recent research on diabetes mellitus

New Report Highlights Diabetes Research Advances and Achievements

Today, the American Diabetes Association® (ADA) released its 2023 Research Report , highlighting investments in advancing diabetes research and clinical practice. ADA research grants focused on innovative projects with high impact and helped researchers establish collaborative networks to move their innovations into the hands of people living with diabetes.

“Research at the ADA is the engine that drives clinical advances by catapulting them into practice. 2023 has brought many prominent achievements. We are incredibly proud of our legacy of highlighting science and eager to build on this research to move even closer to a world free of diabetes and all its burdens,” said Charles “Chuck” Henderson, the ADA’s chief executive officer.

The report highlights include:

Support behavioral and mental health of people with diabetes
Tackle the epidemic of youth-onset type 2 diabetes
Improve the lives of women living with diabetes
Increased investment in early career researchers by expanding funding opportunities for postdoctoral fellowship awards to ensure these researchers can stay within the field of diabetes.
Takeaways from the 2023 Scientific Sessions, where researchers from all over the world shared the latest progress and study results with the global diabetes community.
Identify and address disparities in access and outcomes for Hispanic/Latino communities
Implement virtual interventions for those living with type 1 diabetes
Improve outcomes for the deaf community through specially designed diabetes self-management education and support (DSMES)

In addition, the report provides an update on the Pathway to Stop Diabetes® (Pathway) program, which pairs talented early-career scientists with mentorship from world-renowned diabetes scientists to drive research innovation free from traditional project constraints. This year, through the Pathway program, ADA dedicated over $4.8 million dollars in new grant funding to support breakthroughs in translation and clinical science, technology, care, and potential cures in the field of diabetes.

To learn more about the ADA’s research findings and ongoing areas of study, visit professional.diabetes.org .

About the American Diabetes Association The American Diabetes Association (ADA) is the nation’s leading voluntary health organization fighting to bend the curve on the diabetes epidemic and help people living with diabetes thrive. For 83 years, the ADA has driven discovery and research to treat, manage, and prevent diabetes while working relentlessly for a cure. Through advocacy, program development, and education we aim to improve the quality of life for the over 136 million Americans living with diabetes or prediabetes. Diabetes has brought us together. What we do next will make us Connected for Life ® . To learn more or to get involved, visit us at diabetes.org or call 1-800-DIABETES (1-800-342-2383). Join the fight with us on Facebook ( American Diabetes Association ), Spanish Facebook ( Asociación Americana de la Diabetes ), LinkedIn ( American Diabetes Association ), Twitter ( @AmDiabetesAssn ), and Instagram ( @AmDiabetesAssn ).

Contact Virginia Cramer for press-related questions.

Give Today and Change lives!

With your support, the American Diabetes Association® can continue our lifesaving work to make breakthroughs in research and provide people with the resources they need to fight diabetes.

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Diabetes mellitus-Progress and opportunities in the evolving epidemic

Affiliations.

1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: [email protected].
2 Department of Pediatrics, Division of Endocrinology & Diabetes, Department of Genetics, Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
4 Division of Endocrinology, Diabetes and Metabolism, The Ohio State University College of Medicine, Columbus, OH, USA.
5 Department of Metabolism, Digestion and Reproduction, Imperial College London, and Imperial College NHS Trust, London, UK.
6 Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
7 Howard Hughes Medical Institute, Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
8 Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
9 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada.
PMID: 39059357
PMCID: PMC11299851 (available on 2025-07-25 )
DOI: 10.1016/j.cell.2024.06.029

Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.

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Conflict of interest statement

Declaration of interests E.D.A. has served as a consultant within the past 12 months to Amgen and Pfizer, Inc. C.E.-M. has served on advisory boards for Isla Technologies, Avotres, DiogenyX, and Neurodon. She is a member of the INNODIA external advisory board, has received in-kind research support from Bristol Myers Squibb and Nimbus Pharmaceuticals, and investigator-initiated grants from Lilly Pharmaceuticals and Astellas Pharmaceuticals. A.L.G.’s spouse is employed by Genentech and holds stock options in Roche. J.J.J. is a board member for Buckeye Health Plan. S.M. has received speaker Honoraria from Lilly and Sanofi, UK. K.S. has served as consultant within the past 12 months to Otsuka, Pfizer, Jnana, Maze, Chinook/Novartis, and her laboratory received funding from Astra Zeneca, Boehringer Ingelheim, Genentech, Gilead, Novartis, Novo Nordisk, Regeneron, ONO Pharma, KKC, and Calico. J.S. has served as an invited speaker to Altos and Sanford Burnham Prebys in the last 12 months. D.J.D. has served as a consultant or speaker within the past 12 months to Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Kallyope, Merck Research Laboratories, Novo Nordisk Inc., Pfizer Inc., and Zealand Pharma. Neither D.J.D. nor his family members hold issued stock directly or indirectly in any of these companies. D.J.D. holds non-exercised options in Kallyope.

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Semaglutide seems beneficial for comorbid type 2 diabetes mellitus, tobacco use disorder

by Elana Gotkine

Semaglutide seems beneficial for comorbid T2DM, tobacco use disorder

For patients with type 2 diabetes mellitus (T2DM) and tobacco use disorder (TUD), new use of semaglutide is associated with lower risk of TUD-related health care measures compared with other antidiabetes medications, according to a study published online July 30 in the Annals of Internal Medicine .

William Wang, from the Case Western Reserve University School of Medicine in Cleveland, and colleagues examined the association of semaglutide with TUD-related health care measures in patients with comorbid T2DM and TUD in an emulation target trial. Seven target trials were emulated among eligible patients comparing the new use of semaglutide with seven other antidiabetes medications. The analyses included 222,942 new users of antidiabetes medications, of whom 5,967 were new users of semaglutide.

The researchers found that compared with other antidiabetes medications, semaglutide was associated with a significantly lower risk for medical encounters for TUD diagnosis, with the strongest association compared with insulins (hazard ratio, 0.68) and the weakest, but statistically significant, association compared with other glucagon-like peptide 1 receptor agonist medications (hazard ratio, 0.88).

