other areas of their life such as social activities. This implies patients with T2DM may have an ongoing fear of disease complications or encounter challenges of self-management regardless of their latest glycaemic control.

The strengths of this study were that it was a multi-center study and there was a relatively high response rate. Measures such as invitations by healthcare providers could help reduce the number of non-responders. Moreover, it was one of the pioneer studies regarding DRD in the primary care setting in HK.

However, there are several limitations of this study. First, the use of a self-reported instrument in this study was influenced by social desirability bias. Physician-related distress might be underestimated in this study as patients might worry about negative effects on their treatment process if they declare a lack of confidence in the physician’s expertise in their diabetes management 30 . Second, the causality of the relationships could not be determined due to the study’s cross-sectional design. Further longitudinal studies are suggested to delineate causal relationships. Third, this study was conducted in three GOPCs only and there could be selection bias, therefore the study findings cannot be generalized to all patients with T2DM in HK. Fourth, it is important to acknowledge the restricted scope of this study on assessing other comorbidities such as hypertension and hyperlipidaemia. This study focused primarily on the clinical conditions directly associated with diabetes, including macrovascular and microvascular complications. Future studies could consider incorporating a boarder range of comorbidities to gain a more comprehensive understanding of the impact of diabetes-related distress. Lastly, as the study period coincided with the fifth wave of COVID-19 in HK, it could be a particularly stressful time for patients with T2DM to comply with their diet plan and exercise routine.

There are some clinical implications drawn from this study. Family physicians are on the frontlines responsible for the diagnosis and management of patients with T2DM and this study showed that a high proportion of patients with T2DM experience psychological distress. This finding alerts family physicians about the importance of a holistic approach in T2DM management. Regular evaluation of DRD by a self-reported instrument could be considered to incorporate with the annual assessment of T2DM in the GOPC setting. DRD does not typically disappear when left unaddressed, but DRD interventions do not require the expertise of a mental health professional 4 . In most cases, interventions offered by family physicians including motivational interviewing can help relieve DRD and thus improve the self-management of T2DM 4 , 8 . A practical guide on addressing DRD in clinical care is also available 4 . Further research on monitoring and addressing DRD in primary care in HK is warranted.

The psychological component of diabetes is not routinely assessed in most of the primary care practices in HK. This study demonstrated that a high proportion of patients with T2DM in GOPCs experience clinically significant DRD. Younger age was identified as an associated factor. Evaluation of DRD is suggested to integrate as a part of comprehensive diabetes care in the primary care setting.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

I would like to thank American Diabetes Association for granting us permission to use the CDDS-15 questionnaire in our study. In addition, I would like to thank all the doctors, nurses and staff for supporting this study.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Family Medicine and Primary Health Care Department, Kowloon West Cluster, Hospital Authority, Kowloon, Hong Kong

Man Ho Wong, Sin Man Kwan, Man Chi Dao, Sau Nga Fu & Wan Luk

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All authors contributed to the concept or design of the study, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

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Correspondence to Man Ho Wong .

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Wong, M.H., Kwan, S.M., Dao, M.C. et al. Prevalence and factors associated with diabetes-related distress in type 2 diabetes patients: a study in Hong Kong primary care setting. Sci Rep 14 , 10688 (2024). https://doi.org/10.1038/s41598-024-61538-w

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DOI : https://doi.org/10.1038/s41598-024-61538-w

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Diabetes in Young People Is on the Rise

• Both type 1 and type 2 diabetes affect kids and teens.
• Diabetes in young people is projected to increase.
• New research shows what might be coming by the year 2060.

What did this study examine?

Researchers studied data from 2002 to 2017. They examined the number of young people (under 20) with type 1 or type 2 diabetes, and how cases have increased. They used mathematical models based on these past trends to predict how diabetes cases in young people will increase by 2060.

Terms to know

Type 1 diabetes is when the body does not produce enough insulin, the hormone that balances blood sugar levels. There is no known way to prevent type 1 diabetes at this time.

Type 2 diabetes is when the body loses the ability over time to use insulin. In some people, type 2 diabetes can be prevented or delayed through lifestyle changes.

Incidence refers to the number of people diagnosed with a condition over a certain timeframe. Incidence in this study is measured in two ways:

• Constant incidence is when the rate of new cases stays the same.
• Increasing incidence is when the rate of new cases increases based on past trends.

Study results

Researchers forecasted two scenarios of how many kids and teens will be diagnosed with diabetes by 2060:

Constant incidence: If the rate of new diagnoses stays the same, type 1 diabetes cases would remain about the same. Type 2 diabetes cases would increase about 70%.

Increasing incidence: If the rate of new diagnoses continues to increase, type 1 diabetes cases would increase about 65%. Type 2 diabetes cases would increase about 700%.

Researchers also examined data by race and ethnicity. They predicted higher diabetes increases in Black, Hispanic or Latino, Asian, Pacific Islander, and American Indian or Alaska Native young people. This finding reinforces CDC's actions to advance health equity .

Researchers created a hypothetical model that decreased the annual incidence of type 2 diabetes by 2% through prevention efforts. This model reduced the increase of diabetes among young people with to 294,000, compared to 526,000 without prevention efforts.

What's important about this study?

In both scenarios presented in this study, researchers expect diabetes in young people to increase over the next 40 years. This study highlights the importance of type 2 diabetes prevention efforts, where possible, for kids and teens. It also shows the increasing need for diabetes management for young people.

Diabetes is a chronic disease that affects how your body turns food into energy. About 1 in 10 Americans has diabetes.

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May 9, 2024

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Q&A: Study details how major advances have been implemented in intensive diabetes management

by Erin Digitale, Stanford University

For 30 years, doctors have known that maintaining near-normal blood sugar has huge benefits for people with type 1 diabetes.

A 1993 clinical trial found that participants who were taught methods for tightly managing their disease—checking their blood sugar many times each day, making adjustments to insulin doses and receiving frequent help from their medical caregivers—reduced their risk for long-term complications, including blindness, kidney failure and peripheral nerve damage, by 50% to 70%.

Yet, since that trial, physicians have struggled to roll out intensive diabetes management programs to all patients. On average, patients across the U.S. still don't achieve the level of diabetes control that would minimize their long-term risks.

"It's not because people haven't been trying," said David Maahs, MD, Ph.D., a pediatric endocrinologist at Stanford Medicine Children's Health. "It's a complicated condition to take care of, and for the individual with diabetes and their family, it's constant work."

Stanford Medicine experts are making headway on the problem. A new study published in Nature Medicine describes how the research team, led by Maahs and Priya Prahalad, MD, Ph.D., have implemented major advances in intensive diabetes management.

First, they tackled equity issues to ensure the latest diabetes technology got into the hands of every patient as soon as they were diagnosed. They also built artificial intelligence tools that gave diabetes caregivers the ability to identify which patients most needed their help quickly. Ultimately, these steps enabled adolescent type 1 diabetes patients to maintain better control of their blood sugar levels.

Maahs talked about the methods used and the long-term ramifications. This interview was edited for length and clarity.

Your study is built on recent technological advances that automate many tasks involved in living with diabetes. What are the advantages of the newer devices?

Patients can now wear continuous glucose monitors, which have a sensor inserted under the skin that reads a glucose value every 5 to 15 minutes. This is really helpful because you don't have to poke your finger six to 10 times a day to measure glucose levels , and the monitor can warn you if you're going low or high. If you're the parent of a child with type 1 diabetes, you can get their glucose data from the cloud and onto your phone.

Another recent improvement in diabetes technology is that continuous glucose monitors can now communicate with an insulin pump. An algorithm helps control dosing to reduce or stop insulin if it predicts your blood sugar is going to go low, and it adds a bit more insulin if you're going high. You still have to give an insulin dose before you eat, but it really takes a lot of the burden out of managing type 1 diabetes.

It's been a big challenge to get these improved diabetes devices into the hands of every U.S. patient; your earlier work shows that disadvantaged groups tend to be left behind. How did your new study tackle equity concerns?

We were testing the benefits of starting pediatric type 1 diabetes patients on continuous glucose monitors as soon as possible after they were diagnosed, which we were usually able to do in the first week after diagnosis. Although insulin pumps were not a focus of this study, about half of our patients began using an insulin pump within a year of their diagnosis.

We all agreed that we wanted every new patient we saw to be included. If you look at earlier studies of diabetes technology, it tended to be tested in college-educated, white, privately insured people and not in other populations. We had to figure out how to meet the challenges faced by less-advantaged patients. We learned that this went beyond the most obvious barriers we addressed, such as providing care in multiple languages.

For instance, at first, it seemed like some groups of patients were wearing their continuous glucose monitors less than we asked them to. But in fact, the transmission of their data to our system was incomplete because they had poor Wi-Fi access at home. That's an equity issue. We've been giving out devices to those who need them as part of the research so that everyone has enough internet connectivity to upload their data.

Also, at diagnosis, we sometimes can't tell whether someone has type 1 or type 2 diabetes. This happens more in minoritized populations, in youth who have an elevated body mass index, and these children are more likely to be publicly insured or non-English speakers. We made a conscious decision to include all these patients while we waited to learn the details of their diagnosis so as not to miss anyone who might be eligible for our study.

Close to 90% of our new type 1 diabetes patients participated in this study, and a lot of those who chose not to participate enrolled instead in a different study of artificial pancreas technology, so we did quite a good job of including everyone. It was a very diverse population: About 35% of patients were publicly insured, and only about 40% were non-Hispanic white.

Getting the new technology to every patient was important. What else was needed to make sure all patients could succeed in managing their blood sugar levels?

The 1993 trial showed that it was really useful for patients to have frequent communication with their diabetes team. That can be hard to do with the resources of a typical diabetes clinic, where each diabetes educator has many patients to track.

To address this problem, we built an AI-powered data dashboard, which filters our patients' continuous glucose monitor data and puts it into a format that helps our team identify who is struggling. Instead of spending a lot of time manually evaluating their data, we can automatically rank which patients most need our help.

We look at the percentage of time the continuous glucose monitor has been worn, and if it's below a certain threshold, that's our first starting point. Sometimes people have lost their prescription for their CGM, continuous glucose monitor, and need a new one. We're able to reach out and help them.

If a patient is having too many low blood sugar readings, which are dangerous, that's another reason for them to go to the top of the list. Our diabetes educators can contact them to help adjust their insulin dosing. Likewise, if their average glucose is out of the target range less than 70% of the time, we can flag that they need some extra attention between their visits to the clinic.

On the other hand, if someone is wearing their monitor, they're not having low blood sugar readings and they are in the right blood sugar range most of the time, they're doing well. We'll check in with them at their quarterly clinic visit, but they don't need outreach in between. That knowledge helps our team shift its attention to the patients who most need it.

How did you build the algorithm that powers this dashboard?

The platform was developed at Stanford with systems design expert David Scheinker, Ph.D., and his SURF team; they use tools such as machine learning and statistics to improve how health care is delivered. He teaches a class in which engineering undergraduates and grad students solve technical problems in health care.

We presented our concept to his class. Our problem was that each brand of diabetes equipment had a different system to share data. A diabetes educator with 10 patients might have had five or six different places to go, look at their data, log in, and so on. This made it extremely time-consuming to figure out which patients needed help.

Instead, our system has all the data in one place. It was built through an iterative process between our diabetes educators and the engineering team so that, ultimately, the data is presented in the way that is most useful to the diabetes educators.

We published a study showing that the dashboard has shifted the diabetes educators' workload in a helpful way. They spend less time sifting through troves of data—something an algorithm can do perfectly—and more time talking to patients who need extra help between clinic visits.

How do you know that your approach worked?

Compared with our past patients who were diagnosed with type 1 diabetes before this research began, our newer patients were more likely to reach their glucose targets after a year of living with the disease.

One treatment target for our patients, after a year with diabetes , was a glycosylated hemoglobin A1c measurement below 7%. This laboratory test assesses patients' blood sugar control over the prior three months, and a reading below 7% is the target for optimum health.

In our earlier data, 28% of patients met this target 12 months after diagnosis; now, we have 64% of our patients meeting this goal. We also looked at how many people had very high A1c measurements, with values above 9%, and that measure has reduced dramatically. Similarly, by one year after diagnosis, our patient's blood sugar was in the target range 68% of the time.