Reduced smoking cessation medication prescription and reduced counseling were seen in association with semaglutide. Patients with and without a diagnosis of obesity had similar findings.

"Although our results may be consistent with the hypothesis that semaglutide might be beneficial for smoking cessation, study limitations preclude firm conclusions and should not be interpreted to justify clinicians' use of semaglutide off-label for smoking cessation," the authors write.

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Future Surge in Diabetes Could Dramatically Impact People Under 20 in U.S.

For Immediate Release: Thursday, December 29, 2022 Contact: Media Relations (404) 639-3286

The number of young people under age 20 with diabetes in the United States is likely to increase more rapidly in future decades, according to a new modeling study published today in Diabetes Care . Researchers forecasted a growing number of people under age 20 newly diagnosed with diabetes during 2017–2060.

This expected upward trend may lead to as many as 220,000 young people having type 2 diabetes in 2060 —a nearly 700% increaseand the number of young people with type 1 diabetes could increase by as much as 65% in the next 40 years. Even if the rate of new diabetes diagnoses among young people remains the same over the decades, type 2 diabetes diagnoses could increase nearly 70% and type 1 diabetes diagnoses could increase 3% by 2060.

Type 1 diabetes remains more common in U.S. youth, but type 2 diabetes has substantially increased among young people over the last two decades. Given this upward trend, a total of 526,000 young people may have diabetes (including both type 1 and type 2 diabetes) by 2060. Comparatively, 213,000 young people in the United States had diabetes in 2017.

“This new research should serve as a wake-up call for all of us. It’s vital that we focus our efforts to ensure all Americans, especially our young people, are the healthiest they can be,” said CDC Acting Principal Deputy Director Debra Houry, MD, MPH. “The COVID-19 pandemic underscored how critically important it is to address chronic diseases, like diabetes. This study further highlights the importance of continuing efforts to prevent and manage chronic diseases, not only for our current population but also for generations to come.”

In addition to the overall predictions, analyses of these data by race and ethnicity predicted a higher burden of type 2 diabetes for Black, Hispanic/Latino, Asian, Pacific Islander, and American Indian/Alaska Native youth.

“Increases in diabetes—especially among young people—are always worrisome, but these numbers are alarming,” said Christopher Holliday, PhD, MPH, MA, FACHE, director of CDC’s Division of Diabetes Translation. “This study’s startling projections of type 2 diabetes increases show why it is crucial to advance health equity and reduce the widespread disparities that already take a toll on people’s health.”

There could be several explanations for the rise in type 2 diabetes, including the increasing prevalence of childhood obesity. The presence of diabetes in people of childbearing age might be another important factor, because maternal diabetes increases risk of diabetes in children.

People with diabetes are at higher risk for heart disease or a stroke, diabetes complications, and premature death than those who do not have diabetes. Researchers are actively investigating ways of preventing type 1 diabetes and studies in adults have identified steps that can be taken to reduce the risk factors for type 2 diabetes. To learn more about diabetes and how to prevent type 2 diabetes visit https://www.cdc.gov/diabetes/prevention-type-2/ .

These findings come from the SEARCH for Diabetes in Youth study, funded by the Centers for Disease Control and Prevention and the National Institutes of Health.

### U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

CDC works 24/7 protecting America’s health, safety and security. Whether diseases start at home or abroad, are curable or preventable, chronic or acute, or from human activity or deliberate attack, CDC responds to America’s most pressing health threats. CDC is headquartered in Atlanta and has experts located throughout the United States and the world.

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COVID-19 and Incident Diabetes—Recovery Is Not So Sweet After All

1 Center for Community Health Integration, Case Western Reserve University, Cleveland, Ohio
2 Center for Artificial Intelligence and Drug Discovery, Case Western Reserve University, Cleveland, Ohio
Original Investigation Association of COVID-19 Infection With Incident Diabetes Zaeema Naveed, MBBS, PhD; Héctor A. Velásquez García, MD, PhD; Stanley Wong, MS; James Wilton, MPH; Geoffrey McKee, MD; Bushra Mahmood, PhD; Mawuena Binka, PhD; Drona Rasali, PhD; Naveed Z. Janjua, MBBS, DrPH JAMA Network Open

Infection with SARS-CoV-2 leads not only to acute disease but also to long-term consequences. Post–COVID-19 condition (colloquially called long COVID ) is the most frequent of the postacute sequelae of COVID-19, but SARS-CoV-2 infection can trigger or accelerate other debilitating and costly chronic diseases, including cardiac and neurological disorders. Naveen and colleagues 1 add their Canadian study to the international reports 2 , 3 of increased occurrence of diabetes following SARS-CoV-2 infection. A meta-analysis 2 of reports from the US, Norway, the UK, Germany, and multisite consortia found an overall 66% increase in the incidence of new-onset diabetes following SARS-CoV-2 infection. Another review 3 showed that 12 of 14 population-based studies found significantly increased incidence of diabetes following COVID-19, with excess cases ranging from 11% to 276% above control. Where subanalyses were conducted, the rates were usually higher among men than among women, and new diagnoses tended to occur in the first few months following infection and were more likely in patients with more severe COVID-19 infection. Since most studies were conducted in adults, it is likely that most of the new cases are type 2 diabetes, but separation of type 1 diabetes and type 2 diabetes may be difficult in population studies. However, in a US study 4 using electronic health records that was restricted to children with a specified diagnoses of type 1 diabetes, even children younger than 10 years of age had an increased risk of new diagnoses. Naveen and colleagues 1 report a significant, although modest, increase in new diagnosis of diabetes in British Columbia, Canada, among adult men following SARS-CoV-2 infection compared with men who tested negative for SARS-CoV-2 at about the same time. In addition, they provide compelling evidence that the increase in diagnoses of diabetes was associated with severity of COVID-19, with a hazard ratio of 2.42 (95% CI, 1.87-3.15) for persons hospitalized with COVID-19, and a hazard ratio of 3.29 (95% CI, 1.98-5.48) for those who required intensive care. 1 For those with severe COVID-19, the increase in new diagnoses of diabetes was significant for women as well. Results were significant only for non–insulin-dependent diabetes, although this finding may not represent a clean separation into type 2 and type 1 disease. This study 1 represents a population-based investigation that adds to the existing literature suggesting an increased risk for developing diabetes following COVID-19.

There is good reason to expect an impact of SARS-CoV-2 on new diagnoses of diabetes. SARS-CoV-2 infects pancreatic β-cells via the angiotension-converting enzyme 2 receptor and causes apoptosis, 5 which could accelerate manifestations of type 1 or type 2 diabetes. In addition, the stress from severe symptomatic COVID-19 infection can activate the endoplasmic reticulum stress response in β-cells, leading to apoptosis. Such a stress may move a patient from a prediabetic state into diabetes. Another factor may be that SARS-CoV-2 infection provokes production of autoantibodies, more so in those with severe COVID-19. 6 It is reasonable to speculate that anti–β-cell antibodies could be generated in susceptible individuals. A patient accumulating such antibodies and progressing toward type 1 diabetes could have its manifestations accelerated by additional autoantibodies. Finally, several viral infections have been associated with development of type 1 diabetes by mechanisms that are uncertain, 7 and SARS-CoV-2 may fall into this category. Interestingly, for some of these viruses, such as hepatitis C, treatment of the viral disease reduces the subsequent development of diabetes. 8 In the short term, the stress response of hyperglycemia during the acute COVID-19 illness could require treatment but then subside when the stress is relieved by resolution of the infection.

Naveen and colleagues 1 estimate that in their population, the COVID-19 pandemic was associated with a 3% to 5% increase in the number of persons with diabetes. If this proportion is similar in the US, it will represent a substantial financial burden. In 2017, the cost of diabetes care was estimated at $237 billion, not including lost productivity, 9 so a 5% increase would cost an additional $12 billion per year. Now, 6 years later, the cost is probably much greater. In addition, Naveen et al 1 studied only adults, but US children also had an increased incidence rate of diabetes following COVID-19, 4 so the length of time that these increased costs will accumulate will be even greater.

How can we use the information from these international studies? It is important to better understand the trajectory of new diagnoses of diabetes in patients following COVID-19. Although some studies suggest that diabetes following COVID-19 is more severe and more likely to present with ketoacidosis than diabetes diagnosed before the pandemic, 10 these findings are not well established. Is it possible, for example, that the metabolic disturbance will subside over time, and if so, in what proportion of patients? In addition, is it possible that the SARS-CoV-2 infection only accelerates the clinical manifestations of diabetes in those destined to develop the disease eventually, so our current observations represent only a temporary acceleration in the diagnosis, rather than a true increase in the total number of cases over the long term? It is also important to determine the impact of treatment on subsequent development of diabetes. If COVID-19 is treated with antiviral agents or immunomodulatory drugs, is the subsequent risk of developing diabetes reduced? We need to understand the risk factors for development of diabetes following COVID-19 to determine how they apply to different age groups, racial and ethnic groups, genders, or patients with certain underlying characteristics. For example, for type 1 diabetes, are the genetic risk factors for diabetes following COVID-19 the same as those for diabetes before the pandemic? Can we focus on persons most likely to develop diabetes following COVID-19 and mitigate the most severe consequences or even prevent diabetes, either by treating COVID-19 or by administering immunomodulatory drugs?

An international registry to collect information on new diagnoses of diabetes following COVID-19 (COVIDIAB) 10 and longer follow-up in registry or electronic health record studies may address some of these questions. Studies on larger numbers of patients could provide a profile of those most likely to be affected. Together, these data will inform prospective studies. Might we be able to intervene and prevent a surge in new cases of diabetes and their subsequent burden and cost? In the short term, however, glucose monitoring of high-risk patients in the months following COVID-19 infection might provide early warning of hyperglycemic crisis and allow prospective management of diabetes as it develops.

Published: April 18, 2023. doi:10.1001/jamanetworkopen.2023.8872

Corresponding Author: Pamela B. Davis, MD, PhD, Center for Community Health Integration, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Sears Tower, T402, Cleveland, OH 44106 ( [email protected] ).

Conflict of Interest Disclosures: Dr Davis reported receiving grants from National Institutes of Health, the National Center for the Advancing Translational Sciences, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Aging. Dr Xu reported receiving grants from National Institutes of Health, the National Center for the Advancing Translational Sciences, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Aging.

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Davis PB , Xu R. COVID-19 and Incident Diabetes—Recovery Is Not So Sweet After All. JAMA Netw Open. 2023;6(4):e238872. doi:10.1001/jamanetworkopen.2023.8872

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World J Diabetes
v.6(6); 2015 Jun 25

Diabetes mellitus: The epidemic of the century

Correspondence to: Akram T Kharroubi, PhD, Associate Professor of Biochemistry and Endocrinology, Dean of Faculty of Health Professions, Department of Medical Laboratory Sciences, Faculty of Health Professions, Al-Quds University, P.O. Box 51000, Abed Elhamaid Shoman Street, Beit Hanina-Jerusalem, Jerusalem 91000, Palestine. [email protected]

Telephone: +972-2-2791243 Fax: +972-2-2791243

The epidemic nature of diabetes mellitus in different regions is reviewed. The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of diabetes (37.5%). Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field. A large array of mutations and single nucleotide polymorphisms in genes that play a role in the various steps and pathways involved in glucose metabolism and the development, control and function of pancreatic cells at various levels are reviewed. The major advances in the molecular understanding of diabetes in relation to the different types of diabetes in comparison to the previous understanding in this field are briefly reviewed here. Despite the accumulation of extensive data at the molecular and cellular levels, the mechanism of diabetes development and complications are still not fully understood. Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate objective to improve diagnoses, therapy and minimize the chance of chronic complications development.