We also have data showing that compared with our historical cohort, everyone received a similar benefit from our intensive approach to treatment, meaning that if you looked at people who had public versus private insurance or were or were not English speakers, every group had similar improvements when we implemented our study.

There are still some gaps between more- and less-privileged patients, so we still have work to do, but everyone benefits a similar amount. Often, when new medical technology becomes available, more privileged people get more benefits; it is very encouraging that we could buck that trend.

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• Open access
• Published: 10 May 2024

Association of neutrophil-lymphocyte ratio with all-cause and cardiovascular mortality in US adults with diabetes and prediabetes: a prospective cohort study

• Guangshu Chen 1   na1 ,
• Li Che 2 , 3   na1 ,
• Meizheng Lai 1 ,
• Ting Wei 4 ,
• Chuping Chen 1 ,
• Ping Zhu 1 &
• Jianmin Ran 1  

BMC Endocrine Disorders volume  24 , Article number:  64 ( 2024 ) Cite this article

112 Accesses

Metrics details

The neutrophil-lymphocyte ratio (NLR) is a novel hematological parameter to assess systemic inflammation. Prior investigations have indicated that an increased NLR may serve as a potential marker for pathological states such as cancer and atherosclerosis. However, there exists a dearth of research investigating the correlation between NLR levels and mortality in individuals with diabetes and prediabetes. Consequently, this study aims to examine the connection between NLR and all-cause as well as cardiovascular mortality in the population of the United States (US) with hyperglycemia status.

Data were collected from a total of 20,270 eligible individuals enrolled for analysis, spanning ten cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. The subjects were categorized into three groups based on tertiles of NLR levels. The association of NLR with both all-cause and cardiovascular mortality was evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. Restricted cubic splines were used to visualize the nonlinear relationship between NLR levels and all-cause and cardiovascular mortality in subjects with diabetes after accounting for all relevant factors.

Over a median follow-up period of 8.6 years, a total of 1909 subjects with diabetes died, with 671 deaths attributed to cardiovascular disease (CVD). And over a period of 8.46 years, 1974 subjects with prediabetes died, with 616 cases due to CVD. The multivariable-adjusted hazard ratios (HRs) comparing high to low tertile of NLR in diabetes subjects were found to be 1.37 (95% CI, 1.19–1.58) for all-cause mortality and 1.63 (95% CI, 1.29–2.05) for CVD mortality. And the correlation between high to low NLR tertile and heightened susceptibility to mortality from any cause (HR, 1.21; 95% CI, 1.03–1.43) and CVD mortality (HR, 1.49; 95% CI, 1.08–2.04) remained statistically significant (both p -values for trend < 0.05) in prediabetes subjects. The 10-year cumulative survival probability was determined to be 70.34%, 84.65% for all-cause events, and 86.21%, 94.54% for cardiovascular events in top NLR tertile of diabetes and prediabetes individuals, respectively. Furthermore, each incremental unit in the absolute value of NLR was associated with a 16%, 12% increase in all-cause mortality and a 25%, 24% increase in cardiovascular mortality among diabetes and prediabetes individuals, respectively.

Conclusions

The findings of this prospective cohort study conducted in the US indicate a positive association of elevated NLR levels with heightened risks of overall and cardiovascular mortality among adults with diabetes and prediabetes. However, potential confounding factors for NLR and the challenge of monitoring NLR’s fluctuations over time should be further focused.

Peer Review reports

The increasing rates of diabetes worldwide and the high number of diabetes-related deaths, especially from cardiovascular issues, have led to a focus on identifying factors that can predict mortality in individuals with diabetes [ 1 , 2 , 3 ]. Extensive research has consistently revealed a strong association between cardiovascular disease and inflammatory biomarkers [ 4 , 5 ]. The body’s innate (neutrophils) and adaptive (lymphocytes) immune responses are balanced by the neutrophil-to-lymphocyte ratio [ 6 ]. It has recently gained recognition as a valuable indicator of systemic inflammation, encompassing both infectious and non-infectious conditions, such as cardiovascular disease [ 7 , 8 ], tumors [ 9 , 10 , 11 , 12 ], septicemia [ 13 , 14 ], and mental disorders [ 15 , 16 ]. The development of diabetes may be caused by chronic inflammation, according to research [ 17 , 18 ].

However, because of the related costs and measurement challenges, the use of several inflammatory markers in ordinary clinical practice has been restricted. Neutrophils’ negative effects on blood vessel linings are measured with NLR, an easy-to-use, affordable test based on well-studied white blood cell traits. Few cohort studies have examined the relationship between NLR levels and long-term health effects [ 19 , 20 , 21 , 22 ]. Regrettably, most of these studies have mainly concentrated on investigating the correlation between NLR and diabetes-related complications. To date, there has been limited scholarly investigation into the correlation between NLR and mortality among individuals with diabetes and prediabetes. Thus, the goal of this study is to look at the relationship between NLR and cardiovascular and overall mortality in US adults with hyperglycemia.

The design and population of the study

A population-based cross-sectional survey, the NHANES was created expressly to collect detailed information on the health and nutritional status of US households. The NHANES interview component encompasses inquiries on demographics, socioeconomic factors, dietary habits, and health-related matters and is accessible to external researchers. The NHANES study methodology has been extensively described by the US Centers for Disease Control and Prevention [ 23 ]. The National Center for Health Statistics granted approval for NHANES, and each participant gave written consent. Data from 10 cycles of NHANES conducted between 1999 and 2018 were utilized. Initially, a total of 52,398 individuals aged 20 years and above were included. Subsequently, 1159 cases of pregnant women were excluded, screening out 9433 diabetes cases and 17,200 prediabetes cases according to diagnosis standards. Then we exclude cases without complete data on NLR and within 1% extreme of NLR. To consider the possible influence of glucocorticoid-steroid usage on neutrophil and lymphocyte levels, extra individuals who had consumed oral or inhaled cortisol in the previous month were not included. Furthermore, cases were excluded due to factors such as inadequate follow-up time, and mortality within two years. In the analysis, a grand total of 7246 cases of eligible diabetes and 13,024 cases of eligible prediabetes were ultimately considered (refer to Fig.  1 ).

Flowchart about the inclusion and exclusion of eligible subjects

Based on NLR tertiles, baseline characteristics of participants with diabetes and prediabetes were acquired. The study employed weighted Kaplan-Meier (KM) survival curves to investigate differences in overall and CVD mortality among different NLR levels. Cumulative survival rates were presented in a risk table as weighted percentages. Among hyperglycemia subjects, dose-response relationships between NLR and mortality were demonstrated using restricted cubic splines (RCS) curves. The RCS curves depicted hazard ratios and 95% confidence intervals (CIs) through a solid line and gray shading. Any variants that influence neutrophil and lymphocyte counts were considered in our models to adjust the association between NLR and mortality. The models were modified to account for factors such as age, gender, ethnicity, level of education, ratio of family income to poverty, drinking habits, smoking habits, BMI, eGFR, HbA1c levels, duration of diabetes, medication for lowering glucose, CVD, hypertension, hyperlipidemia, cancer, chronic obstructive pulmonary disease (COPD), depression, and anemia. We further stratified different confounders to see the interaction effect on the association of NLR with overall and CVD mortality.

Assessment of hyperglycemia and NLR

Diabetes was characterized by fulfilling any of the subsequent conditions: surpassing 7.0 mmol/L in fasting plasma glucose levels, having random plasma glucose levels or 2 h-glucose of 75-g oral glucose tolerance above 11.0 mmol/L, exhibiting HbA1c levels of 6.5% or greater (with serum hemoglobin level higher than 100 g/dL), utilizing insulin or self-reporting a medical professional’s diagnosis. Prediabetes was diagnosed according to one of the following conditions: fasting plasma glucose levels being 5.6-7.0mmol/L, random plasma glucose levels or 2 h-glucose of 75-g oral glucose tolerance being 7.8–11.0 mmol/L, HbA1c levels being 5.7–6.4% (with serum hemoglobin level higher than 100 g/dL), or self-reported history.

Automated hematology analyzing devices were used to obtain the counts of lymphocytes and neutrophils, with the unit expressed as ×1,000 cells/mm3. To calculate the neutrophil-to-lymphocyte ratio, divide the count of neutrophils by the count of lymphocytes. We categorized NLR into tertiles to further explore the relationship between different levels of NLR and mortality.

All-cause and CVD mortality ascertainment

Mortality data, including all-cause and cardiovascular disease outcomes, were obtained from the National Death Index linked to the NHANES database until the end of December 2019.

The follow-up period persisted until the time of death or the conclusion of the period, starting from the date of blood analysis. The International Classification of Diseases, Tenth Revision (ICD-10) codes I00–09, I11, I13, I20–51, and I60–69 were used to identify mortality related to cardiovascular disease.

Covariates assessment

Baseline data on eligible respondents were gathered using the Computer-Assisted Personal Interviewing (CAPI) system and the Family and Sample Person Demographics questionnaires. This data included information on age, gender, ethnicity, education level, family income-poverty ratio, smoking and drinking habits, usage of glucose-lowering medication, healthy eating index (HEI) scores, and past medical history such as cardiovascular disease (coronary heart disease, congestive heart failure, angina, heart attack or stroke), hypertension, cancer, and COPD. The NHANES protocol was used to assign weights to all baseline data. Using the physical examination data from NHANES, the body mass index (BMI) was calculated by dividing the body weight (measured in kilograms) by the square of the height (measured in meters). The study collected neutrophil, lymphocyte, and hemoglobin counts from a peripheral whole-blood test. Furthermore, serum creatinine, HbA1c, TC, LDL-C, HDL-C, TG, and fasting glucose were obtained through laboratory tests. To guarantee precise and uniform blood test procedures, the NHANES followed the Laboratory Procedure Manual. Interviewers recorded the duration of diabetes, considering newly diagnosed cases as having a duration of 0 year. The CKD-EPI equation was utilized to determine the estimated glomerular filtration rate (eGFR). Hyperlipidemia was characterized by fulfilling any of the subsequent conditions: total cholesterol (TC) levels equal to or exceeding 200 mg/dL, triglyceride (TG) levels equal to or surpassing 150 mg/dL, high-density lipoprotein cholesterol (HDL-C) levels less than or equal to 40 mg/dL in males and 50 mg/dL in females, low-density lipoprotein cholesterol (LDL-C) levels equal to or exceeding 130 mg/dL, or self-reported utilization of medications for reducing cholesterol. The depression group was identified using the PHQ-9 [ 24 ]. Depression status was defined as having a depression score greater than four. Anemia was diagnosed by establishing the serum hemoglobin (Hb) threshold (g/dL) for different demographic groups (non-pregnant women over 15 years old with levels below 120 g/dL, and men over 15 years old with levels below 130 g/dL). The HEI-2015 scores were employed as an indicator of dietary quality, with a higher score indicating a more nutritionally balanced diet [ 25 ]. MET scores were utilized to evaluate physical activity levels following the national physical activity guidelines (low physical activity being defined as less than 500 MET/wk and high physical activity being defined as 500 MET/wk or more) [ 26 ].