Core tip: Diabetes mellitus is rising to an alarming epidemic level. Early diagnosis of diabetes and prediabetes is essential using recommended hemoglobin A1c criteria for different types except for gestational diabetes. Screening for diabetes especially in underdeveloped countries is essential to reduce late diagnosis. Diabetes development involves the interaction between genetic and non-genetic factors. Biomedical research continues to provide new insights in our understanding of the mechanism of diabetes development that is reviewed here. Recent studies may provide tools for the use of several genes as targets for risk assessment, therapeutic strategies and prediction of complications.

DEFINITION OF DIABETES MELLITUS

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Metabolic abnormalities in carbohydrates, lipids, and proteins result from the importance of insulin as an anabolic hormone. Low levels of insulin to achieve adequate response and/or insulin resistance of target tissues, mainly skeletal muscles, adipose tissue, and to a lesser extent, liver, at the level of insulin receptors, signal transduction system, and/or effector enzymes or genes are responsible for these metabolic abnormalities. The severity of symptoms is due to the type and duration of diabetes. Some of the diabetes patients are asymptomatic especially those with type 2 diabetes during the early years of the disease, others with marked hyperglycemia and especially in children with absolute insulin deficiency may suffer from polyuria, polydipsia, polyphagia, weight loss, and blurred vision. Uncontrolled diabetes may lead to stupor, coma and if not treated death, due to ketoacidosis or rare from nonketotic hyperosmolar syndrome[ 1 - 3 ].

CLASSIFICATION OF DIABETES MELLITUS

Although classification of diabetes is important and has implications for the treatment strategies, this is not an easy task and many patients do not easily fit into a single class especially younger adults[ 1 , 4 - 6 ] and 10% of those initially classified may require revision[ 7 ]. The classical classification of diabetes as proposed by the American Diabetes Association (ADA) in 1997 as type 1, type 2, other types, and gestational diabetes mellitus (GDM) is still the most accepted classification and adopted by ADA[ 1 ]. Wilkin[ 8 ] proposed the accelerator hypothesis that argues “type 1 and type 2 diabetes are the same disorder of insulin resistance set against different genetic backgrounds”[ 9 ]. The difference between the two types relies on the tempo, the faster tempo reflecting the more susceptible genotype and earlier presentation in which obesity, and therefore, insulin resistance, is the center of the hypothesis. Other predictors of type 1 diabetes include increased height growth velocity[ 10 , 11 ] and impaired glucose sensitivity of β cells[ 12 ]. The implications of increased free radicals, oxidative stress, and many metabolic stressors in the development, pathogenesis and complications of diabetes mellitus[ 13 - 18 ] are very strong and well documented despite the inconsistency of the clinical trials using antioxidants in the treatment regimens of diabetes[ 19 - 21 ]. The female hormone 17-β estradiol acting through the estrogen receptor-α (ER-α) is essential for the development and preservation of pancreatic β cell function since it was clearly demonstrated that induced oxidative stress leads to β-cell destruction in ER-α knockout mouse. The ER-α receptor activity protects pancreatic islets against glucolipotoxicity and therefore prevents β-cell dysfunction[ 22 ].

TYPE 1 DIABETES MELLITUS

Autoimmune type 1 diabetes.

This type of diabetes constitutes 5%-10% of subjects diagnosed with diabetes[ 23 ] and is due to destruction of β cells of the pancreas[ 24 , 25 ]. Type 1 diabetes accounts for 80%-90% of diabetes in children and adolescents[ 2 , 26 ]. According to International Diabetes Federation (IDF), the number of youth (0-14 years) diagnosed with type 1 diabetes worldwide in 2013 was 497100 (Table (Table1) 1 ) and the number of newly diagnosed cases per year was 78900[ 27 ]. These figures do not represent the total number of type 1 diabetes patients because of the high prevalence of type 1 diabetes in adolescence and adults above 14 years of age. One reported estimate of type 1 diabetes in the United States in 2010 was 3 million[ 28 , 29 ]. The number of youth in the United States younger than 20 years with type 1 diabetes was estimated to be 166984 in the year 2009[ 30 ]. The prevalence of type 1 diabetes in the world is not known but in the United States in youth younger than 20 years was 1.93 per 1000 in 2009 (0.35-2.55 in different ethnic groups) with 2.6%-2.7% relative annual increase[ 26 , 31 ]. Type 1 diabetes is mainly due to an autoimmune destruction of the pancreatic β cells through T-cell mediated inflammatory response (insulitis) as well as a humoral (B cell) response[ 25 ]. The presence of autoantibodies against the pancreatic islet cells is the hallmark of type 1 diabetes, even though the role of these antibodies in the pathogenesis of the disease is not clear. These autoantibodies include islet cell autoantibodies, and autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD, GAD65), protein tyrosine phosphatase (IA2 and IA2β) and zinc transporter protein (ZnT8A)[ 32 ]. These pancreatic autoantibodies are characteristics of type 1 diabetes and could be detected in the serum of these patients months or years before the onset of the disease[ 33 ]. Autoimmune type 1 diabetes has strong HLA associations, with linkage to DR and DQ genes. HLA-DR/DQ alleles can be either predisposing or protective[ 1 ]. This autoimmune type 1 diabetes is characterized by the absence of insulin secretion and is more dominant in children and adolescents.

Number of subjects with type 1 diabetes in children (0-14 years), with diabetes in adults (20-79 years) and with hyperglycemia (type 2 or gestational diabetes) in pregnancy (20-49 years)




Africa	39.1	6.4	19.8	5.7%	41.5	6.0%	4.6	14.4%
Europe	129.4	20.0	56.3	6.8%	68.9	7.1%	1.7	12.6%
Middle East and North Africa	64.0	10.7	34.6	10.9%	67.9	11.3%	3.4	17.5%
North America and Caribbean	108.6	16.7	36.8	9.6%	50.4	9.9%	0.9	10.4%
South and Central America	45.6	7.3	24.1	8.2%	38.5	8.2%	0.9	11.4%
South East Asia	77.9	12.5	72.1	8.7%	123.0	9.4%	6.3	25.0%
Western Pacific	32.5	5.3	138.2	8.1%	201.8	8.4%	3.7	11.9%
World	497.1	78.9	381.8	8.3%	592.0	8.8%	21.4	14.8%

Data extracted from International Diabetes Federation Diabetes Atlas, 6th ed, 2013.