Statistical analysis

Cox proportional hazards regression after survey-weight was used to explore the association of NLR level with overall and CVD-specific mortality based on different models in diabetes and prediabetes groups. All data were adjusted for survey weights in accordance with the analytic guidelines provided by NHANES due to the complex design. Whereas continuous data were shown as mean (standard error), categorical variables were shown as numbers (percentages). To investigate the disparities among groups in terms of baseline characteristics, we employed Weighted Chi-Square tests and Kruskal-Wallis tests. Using several models in the diabetic and prediabetes groups, Cox proportional hazards regression was used to assess the internal connection between NLR levels and overall and cardiovascular-specific death. The hazard ratios and 95% CIs were derived through survey-weighted calculations. We conducted three models to explore the relationship. Model 1 took into account factors such as age (below 65 or over 65), sex (male or female), race/ethnicity (Hispanic Mexican, non-Hispanic Black, non-Hispanic White, or others), marital status (married/cohabiting, single), family income-to-poverty ratio (< 1.0, 1.0–3.0, or ≥ 3.0), and education level (less than high school, high school or equivalent, or college or above). Model 2 included BMI (< 30 or ≥ 30.0 kg/m2), smoking status (never, former, or current), drinking status (non-drinker or ever drinker), physical activity (low or high), HEI scores, and cancer (no or yes) as additional adjustments. Model 3 further adjusted for eGFR (< 30, 30–60, >=60 ml/min/1.73 m²), anemia (no or yes), hypertension (no or yes), hyperlipidemia (no or yes), depression (no or yes), COPD (no or yes), use of hypotensive drug (no or yes), and use of lipid-lowering drug (no or yes) based on model 2. Diabetes duration, HbA1c levels, and use of antidiabetic drugs were adjusted additionally for diabetes subjects on model 3. The study employed statistical analysis to establish the first tertile of NLR as the reference group for evaluating the correlation between moderate-high NLR levels and mortality across various models. To handle missing values in the covariates of the study, we employed the technique of multiple imputation [ 27 ].

Weighted KM curves were employed to depict cumulative overall and CVD survival probability, stratified by tertiles of NLR levels. The risk table presented precise information regarding deaths and survival probability at different follow-up intervals. After fully adjusting for the mentioned covariates, RCS curves were utilized to visually depict the nonlinear correlation between NLR levels and both overall and CVD mortality in individuals with diabetes and prediabetes.

Subgroup analyses were performed to look at the relationship between NLR levels and death in people with diabetes and prediabetes. The subgroups were categorized using a variety of clinical and demographic characteristics, including age, gender, ethnicity, education, BMI, drinking and smoking habits, physical activity levels, and the occurrence of cancer, hypertension, and CVD. To ensure the strength of our findings, we performed sensitivity analyses. A particular analysis was carried out on individuals who had a prior record of cardiovascular disease or not. Following that, individuals who reported having no CVD and cancer at the baseline condition were also analyzed. The data underwent analysis using R software version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria), and a two-sided P -value < 0.05 was utilized to ascertain statistical significance.

Baseline characteristics analyses

Our study included a total of 7246 and 13,024 adults aged 20 years or older who had been diagnosed with diabetes and prediabetes, respectively. In the diabetes group, the participants’ average age was 58.6 years, with males accounting for 51.50% and whites representing 35.59%. In the prediabetes group, the participants’ average age was 52.0 years, with males accounting for 52.62% and whites representing 41.75%. For all-cause mortality, approximately one-third of the subjects died from cardiovascular disease both in the diabetes and prediabetes group. Therefore, we conducted an analysis of hazard ratios for both all-cause and CVD mortality. The subjects were categorized into three groups based on tertiles of NLR levels: tertile 1 (0.68–1.71), tertile 2 (0.71–2.48), and tertile 3 (2.48–7.58) for diabetes subjects and tertile 1 (0.62–1.60), tertile 2 (1.60–2.29), tertile 3 (2.29–6.23) for prediabetes subjects. For diabetes subjects, in comparison to the lower tertile of NLR, individuals in the upper tertile of NLR exhibited characteristics such as advanced age, male gender, non-Hispanic white ethnicity, higher educational attainment, and lower HbA1c levels. Additionally, they demonstrated a greater prevalence of alcohol consumption, smoking, hypertension, CVD, cancer, COPD, and anemia. Furthermore, this group displayed moderate family income, BMI, and eGFR. Such a trend was seen in prediabetes subjects, as indicated in Table  1 .

All-cause and CVD mortality with tertiles of NLR levels and survival analyses

Over a period of 8.0 years, 1909 people with diabetes died, with 671 cases attributed to cardiovascular causes, 305 cases to cancer, and 933 cases to other causes. And over a period of 8.46 years, 1974 people with prediabetes died, with 616 cases attributed to cardiovascular causes, 479 cases to cancer, and 879 cases to other causes. The hazard ratios for all-cause and CVD mortality among individuals with diabetes and prediabetes, based on tertiles of NLR levels, are presented in Table  2 a and Table  2 b, respectively.

After adjusting for potential confounders, every unit increment in the absolute value of NLR, equivalent to 50SD in diabetes subjects or 100SD in prediabetes subjects, resulted in a 16% higher risk of mortality from any cause (HR, 1.16; 95% CI, 1.10–1.23) and a 25% higher risk of mortality from cardiovascular disease (HR 1.25; 95% CI 1.14–1.37) in diabetes subjects, and a 12% higher risk of mortality from overall cause (HR, 1.12; 95% CI, 1.05–1.19) and a 24% higher risk of mortality from cardiovascular disease (HR 1.24; 95% CI 1.11–1.37) in prediabetes subjects. The hazard ratios for all-cause mortality and CVD mortality after multiple adjustments in diabetes subjects, comparing high to low NLR tertile, were found to be 1.37 (95% CI, 1.19–1.58) and 1.63 (95% CI, 1.29–2.05), respectively. And the correlation between high to low NLR tertile and heightened susceptibility to mortality from any cause (HR, 1.21; 95% CI, 1.03–1.43) and CVD mortality (HR, 1.49; 95% CI, 1.08–2.04) remained statistically significant (both p -values for trend < 0.05) in prediabetes subjects.

The Kaplan-Meier survival curves, adjusted for weights, were analyzed based on tertiles of NLR. The findings indicated that individuals in the highest tertile of NLR exhibited the lowest cumulative probability of survival for both all-cause and cardiovascular events, as depicted in Fig.  2 . Specifically, when NLR levels exceeded 2.48 in diabetes participants, the 10-year cumulative survival probability was determined to be 70.34% for all-cause events and 86.21% for cardiovascular events. And when NLR levels exceeded 2.29 in prediabetes participants, the 10-year cumulative survival probability was found to be 84.65% for all-cause events and 94.54% for cardiovascular events.

Weighted Kaplan–Meier survival curves for all-cause mortality for diabetes ( a ) and prediabetes ( b ) subjects according to tertiles of NLR. Tertiles of NLR in diabetes subjects: Tertile 1: 0.68–1.71; Tertile 2: 1.71–2.48; Tertile 3: 2.48–7.58; Tertiles of NLR in prediabetes subjects: Tertile 1: 0.62–1.60; Tertile 2: 1.60–2.29; Tertile 3: 2.29–6.23. Weighted Kaplan–Meier survival curves for CVD mortality for diabetes ( c ) and prediabetes ( d ) subjects according to tertiles of NLR. Tertiles of NLR in diabetes subjects: Tertile 1: 0.68–1.68; Tertlie 2: 1.68–2.42; Tertile 3: 2.42–7.58; Tertiles of NLR in prediabetes subjects: Tertile 1: 0.62–1.58; Tertile 2: 1.58–2.25; Tertile 3: 2.25–6.23

The RCS curves effectively depicted the non-linear correlation between NLR levels and both overall and cardiovascular mortality among adults with diabetes and prediabetes, following comprehensive adjustments as illustrated in Fig.  3 . Significantly, there was a clear correlation between NLR levels and the mentioned mortality outcomes, demonstrating a dose-response relationship ( P -value = 0). Furthermore, our analysis revealed a positive linear trend in the correlation between NLR levels and both overall and cardiovascular death, as evidenced by non-significant P -values for nonlinearity ( P -value = 0.706 and 0.997, respectively) in diabetes group and nonlinearity ( P -value = 0.229 and 0.279, respectively) in prediabetes group.

Dose-response associations between NLR and all-cause mortality in diabetes ( a ) and prediabetes ( b ) subjects. Both p -values for overall was 0. p -value for nonlinearity in diabetes and prediabetes subjects was 0.706 and 0.229, respectively. Dose-response associations between NLR and CVD mortality in diabetes ( c ) and prediabetes ( d ) subjects. Both p-values for overall was 0. p -value for nonlinearity in diabetes and prediabetes subjects was 0.997 and 0.279, respectively. The solid line and gray shading showed hazard ratios and 95% CIs, respectively. Models were adjusted for age, sex, race/ethnicity, education level, family income-poverty ratio, drinking status, smoking status, BMI, eGFR, CVD, hypertension, hyperlipidemia, cancer, COPD, depression status, anemia, physical activity, HEI scores, use of hypotensive drug, use of lipid-lowering drug. Diabetes duration, HbA1c, and use of antidiabetic drug were adjusted additionally for diabetes subjects

Subgroup and sensitivity analyses

A noteworthy correlation was observed between NLR levels and baseline history of CVD in the prediabetes group for CVD mortality ( P  = 0.02 for interaction) (Fig.  4 c, d). In the subset of prediabetes individuals without a prior history of CVD, the modified hazard ratio (95% CI) for CVD mortality was 1.15 (1.08, 1.24). On the other hand, in the subset of prediabetes individuals who have a previous CVD, the CVD mortality had an adjusted hazard ratio (95% CI) of 1.05 (0.95, 1.17). The association between NLR levels and overall mortality in hyperglycemia subjects remained stable irrespective of different stratifying factors (Fig.  4 a, b), including age, gender, ethnicity, educational attainment, family income-poverty ratio, alcohol consumption, tobacco use, BMI, eGFR, CVD, hypertension, hyperlipidemia, cancer, COPD, depression, anemia, use of hypotensive drug, and use of lipid-lowering drug. Diabetes duration, HbA1c level, and use of antidiabetic drug were adjusted additionally for diabetes subjects.

Stratified analyses of the association between NLR and all-cause mortality in diabetes ( a ) and prediabetes ( b ) subjects. Stratified analyses of the association between NLR and CVD mortality in diabetes ( c ) and prediabetes ( d ) subjects. Models were adjusted for age, sex, race/ethnicity, education level, family income-poverty ratio, drinking status, smoking status, BMI, eGFR, CVD, hypertension, hyperlipidemia, cancer, COPD, depression, anemia, physical activity, HEI scores, use of hypotensive drug, use of lipid-lowering drug except for the corresponding subgroup variables. Diabetes duration, HbA1c and use of antidiabetic drug were adjusted additionally for diabetes subjects

In the subgroup without prior history of CVD, the multiple-adjusted hazard ratios for all-cause mortality and CVD mortality in diabetes subjects, comparing high to low NLR tertile, were found to be 1.33(95% CI, 1.09–1.61) and 1.93 (95% CI, 1.34–2.78), respectively. And the correlation between high to low NLR tertile and mortality from any cause (HR, 1.26; 95% CI, 1.04–1.54) remained statistically significant in prediabetes subjects (Table S1 a and S1 b). In the subgroup without a baseline history of CVD and cancer, the hazard ratios for overall and cardiovascular mortality exhibit similar significant differences (Table S3 a and S3 b). In the subgroup with a history of CVD, the hazard ratios for all-cause mortality after full adjustments in diabetes subjects, comparing high to low NLR tertile, were found to be 1.57 (95% CI, 1.28–1.593). And the correlation between high to low NLR tertile and mortality from CVD events (HR, 1.62; 95% CI, 1.05–2.50) remained statistically significant in prediabetes subjects (Table S2 a and S2 b).

Our study included 20,270 hyperglycemia subjects with a longer than 8 years of follow-up period. By the conclusion of the study, a total of 1909 deaths were recorded in the diabetes group, with 671 attributed to cardiovascular causes and 1238 attributed to other diseases. And a total of 1974 deaths were recorded in the prediabetes group, with 616 attributed to cardiovascular causes and 1358 attributed to other causes. The findings indicated that participants with elevated levels of NLR exhibited lower levels of HbA1c but a higher prevalence of cardiovascular disease and cancer at the beginning of the study. Additionally, these individuals demonstrated a higher incidence of both overall and cardiovascular mortality. Consequently, it can be inferred that heightened NLR levels may serve as an independent prognostic factor for mortality from any cause and cardiovascular disease in hyperglycemia people.

Many investigations have explored the correlation between NLR and the long-term complications and prognosis of diabetes [ 21 , 22 , 28 ]. For Scottish diabetic populations, higher NLR levels were found to increase the prevalence of retinopathy [ 21 ], particularly among individuals below the age of 65 and those with well-managed glycemic control. A study from Rio de Janeiro [ 29 ] noted that elevated NLR increased all-cause mortality by up to 19% in patients with type 2 diabetes mellitus (at 10.5 years of follow-up), but the sample size of the study was only 689 people. Through the analysis of a substantial sample size of 32,328 subjects from the NHANES database, Chen discovered a significant association between elevated NLR and increased risk of overall and cardiovascular death in the general population [ 30 ]. When the NLR value was greater than 3, the general population had a 43% increased risk of all-cause mortality and a 44% increased risk of cardiovascular mortality. In contrast, the NLR levels in our study were divided by tertiles, and when the NLR value was greater than 2.48, the diabetic population had a similar risk of all-cause mortality as the general population, but a higher risk of cardiovascular mortality. Such a trend was also significant in subjects with prediabetes. By analyzing seven cycles of 3251 diabetic patients in the NHANSE database, Dong et al. found a strong link between high NLR levels and increased risks of death and heart-related death in people with diabetes [ 31 ]. When the NLR was greater than 3.48, diabetic patients had a doubled risk of all-cause mortality and a 1.8-fold increase in cardiovascular mortality. However, this study failed to adequately incorporate covariates that affect the outcome, such as underlying cardiovascular disease, history of cancer, lifestyle, and medication use, and did not take into account subjects with prediabetes. While most studies have focused on the association of NLR with complications and poor prognosis of diabetes, few studies have been conducted on the association of NLR with poor prognosis of prediabetes. To our current understanding, our study represents the initial comprehensive examination of the relationship between NLR levels and mortality in both diabetes and prediabetes populations after full consideration of multivariable adjustments.

Our research found that diabetes individuals with NLR levels above 2.48 had a significantly higher risk of mortality from any cause (37%) and cardiovascular disease (63%) compared to those with lower NLR levels. Additionally, our dose-response analysis demonstrated a positive correlation between NLR levels and both all-cause and CVD mortality. After accounting for confounding factors in diabetes subjects, there was a 16% increased risk of all-cause mortality and a 25% increased risk of CVD mortality for every unit increase in the absolute value of NLR. The Kaplan-Meier survival plots indicated a notable correlation between heightened NLR levels and heightened susceptibility to mortality from any cause and cardiovascular disease. These findings provide compelling evidence for the close correlation between elevated NLR levels and unfavorable outcomes in terms of overall and cardiovascular mortality. In our study, prediabetes has a higher risk of death due to its progression to diabetes, highlighting the importance of inflammatory markers in predicting poor outcomes in those with high blood sugar. Therefore, it is plausible that NLR, serving as an inflammation marker, may possess intrinsic abilities to predict the probability of all-cause and cardiovascular mortality in individuals with diabetes and prediabetes. The evaluation of the NLR is subject to various influencing factors, including age, race, corticosteroid usage, and the presence of chronic diseases such as cancer, diabetes, obesity, depression, neoplasms, heart disease, and anemia. These factors impact the function, activity, behavior, and dynamic changes of neutrophil and lymphocyte counts [ 32 , 33 , 34 ]. Utilizing the extensive and reliable NHANES database, this study comprehensively accounted for confounding variables related to NLR. It ensured the credibility of NLR’s predictive value for mortality risk in hyperglycemia subjects. There is no normal reference range for NLR in healthy adults, and the average level of NLR is related to race [ 35 , 36 , 37 ]. Forget et al. [ 36 ] found that typical NLR values in a group of healthy, non-elderly people ranged from 0.78 to 3.53 in a sizable retrospective case-control study. In our research, we found a significant increase in deaths from any cause and cardiovascular events among diabetic adults with NLR levels above 2.48 and prediabetic adults with NLR levels above 2.29.

Our primary findings were robust and withstood rigorous sensitivity analyses. Without the influence of a baseline history of CVD and cancer, the relationship between different levels of NLR and mortality was still notable. In subgroup analyses, a noteworthy interaction is observed solely between NLR levels and baseline CVD history among prediabetes subjects. Within this subgroup, participants lacking a history of CVD exhibit a higher risk of overall mortality unexpectedly. This trend persists across three distinct models in sensitivity analyses, particularly among individuals with higher tertile NLR levels. The improvement can likely be credited to the common use of certain diabetes drugs, like GLP-1R agonists and SGLT-2 inhibitors, which have been shown to greatly enhance heart health and reduce death rates [ 38 , 39 , 40 ]. These drugs are often prescribed to diabetics with heart conditions, but people without known heart issues might not get them as promptly or at all. In diabetic participants with concurrent cardiovascular disease, the predictive value of NLR in determining cardiovascular mortality outcomes may be limited. In contrast, NLR may be more valuable in identifying adverse outcomes in participants who have not yet developed cardiovascular disease.

This prospective cohort study possesses several strengths. Notably, the routine administration of a peripheral whole blood test ensured the inclusion of a broader population, owing to its affordability and clinical relevance. As a result, the findings obtained in relation to the correlation between the NLR and the risk of mortality in individuals with diabetes and prediabetes are considered to be more reliable. Ultimately, 7246 eligible diabetes subjects and 13,024 eligible prediabetes subjects were successfully enrolled in the study. Afterward, considering that NLR is susceptible to a variety of possible factors and that there is a correlation between overall and cardiovascular mortality and hyperglycemia, we performed a thorough adjustment for known confounding variables. We developed several clinical models to fully assess the prognostic significance of NLR in the mortality of individuals with diabetes and prediabetes. Nonetheless, it is important to acknowledge that this study has some limitations, as certain unidentified confounding variables may not have been accounted for during the adjustment process. NHANES did not provide information on acute illnesses during blood collection or the reliability of neutrophil and lymphocyte counts. Participants with extreme NLR values, 1%, were removed from the analysis to reduce disease-related distortion and improve the accuracy of the initial NLR assessment. It is essential to highlight that NLR indicates the relative equilibrium between the body’s bone marrow and lymphocyte profiles, and monitoring the dynamic changes in NLR is crucial for predicting mortality outcomes in hyperglycemia adults. The NHANES database did not include any follow-up data on neutrophils and lymphocytes, thus precluding the ability to elucidate the influence of changes in NLR on mortality outcomes. Nevertheless, our study unequivocally demonstrates a positive association between elevated baseline NLR levels and increased risks of all-cause and cardiovascular mortality in participants with diabetes and prediabetes. Therefore, we expect that forthcoming prospective studies will be carried out to determine the exact significance of NLR in forecasting mortality associated with overall and cardiovascular mortality in adults with hyperglycemia.

The measurement of NLR is readily accessible and economically viable in clinical practice. Our study has demonstrated the potential of NLR as a predictive factor for mortality in subjects with both diabetes and prediabetes. In addition to conventional risk factors, it is crucial to acknowledge the impact of low-grade inflammation on the adverse outcomes of all-cause and cardiovascular disease mortality in the hyperglycemia population. It’s crucial to explore other factors that could affect NLR and tackle the difficulties in tracking its changes over time.

Data availability

All data used and analyzed in this study were available on the NHANES website.

Abbreviations

Body mass index

Computer-Assisted Personal Interviewing

Confidence intervals

Chronic obstructive pulmonary disease

Cardiovascular disease

Estimated glomerular filtration rate

Glycated hemoglobin A1c

High-density lipoprotein cholesterol

Healthy eating index

Hazard ratios

Low-density lipoprotein cholesterol

National Health and Nutrition Examination Survey

• Neutrophil-lymphocyte ratio

Total cholesterol

Triglyceride

United States

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Acknowledgements

We express our gratitude to Jing Zhang from the Second Department of Infectious Disease at Shanghai Fifth People’s Hospital, Fudan University, for his valuable contributions to the NHANES database. His exceptional efforts in developing the nhanesR package and webpage have greatly facilitated the exploration of the NHANES database.

This work is supported by the Fundamental and Applied Research Project from Joint Funding between Municipal Government and University/College (202201020073).

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Guangshu Chen and Li Che contributed equally to this work.

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Department of Endocrinology and Metabolism, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, Guangdong, China

Guangshu Chen, Meizheng Lai, Chuping Chen, Ping Zhu & Jianmin Ran

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China

Department of Hematology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China

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JR and PZ took charge of conception and design. GC and LC wrote the main manuscript text. CC prepared Figs.  1 , 2 , 3 and 4 , ML and TW prepared Table  1 , and 2 , S1 - S3 . All authors finally approved the manuscript.

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Supplementary Material 1: Table S1a

Hazard ratios of all-cause and CVD mortality by tertiles of NLR levels in diabetic subjects without baseline history of CVD. Table S1b Hazard ratios of all-cause and CVD mortality by tertiles of NLR levels in prediabetic subjects without baseline history of CVD. Table S2a Hazard ratios of all-cause and CVD mortality by tertiles of NLR levels in diabetic subjects with baseline history of CVD. Table S2b Hazard ratios of all-cause and CVD mortality by tertiles of NLR levels in diabetic subjects with baseline history of CVD. Table S3a Hazard ratios of all-cause and CVD mortality by tertiles of NLR levels in diabetic subjects without baseline history of CVD and cancer. Table S3b Hazard ratios of all-cause and CVD mortality by tertiles of NLR levels in prediabetic subjects without baseline history of CVD and cancer

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Chen, G., Che, L., Lai, M. et al. Association of neutrophil-lymphocyte ratio with all-cause and cardiovascular mortality in US adults with diabetes and prediabetes: a prospective cohort study. BMC Endocr Disord 24 , 64 (2024). https://doi.org/10.1186/s12902-024-01592-7

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DOI : https://doi.org/10.1186/s12902-024-01592-7

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Reversing Type 2 Diabetes: A Narrative Review of the Evidence

Sarah j hallberg.

1 Virta Health, 535 Mission Street, San Francisco, CA 94105, USA; moc.htlaehatriv@einimahs

2 Indiana University Health Arnett, Lafayette, IN 47904, USA; gro.htlaehui@nubzaht

3 Indiana University School of Medicine, Indianapolis, IN 46202, USA

Victoria M Gershuni

4 Department of Surgery, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA 19104, USA; moc.liamg@dminuhsregairotciv

Tamara L Hazbun

Shaminie j athinarayanan.

Background: Type 2 diabetes (T2D) has long been identified as an incurable chronic disease based on traditional means of treatment. Research now exists that suggests reversal is possible through other means that have only recently been embraced in the guidelines. This narrative review examines the evidence for T2D reversal using each of the three methods, including advantages and limitations for each. Methods: A literature search was performed, and a total of 99 original articles containing information pertaining to diabetes reversal or remission were included. Results: Evidence exists that T2D reversal is achievable using bariatric surgery, low-calorie diets (LCD), or carbohydrate restriction (LC). Bariatric surgery has been recommended for the treatment of T2D since 2016 by an international diabetes consensus group. Both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) now recommend a LC eating pattern and support the short-term use of LCD for weight loss. However, only T2D treatment, not reversal, is discussed in their guidelines. Conclusion: Given the state of evidence for T2D reversal, healthcare providers need to be educated on reversal options so they can actively engage in counseling patients who may desire this approach to their disease.

1. Introduction

According to 2017 International Diabetes Federation (IDF) statistics, there are approximately 425 million people with diabetes worldwide [ 1 ]. In the United States, there are an estimated 30.3 million adults living with diabetes, and its prevalence has been rising rapidly, with at least 1.5 million new diabetes cases diagnosed each year [ 2 ]. Diabetes is a major public health epidemic despite recent advances in both pharmaceutical and technologic treatment options.

Type 2 diabetes (T2D) has long been identified as an incurable chronic disease. The best outcome that has been expected is amelioration of diabetes symptoms or slowing its inevitable progression. Approximately 50% of T2D patients will need insulin therapy within ten years of diagnosis [ 3 ] Although in the past diabetes has been called chronic and irreversible, the paradigm is changing [ 4 , 5 ].