In addition to the importance of genetic predisposition in type 1 diabetes, several environmental factors have been implicated in the etiology of the disease[ 9 , 33 ]. Viral factors include congenital rubella[ 34 , 35 ], viral infection with enterovirus, rotavirus, herpes virus, cytomegalovirus, endogenous retrovirus[ 36 , 37 ] and Ljungan virus. Other factors include low vitamin D levels[ 38 ], prenatal exposure to pollutants, improved hygiene and living conditions decreased childhood infections in countries with high socioeconomic status leading to increased autoimmune diseases (hygiene hypothesis), early infant nutrition such as using cow’s milk formula instead of breast feeding[ 39 ] in addition to insulin resistance in early childhood due to obesity or increased height growth velocity. The role of environmental factors remains controversial[ 40 ]. Recent evidence supported the causative effect of viral infections in diabetes[ 41 - 43 ].

Type 1 diabetes often develops suddenly and can produce symptoms such as polydipsia, polyuria, enuresis, lack of energy, extreme tiredness, polyphagia, sudden weight loss, slow-healing wounds, recurrent infections and blurred vision[ 27 ] with severe dehydration and diabetic ketoacidosis in children and adolescents. The symptoms are more severe in children compared to adults. These autoimmune type 1 diabetes patients are also prone to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia[ 1 ]. The complete dependence on insulin of type 1 diabetes patients may be interrupted by a honeymoon phase which lasts weeks to months or in some cases 2-3 years. In some children, the requirement for insulin therapy may drop to a point where insulin therapy could be withdrawn temporarily without detectable hyperglycemia[ 44 ].

Idiopathic type 1 diabetes

A rare form of type 1 diabetes of unknown origin (idiopathic), less severe than autoimmune type 1 diabetes and is not due to autoimmunity has been reported. Most patients with this type are of African or Asian descent and suffer from varying degrees of insulin deficiency and episodic ketoacidosis[ 45 ].

Fulminant type 1 diabetes

This is a distinct form of type 1 diabetes, first described in the year 2000, and has some common features with idiopathic type 1 diabetes being non-immune mediated[ 46 , 47 ]. It is characterized by ketoacidosis soon after the onset of hyperglycemia, high glucose levels (≥ 288 mg/dL) with undetectable levels of serum C-peptide, an indicator of endogenous insulin secretion[ 48 ]. It has been described mainly in East Asian countries and accounted for approximately 20% of acute-onset type 1 diabetes patients in Japan (5000-7000 cases) with an extremely rapid and almost complete beta-cell destruction resulting in nearly no residual insulin secretion[ 48 , 49 ]. Both genetic and environmental factors, especially viral infection, have been implicated in the disease. Anti-viral immune response may trigger the destruction of pancreatic beta cells through the accelerated immune reaction with no detectable autoantibodies against pancreatic beta cells[ 48 , 50 ]. Association of fulminant type 1 diabetes with pregnancy has also been reported[ 51 ].

TYPE 2 DIABETES MELLITUS

The global prevalence of diabetes in adults (20-79 years old) according to a report published in 2013 by the IDF was 8.3% (382 million people), with 14 million more men than women (198 million men vs 184 million women), the majority between the ages 40 and 59 years and the number is expected to rise beyond 592 million by 2035 with a 10.1% global prevalence. With 175 million cases still undiagnosed, the number of people currently suffering from diabetes exceeds half a billion. An additional 21 million women are diagnosed with hyperglycemia during pregnancy. The Middle East and North Africa region has the highest prevalence of diabetes (10.9%), however, Western Pacific region has the highest number of adults diagnosed with diabetes (138.2 millions) and has also countries with the highest prevalence (Figure (Figure1 1 )[ 27 ]. Low- and middle-income countries encompass 80% of the cases, “where the epidemic is gathering pace at alarming rates”[ 27 ]. Despite the fact that adult diabetes patients are mainly type 2 patients, it is not clear whether the reported 382 million adults diagnosed with diabetes also include type 1 diabetes patients.

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Comparative prevalence of diabetes in adults (20-79 years) in countries with high prevalence (≥ 10%). Data extracted from International Diabetes Federation Diabetes Atlas, 6th ed, 2013.

More than 90%-95% of diabetes patients belong to this type and most of these patients are adults. The number of youth (less than 20 years) with type 2 diabetes in the United States in the year 2009 was 0.46 in 1000 and accounted for approximately 20% of type 2 diabetes in youth[ 26 ]. The increased incidence of type 2 diabetes in youth is mainly due to the change in the lifestyle of the children in terms of more sedentary life and less healthy food. Obesity is the major reason behind insulin resistance which is mainly responsible for type 2 diabetes[ 52 - 54 ]. The ADA recommends screening of overweight children and adolescence to detect type 2 diabetes[ 55 , 56 ]. The prevalence of obesity in children in on the rise[ 6 ] which is probably the main reason for the increased incidence of type 2 diabetes in the young (30.3% overall increase in type 2 diabetes in children and adolescence between 2001 and 2009)[ 26 ].

Insulin resistance in type 2 diabetes patients increases the demand for insulin in insulin-target tissues. In addition to insulin resistance, the increased demand for insulin could not be met by the pancreatic β cells due to defects in the function of these cells[ 18 ]. On the contrary, insulin secretion decreases with the increased demand for insulin by time due to the gradual destruction of β cells[ 57 ] that could transform some of type 2 diabetes patients from being independent to become dependent on insulin. Most type 2 diabetes patients are not dependent on insulin where insulin secretion continues and insulin depletion rarely occurs. Dependence on insulin is one of the major differences from type 1 diabetes. Other differences include the absence of ketoacidosis in most patients of type 2 diabetes and autoimmune destruction of β cells does not occur. Both type 1 and type 2 diabetes have genetic predisposition, however, it is stronger in type 2 but the genes are more characterized in type 1 (the TCF7L2 gene is strongly associated with type 2 diabetes)[ 58 ]. Due to the mild symptoms of type 2 diabetes in the beginning, its diagnosis is usually delayed for years especially in countries where regular checkup without symptoms is not part of the culture. This delay in diagnosis could increase the incidence of long-term complications in type 2 diabetes patients since hyperglycemia is not treated during this undiagnosed period.