The recent 2016 World Health Organization (WHO) global report on diabetes added a section on diabetes reversal and acknowledged that it can be achieved through weight loss and calorie restriction [ 4 ]. “Diabetes reversal” is a term that has found its way into scientific articles and the lay press alike; “remission” has also been used. While the exact criteria are still debated, most agree that a hemoglobin A1c (HbA1c) under the diabetes threshold of 6.5% for an extended period of time without the use of glycemic control medications would qualify [ 6 ]. Excluding metformin from the glycemic control medications list, as it has indications beyond diabetes, may also be a consideration [ 7 , 8 ]. Likewise, terms such as “partial” (HbA1c <6.5 without glycemic control medications for 1 year) or “complete” (HbA1c <5.7 without glycemic control medications for 1 year) remission have been defined by an expert panel as more evidence accumulates that points to the possibility of avoiding the presumably progressive nature of T2D [ 9 ]. It is important to note that the term “cure” has not been applied to T2D, as there does exist the potential for re-occurrence, which has been well documented in the literature.

Despite the growing evidence that reversal is possible, achieving reversal is not commonly encouraged by our healthcare system. In fact, reversal is not a goal in diabetes guidelines. Specific interventions aimed at reversal all have one thing in common: they are not first-line standard of care. This is important, because there is evidence suggesting that standard of care does not lead to diabetes reversal. This raises the question of whether standard of care is really the best practice. A large study by Kaiser Permanente found a diabetes remission rate of 0.23% with standard of care [ 10 ]. The status quo approach will not reverse the health crisis of diabetes.

A significant number of studies indicate that diabetes reversal is achievable using bariatric surgery, while other approaches, such as low-calorie diets (LCD) or carbohydrate restriction (LC), have also shown effectiveness in an increasing number of studies. This review will examine each of these approaches, identifying their beneficial effects, supporting evidence, drawbacks, and degree of sustainability.

2. Materials and Methods

A literature search was performed as appropriate for narrative reviews, including electronic databases of PubMed, EMBASE, and Google Scholar from 1970 through December 2018. We reviewed English-language original and review articles found under the subject headings diabetes, bariatric surgery, metabolic surgery, very low-calorie diet, calorie restriction, low carbohydrate diet, ketogenic diet, diabetes remission, and diabetes reversal. References of the identified publications were searched for more research articles to include in this review. Selected studies were reviewed and evaluated for eligibility for inclusion in this review based on their relevance for diabetes reversal and remission. Either remission or reversal needed to be discussed in the paper or the results were consistent with these terms for inclusion. Randomized clinical trials and intervention-based studies were given emphasis for inclusion.

A total of 99 original articles containing information pertaining to diabetes reversal or remission were included in this narrative review.

3. Results and Discussion

3.1. bariatric surgery.

Bariatric surgery has long been recognized as a potential treatment for both morbid obesity and the metabolic processes that accompany it, specifically T2D. While the efficacy of T2D reversal depends on the choice of procedure, there is unilateral improvement in glycemia following operation [ 11 ], and bariatric surgery has been found to be superior to intensive T2D medical management. Accordingly, in 2016, the second Diabetes Surgery Summit (DSS-II) released recommendations, endorsed by 45 medical and scientific societies worldwide, to use bariatric surgery as a treatment for T2D (bariatric surgery is currently approved by the 2016 recommendations for adults with a body mass index (BMI) >40, or >35 kg/m 2 with obesity-related comorbidities) [ 12 ]. Of interest is the consistent finding that glycemic improvements occur rapidly, often within hours to days, and precede weight loss, which likely represents the enteroendocrine responses to altered flow of intestinal contents (i.e., bile acid signaling and changes in microbiota and their metabolome) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ].

The most commonly performed bariatric surgeries in the United States include laparoscopic and robotic Roux-en-Y Gastric Bypass (RYGB) or Sleeve Gastrectomy (SG). While surgical treatment is based on the principles of restriction and intestinal malabsorption, evidence suggests that there are more complex mechanisms at play. Bariatric surgery has consistently been shown to dramatically and rapidly improve blood glucose [ 20 ] while allowing decreased oral hypoglycemic medications and insulin use, effectively reversing diabetes in up to 80% of patients [ 21 ] in the short term. In addition to early post-operative improvement in blood glucose and insulin sensitivity, bariatric surgery has also been shown to cause alterations in GI hormone release, including ghrelin, leptin, cholecystokinin (CCK), peptide-tyrosine-tyrosine (PYY), and glucagon-like peptide 1 (GLP-1), that may impact feeding behavior via the gut–brain axis in addition to modulating euglycemia [ 22 ]. Furthermore, microbial changes in the human gut have been linked to obesity, and surgical alterations to gastrointestinal anatomy have been associated with dramatic changes in gut microbiota populations with reversion from an “obesogenic” to a lean bacterial population [ 13 , 14 , 16 , 19 , 23 , 24 ].

Long-term outcomes from bariatric surgery depend on multiple factors, including type of surgery performed, patient comorbidities, patient readiness for lifelong dietary change, and ongoing surveillance. While bariatric surgery has been demonstrated to be safe and effective overall, it is important to recognize that it is not without risks. Each patient must weigh the risks and benefits associated with untreated morbid obesity versus those associated with surgery or effective dietary management and choose accordingly. Surgery of any type can be associated with complications leading to morbidity or mortality; the complication rates have been stated to be as high as 13% and 21% for SG and RYGB, respectively. The postoperative mortality rate is 0.28–0.34% for SG and 0.35–0.79% for RYGB; in comparison, an elective laparoscopic cholecystectomy is associated with overall complication rates of 9.29% and with a 30-day mortality rate of 0.15–0.6%, depending on the series [ 25 , 26 ]. Significant complications include anastomotic leak or hemorrhage, post-operative readmission, need for reoperation, post-operative hypoglycemia, dumping syndrome, worsening acid reflux, marginal ulceration, and micronutrient deficiencies [ 25 , 26 , 27 , 28 , 29 ].

It is important to consider that while short-duration studies have shown early resolution of comorbidities following bariatric procedures, when followed for multiple decades, there may be decreased efficacy of disease resolution and increased incidence of hospital admission long-term. Long-term reversal of T2D and true glucose homeostasis remain uncertain. Weight loss after surgery is a significant predictor of a return to euglycemia post-operatively. Multiple studies have reported initial T2D remission rates as high as 80% [ 30 , 31 ], however, long-term remission is less durable. The five-year follow-up outcomes of the SLEEVEPASS RCT found complete or partial remission of T2D in 37% of SG and 45% of RYGB patients, which is similar to other studies showing long-term T2D remission in up to a third of patients [ 32 ]. In the large prospective cohort study Longitudinal Assessment of Bariatric Surgery 2 (LABS-2), the investigators found that long-term diabetes remission after RYGB was higher than predicted by weight loss alone, which suggests that the surgery itself impacts metabolic factors that contribute to disease management [ 31 ]. Similarly, the STAMPEDE trial—an RCT that followed 150 patients with T2D who were randomized to intensive medical intervention (IMT) versus IMT plus RYGB versus IMT plus SG for diabetes resolution (defined as HbA1c <6.0%) and followed for five years—revealed increased rates of T2D resolution with RYGB (29%) and SG (23%) compared to IMT alone (5%) ( Figure 1 ). The surgery cohort also demonstrated greater weight loss and improvements in triglycerides, HDL, need for insulin, and overall quality of life [ 33 , 34 , 35 ].

( A ) Mean changes of hemoglobin A1c (HbA1c) from baseline to last published date for each study retrieved to represent the three methods of reversal; ( B ) mean changes of weight from baseline to last published date for each studies retrieved to represent the three methods of reversal. Note: We chose these three studies to represent the three methods of reversal based on publication date and relevance to diabetes reversal. Note that baseline characteristics differ. Surgery trial examined by sleeve gastrectomy and Roux-en-Y gastric bypass separately and were represented as sleeve and bypass in the graph. Surgery: STAMPEDE [ 34 , 35 ]. Low-calorie diets (LCD): DIRECT [ 65 , 66 ]; carbohydrate restriction (LC): IUH [ 99 , 107 ].

Despite the likelihood of improved glycemic control, there are significant financial costs for the patient, health system, and insurance companies associated with bariatric surgery (U.S. average of $14,389) [ 36 ]. Despite the high initial cost of surgery, Pories and colleagues found that prior to surgery, patients spend over $10,000 per year on diabetes medications; after RYGB, the annual cost falls to less than $2000, which represents an $8000 cost savings at the individual level [ 30 ]. Furthermore, economic analyses show that surgery is likely to be cost-effective, especially in patients who are obese [ 37 , 38 ]. In a clinical effectiveness review of the literature that included 26 trials extracted from over 5000 references, Picot et al. found that bariatric surgery was a more effective intervention for weight loss than non-surgical options; however, there was extreme heterogeneity and questionable long-term adherence to the non-surgical interventions [ 39 ]. After surgery, metabolic syndrome improved, and there were higher rates of T2D remission compared to the non-surgical groups [ 39 ]. Further, while there were improvements in comorbidities after surgery independent of bariatric procedure, there was also an increased likelihood of adverse events. While the overall event rate remained low, major adverse events included medication intolerance, need for reoperation, infection, anastomotic leakage, and venous and thromboembolic events [ 39 ].

It is imperative to consider that one of the requirements of qualifying for bariatric surgery is demonstration of at least six months of unsuccessful attempts at weight loss using traditional dietary and exercise advice according to the 2016 Recommendations [ 12 ]. There are, however, no requirements as to what weight loss strategy is employed, which may represent a time point where dietary intervention, including low-calorie, ketogenic, or carbohydrate-restricted diets, should be utilized. At least two recent clinical trials have demonstrated safety and efficacy in pre-operative very low-carbohydrate ketogenic diets before bariatric surgery for increasing weight loss and decreasing liver volume [ 40 , 41 ].

Furthermore, despite technically adequate surgery, an alarming number of patients may still experience weight regain and/or recurrence of comorbid obesity-associated conditions. In these patients, effective strategies for dietary intervention are even more important. Approximately 10–15% of patients fail to lose adequate weight (failure defined as <50% of excess weight) or demonstrate significant weight regain after bariatric surgery without evidence of an anatomic or technical reason [ 42 ]. Additionally, in 25–35% of patients who undergo surgery, significant weight regain (defined as >15% of initial weight loss) occurs within two to five years post-operatively [ 43 ]. These patients often require further medical management with weight loss medications, further dietary and behavioral intervention, and, for some, reoperation. Reoperation can be for either revision for further weight loss (narrowing of the gastric sleeve, conversion of VSG to RYGB , and increasing the length of the roux limb) or reversal of RYGB due to health concerns, most commonly associated with malnutrition. A small cohort of patients (4%) may experience severe weight loss with significant malnutrition leading to hospitalization in over 50%, mortality rates of 18%, and need for reversal of RYGB anatomy. While the incidence of RYGB reversal is unknown, based upon a systematic review that included 100 patients spanning 1985–2015, the rate of reversal parallels the increasing rate of bariatric surgery [ 44 ].

In the short term, T2D reversal rates with surgery have been reported to be as high as 80%, with an additional 15% demonstrating partial improvement in T2D despite still requiring medication [ 17 ]. Within one week after RYGB, patients experience improved fasting hepatic insulin clearance, reduced basal de novo glucose production, and increased hepatic insulin sensitivity; by three months and one year after surgery, patients have improved beta-cell sensitivity to glucose, increased GLP-1 secretion from the gut, and improved insulin sensitivity in muscle and fat cells [ 45 ]. Over time, T2D remission rates remain high but do decline; Purnell and colleagues reported three-year remission rates of 68.7% after RYGB [ 29 ]. However, Pories published results from a 14-year prospective study with mean follow-up of 7.6 years, and found 10-year remission rates remained around 83% [ 46 ]. In a 10-year follow-up study of participants from the Swedish Obese Subjects (SOS) study that prospectively followed patients who underwent bariatric surgery, the authors reported a 72% ( n = 342) and 36% ( n = 118) recovery rate from T2D for RYGB at two years and 10 years, respectively [ 47 ].

The long-term metabolic impact and risk reduction from surgery remain high in a substantial number of patients and this route to reversal clearly has the most robust data to support its use. As evidenced by the dramatic improvements in metabolic state that precede weight loss, bariatric surgery is far more than merely a restrictive and/or malabsorptive procedure. Large shifts in bile acid signaling in the lumen of the small intestine, gut nutrient sensing, and changes in the microbiota community appear to greatly impact overall host health. Further research is ongoing using both basic and translational science models to identify the role of these various hormones and metabolites; perhaps there will be a way to one day harness the beneficial effects of bariatric surgery without the need for anatomic rearrangement.