In addition to diabetes, insulin resistance has many manifestations that include obesity, nephropathy, essential hypertension, dyslipidemia (hypertriglyceridemia, low HDL, decreased LDL particle diameter, enhanced postprandial lipemia and remnant lipoprotein accumulation), ovarian hyperandrogenism and premature adrenarche, non-alcoholic fatty liver disease and systemic inflammation[ 6 , 54 ]. The presence of type 2 diabetes in children and adolescence who are not obese[ 59 - 61 ], the occasional severe dehydration and the presence of ketoacidosis in some pediatric patients with type 2 diabetes[ 55 ] had led to the misclassification of type 2 to type 1 diabetes.

Some patients with many features of type 2 diabetes have some type 1 characteristics including the presence of islet cell autoantibodies or autoantibodies to GAD65 are classified as a distinct type of diabetes called latent autoimmune diabetes in adults (LADA)[ 62 ]. People diagnosed with LADA do not require insulin treatment. In a recent study, Hawa et al[ 63 ] reported 7.1% of European patients with type 2 diabetes with a mean age of 62 years, tested positive for GAD autoantibodies and the prevalence of LADA was higher in patients diagnosed with diabetes at a younger age. This classification of LADA as a distinct type of diabetes is still controversial[ 6 , 64 - 66 ].

Insulin resistance and signaling

Defects in the insulin-dependent substrate proteins IRS-1 and IRS-2 mediated signaling pathway are implicated in the development of metabolic disorders, mainly diabetes. This pathway mediates the cellular response to insulin and involves a large array of insulin-stimulated protein kinases including the serine/threonine kinase AKT and protein kinase C (PKC) that phosphorylate a large number of Ser/Thr residues in the insulin receptor substrate (IRS) proteins involved in the metabolic response to insulin[ 67 ]. In addition, other non-insulin dependent kinases including the AMP-activated protein kinase, c-Jun N-terminal protein kinase and G protein-coupled receptor kinase 2 that are activated under various conditions can phosphorylate the two insulin responsive substrates[ 67 - 71 ]. Disruption in the AKT and PKC kinases is central to the development of diabetes[ 72 ] and is associated with all major features of the disease including hyperinsulinemia, dyslipidemia and insulin resistance[ 73 ]. Replacing the wild type IRS-1 with a mutant version of the protein having alanine instead of tyrosine in three locations using genetic knock-in approach provided evidence to the central role of IRS-1 phosphorylation in the development of insulin resistance[ 74 ]. Using a similar approach to generate IRS-1 mutant with a single mutation involving a specific tyrosine residue, confirmed the role of IRS-1 phosphorylation in the development of insulin resistance pathogenesis[ 75 ]. The large cumulative evidence indicates a complex array of factors including environmental factors[ 76 ] and a wide range of cellular disturbances in glucose and lipid metabolism in various tissues[ 77 ] contribute to the development of insulin resistance. This condition generates complex cellular metabolic changes in a variety of tissues, mainly liver and muscles, that include the inability of the liver to transport and dispose glucose, control glucose production via gluconeogenesis, impaired storage of glucose as glycogen, de novo lipogenesis and hypertriglyceridemia[ 77 ]. Among the factors implicated in the development of insulin resistance, obesity is the most predominant risk factor leading to insulin insensitivity and diabetes which involves several mechanisms that participate in the pathogenesis of the disease[ 78 ]. Obesity-induced insulin resistance is directly linked to increased nutrient flux and energy accumulation in tissues that directly affect cell responsiveness to insulin[ 77 ]. However, it seems that other insulin-independent mechanisms are involved in the overall metabolic disturbances of glucose homeostasis and diabetes including activities in extra-hepatic tissues in addition to the central role of liver.

OTHER TYPES OF DIABETES MELLITUS

Monogenic diabetes.

Characterization of the genetic etiology of diabetes enables more appropriate treatment, better prognosis, and counseling[ 79 ]. Monogenic diabetes is due to a genetic defect in single genes in pancreatic β cells which results in disruption of β cell function or a reduction in the number of β cells. Conventionally, monogenic diabetes is classified according to the age of onset as neonatal diabetes before the age of six months or Maturity Onset Diabetes of the Young (MODY) before the age of 25 years. However, certain familial defects are manifested in neonatal diabetes, MODY or adult onset diabetes[ 2 , 9 , 80 ]. Others believe that classification of diabetes as MODY and neonatal diabetes is obsolete and monogenic diabetes is currently used relating specific genetic etiologies with their specific treatment implications[ 79 ]. Beta cell differentiation depends on the expression of the homeodomain transcription factor PDX1 where mutation in the gene results in early onset diabetes (MODY) and its expression decreases before the onset of diabetes[ 81 ]. The angiopoietin-like protein 8 (ANGPTL8) may represent a potential “betatrophin” that acts to promote the proliferation of beta cells, however, studies using mice lacking the ANGPTL8 active gene or overexpressed protein indicated that it did not seem to play a role in beta cells proliferation[ 82 ].

Mitochondrial diabetes is due to a point mutation in the mitochondrial DNA associated with deafness and maternal transmission of the mutant DNA can result in maternally-inherited diabetes[ 1 , 83 ].

Mutations that result in mutant insulin or the inability to convert proinsulin to insulin result in glucose intolerance in some of these cases. Genetic defects in the insulin receptor or in the signal transduction pathway of insulin have been demonstrated to result in hyperinsulinemia and modest hyperglycemia to severe diabetes[ 1 ].

Disease of the exocrine pancreas

Damage of the β cells of the pancreas due to diffused injury of the pancreas can cause diabetes. This damage could be due to pancreatic carcinoma, pancreatitis, infection, pancreatectomy, and trauma[ 1 ]. Atrophy of the exocrine pancreas leads to progressive loss of the β cells[ 84 ]. Accumulation of fat in the pancreas or pancreatic steatosis could lead to diabetes due to decreased insulin secretion but may require a long time before the damage to β cells occurs[ 85 ]. In most cases, extensive damage of the pancreas is required before diabetes occurs and the exocrine function of the pancreas is decreased in these patients[ 86 ]. Cirrhosis in cystic fibrosis may contribute to insulin resistance and diabetes[ 2 ].

Hormones and drugs

Diabetes has been found in patients with endocrine diseases that secrete excess hormones like growth hormone, glucocorticoids, glucagon and epinephrine in certain endocrinopathies like acromegaly, Cushing’s syndrome, glucagonoma, and pheochromocytoma, respectively[ 1 ]. Some of these hormones are used as drugs such as glucocorticoids to suppress the immune system and in chemotherapy and growth hormone to treat children with stunted growth.

Genetic syndromes

Diabetes has been detected in patients with various genetic syndromes such as Down syndrome, Klinefelter syndrome, Turner syndrome and Wolfram syndrome[ 1 ].

PREDIABETES

Individuals with prediabetes do not meet the criteria of having diabetes but are at high risk to develop type 2 diabetes in the future. According to the ADA Expert Committee, individuals are defined to have prediabetes if they have either impaired fasting plasma glucose (IFG) levels between 100-125 mg/dL (5.6-6.9 mmol/L) or impaired glucose tolerance test (IGT) with 2-h plasma glucose levels in the oral glucose tolerance test (OGTT) of 140-199 mg/dL (7.8-11.0 mmol/L). The World Health Organization (WHO) still adopts the range for IFG from 110-125 mg/dL (6.1-6.9 mmol/L). Prediabetes has been shown to correlate with increased cardiovascular mortality[ 87 , 88 ] and cancer[ 89 ]. The definition of prediabetes with the indicated cut off values is misleading since lower levels of glucose in the normal range are still correlated with cardiovascular disease in a continuous glycemic risk perspective[ 90 ]. In accordance with the recommendation of the ADA in 2009 to use hemoglobin A1c (HbA1c) to diagnose diabetes, ADA also recommended the use of an HbA1c (5.7%-6.4%) to diagnose prediabetes[ 91 ]. The number of people with IGT according to IDF was 316 million in 2013 (global prevalence 6.9% in adults) and is expected to rise to 471 million in 2030[ 27 ]. According to a report in 2014 by the Center for Disease Control and Prevention, 86 million Americans (1 out of 3) have prediabetes[ 92 ]. Four of the top ten countries with the highest prevalence of prediabetes are in the Middle East Arab States of the Gulf (Kuwait, Qatar, UAE and Bahrin with prevalence of 17.9%, 17.1%, 16.6% and 16.3%, respectively)[ 27 ]. The number of people diagnosed with prediabetes is different according to the method and criteria used to diagnose prediabetes. The number of people with prediabetes defined by IFG 100-125 mg/dL is 4-5 folds higher than those diagnosed using the WHO criteria of 110-125 mg/dL[ 93 ]. Diabetes and prediabetes diagnosed using an HbA1c criteria give different estimates compared to methods using FPG or OGTT. Higher percentages of prediabetes were diagnosed using HbA1c compared to FPG[ 94 - 96 ]. Prediabetes is associated with metabolic syndrome and obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension[ 97 ]. Not all individuals with prediabetes develop diabetes in the future, exercise with a reduction of weight 5%-10% reduces the risk of developing diabetes considerably (40%-70%)[ 98 ]. Individuals with an HbA1c of 6.0%-6.5% have twice the risk of developing diabetes (25%-50%) in five years compared to those with an HbA1c of 5.5%-6.0%[ 99 ].

DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS

Diabetes mellitus is diagnosed using either the estimation of plasma glucose (FPG or OGTT) or HbA1c. Estimation of the cut off values for glucose and HbA1c is based on the association of FPG or HbA1c with retinopathy. Fasting plasma glucose of ≥ 126 mg/dL (7.0 mmol/L), plasma glucose after 2-h OGTT ≥ 200 mg/dL (11.1 mmol/L), HbA1c ≥ 6.5% (48 mmol/mol) or a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) along with symptoms of hyperglycemia is diagnostic of diabetes mellitus. In addition to monitor the treatment of diabetes, HbA1c has been recommended to diagnose diabetes by the International Expert Committee in 2009[ 100 ] and endorsed by ADA[ 101 ], the Endocrine Society, the WHO[ 102 ] and many scientists and related organizations all over the world. The advantages and disadvantages of the different tests used to diagnose diabetes have been reviewed by Sacks et al[ 103 ]. The advantages of using HbA1c over FPG to diagnose diabetes include greater convenience and preanalytical stability, lower CV (3.6%) compared to FPG (5.7%) and 2h OGTT (16.6%), stronger correlation with microvascular complications especially retinopathy, and a marker for glycemic control and glycation of proteins which is the direct link between diagnosis of diabetes and its complications[ 104 - 109 ]. It is recommended to repeat the HbA1c test in asymptomatic patients within two weeks to reaffirm a single apparently diagnostic result[ 110 ].

A cut off value for HbA1c of ≥ 6.5% (48 mmol/mol) has been endorsed by many countries and different ethnic groups, yet ethnicity seems to affect the cut off values to diagnose diabetes[ 111 , 112 ]. Cut-off values of 5.5% (37 mmol/mol)[ 113 ] and 6.5% (48 mmol/mol)[ 114 ] have been reported in a Japanese study, 6.0% (42 mmol/mol) in the National Health and Nutrition Examination Survey (NHANES III), 6.2% (44 mmol/mol) in a Pima Indian study, 6.3% (45 mmol/mol) in an Egyptian study as reported by Davidson[ 105 ]; and three cut-off values for Chinese[ 112 ]. The Australians recommended the use of two cut-off values: ≤ 5.5% to “rule-out” and ≥ 7.0% to “rule-in” diabetes[ 115 ]. Variations in the prevalence of diabetes[ 94 , 116 - 119 ] and prediabetes[ 120 ] due to ethnicity have been documented. Most studies diagnosed less subjects with diabetes using HbA1c compared to FPG or OGTT[ 121 - 123 ]. Yet, other studies reported more subjects diagnosed with diabetes using HbA1c[ 96 , 124 - 126 ].