3.2. Low-Calorie Diets (LCD)

As diabetes rates have risen to unprecedented levels [ 1 , 2 ], the number of studies examining diabetes reversal using non-surgical techniques has increased. A handful of studies have reported successful weight loss with decreased insulin resistance, plasma glucose, and medication use following a LCD. As early as 1976, Bistrian et al. [ 48 ] reported that a very low-calorie protein-sparing modified fast allowed for insulin elimination in all seven obese patients with T2D. The average time to insulin discontinuation was only 6.5 days, and the longest was 19 days. In a study by Bauman et al., a low-calorie diet of 900 kcal, including 115 g of protein, led to significant improvement in glycemic control that was mainly attributed to improvements in insulin sensitivity [ 49 ]. Furthermore, a study conducted in obese T2D patients found that a LCD and gastric bypass surgery were equally effective in achieving weight loss and improving glucose and HbA1c levels in the short term [ 50 ]. Weight loss, however, persisted in the diet-treated patients only for the first three months, indicating difficulty with long-term maintenance [ 47 ]. Similarly, other studies also reported similar pattern of early blood glucose normalization without medication use, but the improvements were not sustained long-term [ 51 , 52 , 53 ]. Likewise, the study by Wing et al., even though reported significant and greater improvements of HbA1c at 1 year in the intermittently delivered very low-calorie diet, the HbA1c improvement was not significantly different than what was reported in the patients receiving low-calorie diet (LCD) throughout the one year period [ 54 ]. Furthermore, the glycemic improvements observed at 1 year were not maintained through 2-years, even though the group with intermittent very low-calorie diet had less medication requirement than the group in the LCD arm at 2 years [ 54 ]. Lastly, micronutrient deficiencies with the use of calorie restricted diets has been shown and supplementation and monitoring for deficiencies is a consideration with their use [ 55 , 56 ].

While these previous studies were not assessing diabetes remission or reversal rate per se, they demonstrated the effectiveness of calorie restriction in achieving weight loss and improved glycemic control, which are the core goals of reversal. In 2003, the Look AHEAD trial randomized 5145 overweight or obese patients with T2D to an intervention group that received either an intensive lifestyle intervention (ILI) including calorie restriction and increased physical activity or to a control group that included diabetes support and education (DSE) [ 57 ]. Post hoc analysis of this study revealed that at one year, 11.5% of the participants in the ILI group achieved remission (partial or complete); however, remission rates subsequently decreased over time (9.2% at year two and 7.3% at year four). Nevertheless, the remission rates achieved through ILI were three to six times higher than those achieved in the DSE group. Lower baseline HbA1c, greater level of weight loss, shorter duration of T2D diagnosis, and lack of insulin use at baseline predicted higher remission rate in ILI participants [ 58 ].

Following the Look AHEAD study, other studies have evaluated a LCD for diabetes remission [ 59 , 60 , 61 ]. Most of these studies assessed remission over a short period of time in a small study sample. Bhatt et al. reported that six of the 12 individuals achieved partial remission at the end of the three-month intervention [ 61 ]. Ades et al. studied an intensive lifestyle program including calorie restriction and exercise, and reported that eight of the 10 individuals with recently diagnosed T2D achieved partial remission at six months, including one with complete remission [ 60 ]. The study ended at six months, therefore long term sustainability was not assessed. Another study assessing a one-year diabetes remission retrospectively among those undergoing 12 weeks of the intensive weight loss program “Why Wait” had a much lower remission rate of 4.5%, with 2.3% of them achieving partial remission, while another 2.3% had complete remission [ 59 ]. This study suggests that long-term maintenance of remission is a challenge. Moreover, diabetes remission was more likely reported in those who had a shorter diabetes duration, lower baseline HbA1c, and were taking fewer hypoglycemic medications [ 59 , 61 ].

An initial 2011 diabetes reversal study by Taylor and colleagues showed that a very low-calorie diet of 600 Kcal/day not only normalized glucose, HbA1c, and hepatic insulin sensitivity levels within a week, but also led to decreased hepatic and pancreatic triacylglycerol content and normalization of the insulin response within eight weeks [ 62 ]. At 12 weeks post-intervention, many of the improvements were maintained, but over a quarter of the patients had an early recurrence of diabetes. Further, average weight regain during the 12 weeks post-intervention was 20% [ 62 ]. As a follow-up to the 2011 study, the same group performed a larger and longer study with eight weeks of a very low-calorie meal replacement (624–700 kcal/day) followed by two weeks of solid food replacement and a weight maintenance program of up to six months [ 63 ]. In this study, those who achieved a fasting blood glucose of <7 mmol/L (<126 mg/dL) were categorized as responders, while others were categorized as non-responders. At six months, 40% of participants who initially responded to the intervention were still in T2D remission which was defined by achieving a fasting plasma glucose of <7mmol/L; the majority of those who remitted (60%) had a shorter diabetes duration (<4 years) [ 63 ].

These short-term studies were the foundation for a community-based cluster-randomized clinical trial called DiRECT (Diabetes Remission Clinical Trial). DiRECT enrolled a sample of 306 relatively healthy participants with T2D (people on insulin or with a diabetes duration longer than six years were excluded) [ 64 ] ( Figure 1 ). They were cluster randomized to either standard diabetes care or an intervention using low-calorie meal replacement diet (825–853 kcal/day) for three to five months, followed by stepwise food re-introduction and a long-term weight maintenance program. At one-year follow-up, 46% of patients met the study criteria of diabetes remission (HbA1c <6.5% without antiglycemic medications) [ 64 ] and at two years the remission rate was 36% [ 65 ]. The DiRECT study has extended their follow-up an additional three years to assess the long-term impact on remission.

Taken together, evidence suggests that a LCD is effective in reversing diabetes in the short term up to two years, and its effectiveness was predominantly demonstrated in those with shorter duration since diabetes diagnosis. It is important to note that a substantial level of calorie restriction is needed to generate a sufficient level of weight loss for reversing diabetes. Short-term intervention with moderate energy restriction and metformin for modest weight loss was not as effective in reversing diabetes as compared to standard diabetes care [ 66 ]. Lifestyle intervention with severe energy restriction may have some deleterious effect on the body composition and physiology, which poses a concern for long-term health [ 67 ]. Furthermore, long-term achievement of diabetes remission, adherence to the diet, and weight loss maintenance after the diet remain a challenge. Studies have also suggested that physiological and metabolic adaptation of the body in response to caloric restriction may shift energy balance and hormonal regulation of weight toward weight regain after weight loss [ 67 , 68 ]. Thus, it is crucial that future studies are directed towards assessing the long-term sustainability of diabetes remission led by LCD and feasibility of this diet on the physiological adaptation and body composition changes.

3.3. Carbohydrate-Restricted Diets (LC)

Before the discovery of insulin in 1921, low carbohydrate (LC) diets were the most frequently prescribed treatment for diabetes [ 69 , 70 ]. The paradigm shifted both with the development of exogenous insulin and later with the emergence of the low-fat diet paradigm. A diet low in fat, which by default is high in carbohydrate, became the standard recommendation in guidelines around the globe [ 71 ]. Rather than preventing elevations in glucose, the goal became maintenance of blood sugar control via the increased use of glycemic control medications, including insulin [ 72 ]. Over the last decade, clinical studies have begun to resurrect the pre-insulin LC dietary approach. In response to the new evidence on the efficacy of carbohydrate restriction, low-carbohydrate has recently been endorsed as an eating pattern by the ADA and the European Association for the Study of Diabetes (EASD) [ 5 , 73 ]. In addition, the Veterans Affairs/Department of Defense (VA/DOD) guidelines now recommend carbohydrate restriction as low as 14% of energy intake in its most recent guidelines for treatment of diabetes (VA) [ 74 ].

LC diets are based on macronutrient changes rather than a focus on calorie restriction [ 75 ]. Although the exact definition varies, a low-carbohydrate diet usually restricts total carbohydrates to less than 130 grams per day, while a very low-carbohydrate or ketogenic diet usually restricts total carbohydrates to as low as 20–30 grams per day. Protein consumption is generally unchanged from a standard ADA diet (around 20% of intake), with the remaining energy needs met by fat from either the diet or mobilized body fat stores. Carbohydrate sources are primarily non-starchy vegetables with some nuts, dairy, and limited fruit [ 75 ].

A total of 32 separate trials examining carbohydrate restriction as a treatment for T2D were found when our search was performed [ 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. However, for reasons that may include varied levels of carbohydrate restriction and differing levels of support given, not all studies had results that would be consistent with diabetes reversal. A number of shorter-term trials have found a significant between-group advantage of a low-carbohydrate intervention for T2D [ 80 , 84 , 92 , 97 ]. Data from longer-term trials are limited, and in some follow-up studies, the between-group advantage seen initially was lost or reduced, although it often remains significantly improved from baseline. This raises the question of long-term sustainability using this approach. Due to heterogeneity in methodology and definition of carbohydrate restriction, the ability to fully examine T2D reversal based on the existing studies is limited. Based upon a recent systematic review of LC, it appears that the greatest improvements in glycemic control and greatest medication reductions have been associated with the lowest carbohydrate intake [ 109 ]. In consideration of these limitations, it appears important to assess the level of carbohydrate restriction, support or other methods given to encourage sustainability, and length of follow-up.

A study comparing an ad libitum very low-carbohydrate (<20 g total) diet to an energy-restricted low-glycemic diet in T2D found greater reduction in HbA1c, weight, and insulin levels in the low-carbohydrate arm [ 89 ]. Additionally, 95% of participants in the low-carbohydrate arm reduced or eliminated glycemic control medications, compared to 62% in the low glycemic index arm at 24 weeks. Instruction was given in a one-time session with a dietician and included take-home materials for reference. A slightly longer study (34 weeks) trial [ 85 ] found that a very low-carbohydrate ketogenic diet intervention (20–50 g net carbs per day) resulted in HbA1c below the threshold for diabetes in 55% of the patients, compared to 0% of patients in the low-fat arm. The education sessions were all online and included behavior modification strategies and mindful eating which was aimed to address binge eating. New lessons were emailed to the patients weekly for the first 16 weeks and then every two weeks for the remainder of the study.

A small (34 participants) one-year study of an ad libitum, very low-carbohydrate diet compared to a calorie-restricted moderate carbohydrate diet found a significant reduction in HbA1c between groups favoring the low-carbohydrate arm [ 86 ]. At one year, 78% of participants who began the trial with a HbA1c above 6.5% no longer met the cutoff for the diagnosis of diabetes, no longer required any non-metformin medication, and significantly reduced or eliminated metformin. Total kilocalorie intake was not significantly different between the two groups, even with moderate carbohydrate restriction. Despite equal energy intake, the low carbohydrate group lost significantly more weight and had improved glycemic control, which indicates a potential mechanistic role for carbohydrate restriction itself. The support given was 19 classes over the 12-month period, tapering in frequency over time.

Another one-year trial [ 76 ] found significant HbA1c reduction in the subset of patients with diabetes ( n = 54) assigned to an ad libitum low-carbohydrate diet (<30 total grams per day), compared to an energy-restricted low-fat diet. These results remained significant after adjusting the model for weight loss, indicating an effect of the carbohydrate reduction itself. The support given was four weekly sessions during the first month, followed by monthly sessions for the remaining 11 months.

A metabolic ward study on 10 patients with T2D [ 96 ] found that 24-h glucose curves normalized within two weeks on a very low-carbohydrate diet (<21 g total per day). This was in addition to medication reduction and elimination including insulin and sulfonylureas After accounting for body water changes, the average weight loss during the two-week period was 1.65 kg (average of <2% total body weight which is similar to the results of bariatric surgery, where normoglycemia is seen prior to significant weight loss. Interestingly, despite the diet being ad libitum other than the carbohydrate limit, the average energy intake decreased by 1000 kcal per day. Assuming no further change in glycemic control, HbA1c would be 5.6% after eight weeks, which would represent a reduction of 23% from baseline. The fact that HbA1c reductions were greater than in other, longer-term outpatient studies may indicate that support of dietary changes is the key to longer-term success.

In our published trial providing significant support through the use of a continuous care intervention (CCI), we examined using a low-carbohydrate diet aimed at inducing nutritional ketosis in patients with T2D ( n = 262), compared with usual care T2D patients ( n = 87) [ 98 ] ( Figure 1 ). At one year, the HbA1c decreased by 1.3% in the CCI, with 60% of completers achieving a HbA1c below 6.5% without hypoglycemic medication (not including metformin). Overall, medications were significantly reduced, including complete elimination of sulfonylureas and reduction or elimination of insulin therapy in 94% of users. Most cardiovascular risk factors showed significant improvement [ 110 ]. The one-year retention rate was 83%, which indicates that a non-calorie-restricted, low-carbohydrate intervention can be sustained. Improvements were not observed in the usual care patients. The newly released two-year results of this trial [ 106 ] show sustained improvements in normoglycemia, with 54% of completers maintaining HbA1c below 6.5% without medication or only on metformin. The retention rate at two years was 74%, further supporting the sustainability of this dietary intervention for diabetes reversal. Weight loss of 10% was seen at 2-years despite no intentional caloric restriction instruction. Additionally, this trial involved participants with a much longer duration of diabetes (8.4 years on average) than other nutrition trial interventions [ 58 , 64 , 65 ] and did not exclude anyone taking exogenous insulin. As duration of T2D and insulin use have both been identified to be negative factors in predicting remission after bariatric surgery [ 111 , 112 ], the 2-year results of this trial may be even more significant.

It is interesting to note that most studies utilize ad libitum intake in the carbohydrate-restricted arm. Despite this, in studies that have tracked energy intake, spontaneous calorie restriction has occurred [ 113 , 114 ]. In many trials where energy intake has been prescribed or weight loss has been equal, an advantage has been seen in glycemic control, weight, or both in the low-carbohydrate arm [ 86 , 91 , 107 ]. A better understanding of the role that caloric intake, whether prescribed or spontaneous, plays in the overall success is important. In cases of spontaneous energy intake reduction, elucidating the specific mechanism behind this reduction would help in the overall personalization of this approach.

Multiple studies have evaluated side effects or potential complications of carbohydrate restriction. The diet has been found to be safe and well tolerated although long term hard outcome data is lacking and should be a focus of future research. A transient rise in uric acid early in very low-carbohydrate restriction without an associated increase in gout or kidney stones has been documented [ 84 , 98 , 100 ]. Blood urea nitrogen (BUN) has been found to increase and decrease in different studies without an associated change in kidney function [ 87 , 98 , 100 , 115 , 116 ]. Recently, bone mineral density has been found to be unchanged despite significant weight loss after two years of a ketogenic diet intervention in patients with T2D [ 108 ]. While most studies show an improvement or no change in LDL-C levels in patients with T2D on a low-carbohydrate diet, there have been two studies that have found an increase in LDL-C in participants with T2D [ 99 , 111 ]. In one of the studies that found an increase in calculated LDL-C, a non-significant reduction in measured ApoB lipoproteins and unchanged non-HDL cholesterol were seen. Monitoring LDL-C or a measured value of potentially atherogenic lipoproteins such as ApoB should be considered. Lastly, micronutrient deficiency has been seen with a carbohydrate restricted diet, supplementation and monitoring should be given consideration with this intervention [ 56 ].

Although the use of very low-carbohydrate diets for diabetes reversal shows promising results, the lack of longer-term follow-up studies remains a limitation. Follow up is limited to two years, and therefore longer-term studies are needed to determine the sustainability of the metabolic improvements. Determining the appropriate method of support may be a key to the overall success with disease reversal.

Additional evidence has become available in recent years suggesting that diabetes reversal is a possible alternative to consider in place of traditional diabetes treatment and management. In this paper, we provide a review of three methods that have been shown to successfully reverse type 2 diabetes. The current body of evidence suggests that bariatric surgery is the most effective method for overall efficacy and prolonged remission, even though concerns associated with surgical complications, treatment cost and complete lifestyle modification after surgery remain challenges for wide adoption of this approach. While both the LCD and LC dietary approaches are convincing for reversing diabetes in the short term (up to two years), long term maintenance of diabetes remission is still unproven. There are limited available data supporting long term maintenance of weight loss and its associated glycemic improvements in response to LCD; similarly, long-term adherence to a low carbohydrate diet will likely remain an obstacle without the development of proper patient education and optimal support for long-term behavioral change. Moreover, research in understanding the mechanism of diabetes reversibility in all three approaches and its overlapping mechanistic pathways are lacking; this is an area for future research emphasis.

There are similar identified negative predictors of remission for all three approaches. These factors include longer diabetes duration and increased severity, lower BMI, advanced age, poor glycemic control, and low C-peptide levels (indicating decreased endogenous insulin production) [ 117 ]. Further exploration into the heterogeneity of these factors will help personalize the approach, determine realistic goals for each patient, and should be considered during treatment discussions. Ongoing research into algorithm development will be helpful in this regard.

5. Conclusions

Overall, as a society we can no longer afford or tolerate the continued rising rates of diabetes. Despite many barriers within the healthcare system as a whole, providers are responsible on a daily basis for the lives of patients caught up in this unprecedented epidemic. The current standard of care may be suitable for some, but others would surely choose reversal if they understood there was a choice. The choice can only be offered if providers are not only aware that reversal is possible but have the education needed to review these options in a patient-centric discussion.

Acknowledgments

We thank James McCarter and Stephen Phinney for their edits, which greatly improved the manuscript.

Abbreviations:

Author contributions.

Conceptualization, S.J.H. and S.J.A. Investigation, S.J.H., V.M.G., T.L.H., S.J.A. Writing—original draft, S.J.H., V.M.G., S.J.A. Writing—review and editing, S.J.H., V.M.G., T.L.H., S.J.A. All authors approved of the final manuscript.

Conflicts of Interest

S.J.H. is an employee and shareholder of Virta Health, a for-profit company that provides remote diabetes care using a low-carbohydrate nutrition intervention, and serves as an advisor for Atkins Corp. V.M.G. has no conflicts of interest to declare. T.L.H. is an employee of Virta Health. S.J.A. is an employee and shareholder of Virta Health.

'Surprisingly' high number of adults in the U.S. at risk of heart syndrome

Nearly 90% of adults over age 20 in the United States are at risk of developing heart disease , an alarming new study suggests. 

While the unexpectedly high number doesn't mean that the majority of adults in the U.S. have full-blown heart disease, it does indicate that many are at risk of developing the condition, even younger people.

Researchers identified people at high risk using a recently defined syndrome that takes into account the strong links between heart disease, obesity, diabetes and kidney disease, according to the research published Wednesday in JAMA.

The American Heart Association alerted doctors in October about cardiovascular-kidney-metabolic (CKM) syndrome , a condition which affects major organs in the body, including the brain, heart, liver and kidneys. CKM is diagnosed in stages ranging from zero — no risk factors for heart disease — to 4 — people with diagnosed heart disease plus excess body fat, metabolic risk factors such as hypertension and diabetes, or kidney disease.

For the new study, researchers analyzed almost a decade’s worth of data from more than 10,000 people who were participating in the National Health and Nutrition Examination Survey (NHANES).

“We absolutely were surprised that almost 90% of people met the criteria,” said study co-author Dr. Rahul Aggarwal, a cardiology fellow at Brigham and Women’s Hospital, Harvard Medical School, in Boston. “It was much higher than we anticipated in a database that included younger adults.”

Especially concerning was the finding that almost 50% of the NHANES participants were at stage 2 of CKM, meaning that they were at moderate risk because they had either high blood sugar, hypertension, high cholesterol or chronic kidney disease, Aggarwal said.

Just more than a quarter of the group — people listed as stage 1 — were at increased risk of developing heart disease because of being obese or overweight, having excess belly fat and fat around their organs, but didn't have specific symptoms.

The researchers found that 15% of the participants had advanced disease, a number that remained fairly constant between 2011 and 2020.  

“I think one of the biggest factors contributing to the fact that the percentage of people in advanced stages is not improving is obesity, which is very prevalent in the U.S.,” Aggarwal said, adding that 40% of people in America are obese. Another 32% are overweight based on body mass index calculations , according to the Centers for Disease Control and Prevention. 

Carrying excess pounds increases the likelihood a person will have high blood pressure, high blood sugar and high cholesterol, although some have metabolic risk factors even if they are at a healthy weight.

 Participants older than 65 were more likely to be at an advanced stage than people between 45 to 64. But being young wasn’t as protective as one might assume. Only 18% of people ages 20 through 44 were at stage zero. That is, they had no risk factors.  

The new findings show that health care providers need to be picking up on these conditions earlier “before they lead to downstream effects,” such as increased risk of heart attack, heart failure and stroke, Aggarwal said. “We need to diagnose earlier and be more aggressive at treating people.”

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Adopting lifestyle changes, such as improved diets and increased activity, can help protect against heart attack and stroke.The findings also show that “young adults, those younger than 45, are not as healthy as we thought they were,” Aggarwal said. 

Experts were also surprised by the high rates of CKM. 

“It is alarming that 90% of the population is at least stage 1 and only 10% have no risk factors,” said Dr. Sripal Bangalore, a professor of medicine and director of invasive and interventional cardiology at NYU Langone Health in New York City. 

He blames the epidemic of overweight and obesity for those numbers. 

“We have a lot of work to do to reduce the rates of overweight and obesity,” Bangalore said. “If we can do that, then hopefully we can reduce the number of people who progress to stage 2 and also move the needle down for higher stages.”

The inclusion of kidney disease in the risk assessments for cardiovascular disease makes a lot of sense, said Dr. Adriana Hung, a kidney specialist and epidemiologist and a professor of medicine at the Vanderbilt University Medical Center in Nashville, Tennessee. 

“Kidney disease magnifies cardiovascular disease,” she said. “Some studies show that a patient has as much as six times the risk of dying from cardiovascular disease if kidney disease is also present.”

The new, broader approach to heart disease is likely to help identify more people who are at risk, said Dr. Robert Rosenson, director of lipids and metabolism for the Mount Sinai Health System in New York City. 

“The main message from this study should be that many common behaviors are leading to an accumulation of diseases over one’s lifetime, which will impact quality of life and survival,” he said. 

The large numbers of people with CKM in this study are related to overweight and obesity, insulin resistance and a diet that is high in fat and salt, Rosenson added. 

People need to realize that it’s not just the heart that is being harmed by unhealthy diets and lack of exercise, he said, but that lifestyle factors also have an effect on cognition.

Linda Carroll is a regular health contributor to NBC News. She is coauthor of "The Concussion Crisis: Anatomy of a Silent Epidemic" and "Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings." 

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Semaglutide can produce clinically meaningful weight loss and reduce waist size for at least 4 years in adults with overweight or obesity who don’t have diabetes, and delivers cardiovascular benefits irrespective of weight lost

European Association for the Study of Obesity

Two important studies based on the largest and longest clinical trial of the effects of semaglutide on weight in over 17,000 adults with overweight and obesity but not diabetes find patients lost on average 10% of their body weight and over 7cm from their waistline after 4 years.

Clinically meaningful weight loss was achieved by men and women of all races, ages, and body sizes, across all regions, with a lower rate of serious adverse events compared with placebo.

Over half of adults taking semaglutide moved down at least one BMI category after 2 years compared to 16% receiving placebo; and 12% reached a healthy BMI (25 kg/m² or less) compared with 1% in the placebo group.

Importantly, the findings also indicate that semaglutide delivers cardiovascular benefits irrespective of starting weight and the amount of weight lost—suggesting that even patients with mild obesity or those not losing weight are likely to gain some advantage.

Two important studies are being presented at this year’s European Congress on Obesity (ECO) in Venice, Italy (12-15 May), based on the landmark Semaglutide and Cardiovascular Outcomes (SELECT) trial from the same international author group. The first new study, led by Professor Donna Ryan from Pennington Biomedical Research Centre, New Orleans, USA, and being published simultaneously in Nature Medicine , examines the long-term weight effects of semaglutide. The second study led by led by Professor John Deanfield from University College London, UK, investigates whether the cardiovascular benefits are related to starting weight or the amount of weight lost.

Semaglutide is a GLP-1 medication primarily prescribed for adults with type 2 diabetes but is also approved for weight loss in people with obesity or overweight who have at least one other health issue. This class of medications simulate the functions of the body’s natural incretin hormones, which help to lower blood sugar levels after a meal. Adjusting these hormone levels can also make people feel full, and in doing so, helps lower their daily calorie intake.

In 2023, the SELECT trial reported that adults with overweight or obesity but not diabetes taking semaglutide for more than 3 years had a 20% lower risk of heart attack, stroke, or death due to cardiovascular disease, and lost an average 9.4% of their bodyweight [1]. 

Between October 2018 and June 2023, 17,604 adults (aged 45 or older; 72% male) from 804 sites in 41 countries with overweight or obesity (BMI of 27 kg/m² or higher) were enrolled and treated with Semaglutide (2.4mg) or placebo for an average of 40 months. They had previously experienced a heart attack, stroke and/or had peripheral artery disease, but did not have type 1 or type 2 diabetes when they joined the study.

The researchers examined markers of obesity that include body composition and fat distribution (waist circumference and waist circumference-to-height ratio [WHtR]), rather than just BMI alone, to help clarify the effect of semaglutide on central abdominal fat which has been proven to cause greater cardiovascular risk than general obesity.

Clinically meaningful weight loss in all sexes, races, body sizes, and regions

The first new study shows that once-weekly treatment with semaglutide can produce clinically meaningful and sustained weight loss and decrease waist size for at least 4 years in adults with overweight or obesity who do not have diabetes, with a lower rate of serious adverse events compared with placebo.

Importantly, men and women of all races, ages, and body sizes, across all geographical regions were able to achieve sustained, clinically meaningful weight loss.

“Our long-term analysis of semaglutide establishes that clinically relevant weight loss can be sustained for up to 4 years in a geographically and racially diverse population of adults with overweight and obesity but not diabetes,” says Professor Ryan. “This degree of weight loss in such a large and diverse population suggests that it may be possible to impact the public health burden of multiple obesity-related illnesses. While our trial focused on cardiovascular events, many other chronic diseases including several types of cancer, osteoarthritis, and anxiety and depression would benefit from effective weight management.”

In the semaglutide group, weight loss continued to week 65 and was sustained for 4 years, with participants’ losing on average 10.2% of their body weight and 7.7cm from their waistline, compared with 1.5% and 1.3cm respectively in the placebo group.

Similarly, in the semaglutide group, average WHtR fell by 6.9% compared with 1% in the placebo group.

These improvements were seen across both sexes and all categories of race and age, irrespective of starting blood sugar (glycaemic) status or metabolically unhealthy body fat. However, women taking semaglutide tended to lose more weight on average than men, and Asian patients lost less weight on average than other races.

Interestingly, after 2 years over half (52%) of participants treated with semaglutide had transitioned to a lower BMI category compared with 16% of those given placebo. For example, the proportion of participants with obesity (BMI 30kg/m² or higher) declined from 71% to 43% in the semaglutide group, and from 72% to 68% in the placebo group. Moreover, 12% of adults in the semaglutide group achieved a healthy weight (BMI 25kg/m² or less) compared with 1.2% in the placebo group

For each BMI category (<30, ≤30-<35, ≤35-<40, and ≥40 kg/m2) there were lower rates (events per 100 years of observation) of SAEs with semaglutide (43.23, 43.54, 51.0, 47.06) than with placebo (50.48, 49.66, 52.73, 60.85) respectively.

There were no unexpected safety issues with semaglutide in the SELECT trial. The proportion of participants with serious adverse events (SAEs) was lower in the semaglutide group than the placebo group (33% vs 36%), mainly driven by differences in cardiac disorders (11.5% vs 13.5%).   More patients receiving semaglutide discontinued the trial due to gastrointestinal symptoms, including nausea and diarrhoea, mainly during the 20-week dose escalation phase. Importantly, semaglutide did not lead to an increased rate of pancreatitis, but rates of cholelithiasis (stones in gallbladder) were higher in the semaglutide group.   

Cardiovascular benefits irrespective of weight loss

The second study examined the relationship between weight measures at baseline, and change in weight during the study with cardiovascular outcomes.  These included time to first major adverse cardiovascular event (MACE) and heart failure measures.

The findings showed that treatment with semaglutide delivered cardiovascular benefits, irrespective of the starting weight and the amount of weight lost. This suggests that even patients with relatively mild levels of obesity, or those who only lose modest amount of weight, may have improved cardiovascular outcome.

“These findings have important clinical implications”, says Professor Deanfield. “Around half of the patients that I see in my cardiovascular practice have levels of weight equivalent to those in the SELECT trial and are likely to derive benefit from taking Semaglutide on top of their usual level of guideline directed care.” 

He adds, “Our findings show that the magnitude of this treatment effect with semaglutide is independent of the amount of weight lost, suggesting that the drug has other actions which lower cardiovascular risk beyond reducing unhealthy body fat. These alternative mechanisms may include positive impacts on blood sugar, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels, or a combination of one or more of these.”

Despite these important findings, the authors caution that SELECT is not a primary prevention trial so that the data cannot be extrapolated to all adults with overweight and obesity to prevent MACE; and despite being large and diverse, it does not include enough individuals from different racial groups to understand different potential effects.

Nature Medicine

COI Statement

DR is an Advisor/consultant: Altimmune, Amgen, Biohaven, Calibrate, Carmot, CINRx, Currax, Epitomee, Gila, Ifa Celtic, Lilly, Nestle, Novo Nordisk, Scientific Intake, Structure Therapeutics, Wondr Health, Xeno Bioscience, Zealand. Speaker’s Bureau: Novo Nordisk, Lilly. Stock Options: Epitomee, Calibrate, Roman, Scientific Intake, Xeno. Research: SELECT Steering Committee (Novo Nordisk). DSMB: IQVIA setmelanotide (2); Lilly(1). JD received CME honoraria and/or consulting fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis,  Sanofi, Takeda, Novo Nordisk, Bayer. Research grants from British Heart Foundation, MRC(UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate, Roche.  Member of Study Steering Committees for Novo Nordisk (SOUL and SELECT) Editorial support was provided by Richard Ogilvy-Stewart of Titan, OPEN Health Communications, and funded by Novo Nordisk A/S, in accordance with Good Publication Practice guidelines (www.ismpp.org/gpp-2022). Funding Research relating to this abstract was funded by Novo Nordisk.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Can weight-loss drugs such as Ozempic also treat addiction and dementia?

Studies show active ingredient semaglutide can reduce the risk of heart attack, improve fertility and help treat diabetes

It is a drug that has dominated headlines, first as a medication for type 2 diabetes, then as a weight-loss aid. Now it seems semaglutide – often called by its brand names Ozempic or Wegovy – could bring benefits in myriad areas of healthcare, from addiction to dementia.

Semaglutide, which can be taken as a tablet or via injection, mimics a hormone produced in the body called GLP-1 – a substance that is released in the gut when we eat.

GLP-1, and hence also semaglutide, slows the rate at which food is digested in the stomach, and acts on the brain to reduce appetite. Crucially, it also triggers an increase in the production of insulin – a hormone that plays an important role in regulating blood sugar levels.

Myriad studies have shown regular dosing with semaglutide results in significant improvements in blood sugar control in people with type 2 diabetes – although some trials have been funded by the maker of the drug , Novo Nordisk.

As a result, drugs such as semaglutide are available on the NHS for people with type 2 diabetes and are considered a valuable tool.

Weight loss

A key finding from studies looking at semaglutide for type 2 diabetes was that the drug is associated with a reduction in body weight. As a result, semaglutide has found a new market as a slimming aid in people without type 2 diabetes, nicknamed the “skinny jab”.

Research published in the New England Journal of Medicine , involving 1,961 overweight obese adults without type 2 diabetes, found that while those given a placebo in addition to lifestyle interventions lost an average of 2.6kg over the course of the 68-week study, those given a weekly injection with semaglutide alongside lifestyle interventions lost 15.3kg on average.

Experts say drugs such as semaglutide are an important tool for managing the obesity crisis but many also warn that such drugs do not tackle the root cause of the issue.

At present GLP-1 mimics, including semaglutide, are available for some groups on the NHS, although prescriptions can only be given for a maximum of two years because of a lack of long-term data.

However, results from a trial known as the Select study have shown that continued treatment for four years is not only safe but associated with sustained weight loss.

“It is very encouraging that continued treatment for four years or so is effective in helping people to lose weight at a clinically significant level of 10% on average,” said Tricia Tan, professor of metabolic medicine and endocrinology at Imperial College London.

“Previously, the only evidenced and effective long-term treatment for obesity was weight-loss surgery where we have evidence that surgery is capable of giving long-term weight loss for 20 years or so. This trial helps to support the idea that semaglutide is effective at least in the medium-term.”

But semaglutide is not without side-effects , with some quitting the study because they felt sick or experienced diarrhoea.

Heart attacks

The Select study previously suggested a weekly dose of semaglutide could reduce the risk of heart attack, stroke and death from cardiovascular causes in overweight or obese adults with pre-existing cardiovascular disease by about 20%.

However analysis of the research – yet to be published – has revealed the proportional reduction in such events holds regardless of participants’ starting weight.

The results have led some experts to suggest semaglutide should be routinely prescribed to treat cardiovascular illnesses. However others say there are still unknowns –including the mechanism involved – that may limit such applications.

Studies have suggested the rate of dementia is lower in people with type 2 diabetes who take GLP analogues, such as semaglutide, compared with those given a placebo.

As a result, researchers have teamed up with manufacturers to run trials exploring whether the drug could help people with early Alzheimer’s disease.

“ In our study we are giving it to people who do not have dementia but are at risk through having high levels of the Alzheimer’s disease protein amyloid in-brain,” said Dr Ivan Koychev of the University of Oxford.

When it comes to dementia, there are several mooted mechanisms by which semaglutide might being benefits, from reducing inflammation in the brain, to reducing the accumulation of proteins associated with Alzheimer’s disease .

“This class of drugs is [also] known to reduce risk of vascular events and so the effect on dementia may be through reducing the incidence of major strokes or reducing the likelihood of smaller blood vessel scarring,” added Koychev.

While Koychev is optimistic, it is worth noting many highly promising dementia drugs have fallen by the wayside as trials progressed.

This is a promising area for semaglutide given the drug appears to not only dampen the reward system associated with food but drugs, too.

Indeed research has previously suggested GLP-1 analogues are associated with reduced alcohol consumption and a greater chance of smoking abstinence. Studies in mice and rats have also suggested the medications change addictive behaviours, reducing drug-seeking and consumption.

However large scale, robust studies in humans are needed, while it is unclear if such drugs dampen reward signalling generally in the brain – raising concerns around their use in people with depression.

• Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is thought to affect 8-13% of women of reproductive age , and can cause irregular periods, hormone imbalances and infertility.

While it is thought semaglutide might help people with PCOS because of its effects on weight loss, experts have suggested other mechanisms could also be at play.

Trials are now under way to explore whether semaglutide could help boost rates of ovulation among those with PCOS – an outcome that could also improve fertility – as well as its impact on levels of hormones, including testosterone.

While there have been concerns that GLP-1 mimics might raise the risk of thyroid and pancreatic cancers, recent research has cast doubt on these worries .

Studies have even suggested such drugs could help to reduce the risk of certain cancers, with research published last year suggesting they are associated with reduced risk of colorectal cancer in people with type 2 diabetes both with and without extra body weight.

With more pronounced effects found in overweight and obese patients, the authors say the results could, at least in part, be down to such drugs helping people to lose weight.

Prof Simon Cork of Anglia Ruskin University said the theory makes sense.

“Obesity is known to increase the risk of at least 13 different types of cancer so reducing body weight would almost certainly reduce ones risk for those particular cancers,” he said.

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