GESTATIONAL DIABETES

Hyperglycemia in pregnancy whether in the form of type 2 diabetes diagnosed before or during pregnancy or in the form gestational diabetes has an increased risk of adverse maternal, fetal and neonatal outcome. Mothers with gestational diabetes and babies born to such mothers have increased risk of developing diabetes later in life. Hyperglycemia in pregnancy is responsible for the increased risk for macrosomia (birth weight ≥ 4.5 kg), large for gestational age births, preeclampsia, preterm birth and cesarean delivery due to large babies[ 127 ]. Risk factors for gestational diabetes include obesity, personal history of gestational diabetes, family history of diabetes, maternal age, polycystic ovary syndrome, sedentary life, and exposure to toxic factors[ 3 ].

Diagnosis of type 2 diabetes before or during pregnancy is based on criteria mentioned before. Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) or 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) after a 75 g oral glucose load. However, gestational diabetes has been diagnosed at 24-28 wk of gestation in women not previously diagnosed with diabetes using two approaches: the first approach is based on the “one-step” International Association of the Diabetes and Pregnancy Study Groups (IADPSG) consensus[ 128 ] and recently adopted by WHO[ 129 ]. Gestational diabetes is diagnosed using this method by FPG ≥ 92 mg/dL (5.1 mmol/L), 1-h plasma glucose after a 75 g glucose load ≥ 180 mg/dL (10.0 mmol/L) or 2-h plasma glucose after a 75 g glucose load ≥ 153 mg/dL (8.5 mmol/L). This criteria is derived from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study[ 127 ] even though the HAPO study showed a continuous relationship between hyperglycemia and adverse short-term pregnancy outcome with no threshold reported[ 130 ]. The second approach is used in the United States and is based on the “two-step” NIH consensus[ 131 ]. In the first step 1-h plasma glucose after a 50 g glucose load under nonfasting state ≥ 140 mg/dL (7.8 mmol/L) is followed by a second step under fasting conditions after a 100 g glucose load for those who screened abnormal in the first step. The diagnosis of gestational diabetes is made when at least two of the four plasma glucose levels are met. The four plasma glucose levels according to Carpenter/Coustan criteria are: FPG ≥ 95 mg/dL (5.3 mmol/L); 1-h ≥ 180 mg/dL (10.0 mmol/L); 2-h ≥ 155 mg/dL (8.6 mmol/L); and 3-h ≥ 140 mg/dL (7.8 mmol/L)[ 1 ].

The use IADPSC criteria in comparison with the Carpenter/Coustan criteria was associated with a 3.5-fold increase in GDM prevalence as well as significant improvements in pregnancy outcomes, and was cost-effective[ 132 ]. In another retrospective cohort study of women diagnosed with gestational diabetes, Ethridge et al[ 133 ] have shown that newborns of women diagnosed with gestational diabetes by IADPSG approach have greater measures of fetal overgrowth compared with Carpenter-Coustan “two-step” approach neonates. A strategy of using fasting plasma glucose as a screening test and to determine the need for OGTT is valid[ 134 , 135 ]. According to Sacks[ 136 ], correlation of glucose concentrations and the risk of subsequent complications will eventually lead to universal guidelines.

The use of ADA/WHO cut off value of HbA1c ≥ 6.5% (48 mmol/mol) to diagnose gestational diabetes is not recommended by the “one step” IADPSC criteria or the “two-step” NIH criteria. Further investigation is required in light of recent reports on HbA1c in combination with OGTT and its usefulness to predict adverse effect of gestational diabetes or obviate the use OGTT in all women with gestational diabetes[ 137 - 141 ].

DIABETES AND GENETICS

Diabetes is a complex disease that involves a wide range of genetic and environmental factors. Over the past several years, many studies have focused on the elucidation of the wide spectrum of genes that played a role in the molecular mechanism of diabetes development[ 142 - 144 ]. However, despite the vast flow of genetic information including the identification of many gene mutations and a large array of single nucleotide polymorphisms (SNPs) in many genes involved in the metabolic pathways that affect blood glucose levels, the exact genetic mechanism of diabetes remains elusive[ 145 , 146 ]. Evidently, a major complication is the fact that a single gene mutation or polymorphism will not impose the same effect among different individuals within a population or different populations. This variation is directly or indirectly affected by the overall genetic background at the individual, family or population levels that are potentially further complicated by interaction with highly variable environmental modifier factors[ 147 , 148 ].

Molecular genetics and type 2 diabetes

One of the major focuses of biomedical research is to delineate the collective and broad genetic variants in the human genome that are involved in the development of diabetes. This major effort will potentially provide the necessary information to understand the molecular genetics of the different forms of diabetes including type 1, type 2 and monogenic neonatal diabetes among individuals of all populations and ethnic groups. Despite the fact that linkage and association studies allowed the identification and characterization of many candidate genes that are associated with type 2 diabetes[ 144 , 149 , 150 ], however, not all of these genes showed consistent and reproducible association with the disease[ 151 ]. Genome wide association studies (GWAS) in various populations identified 70 loci associated with type 2 diabetes and revealed positive linkage of many mutations and SNPs that influence the expression and physiological impact of the related proteins and risk to develop type 2 diabetes. One study involved several thousand type 2 diabetes patients and control subjects from the United Kingdom allowed the identification of several diabetes putative loci positioned in and around the CDKAL1 , CDKN2A/B , HHEX/IDE and SLC30A8 genes in addition to the contribution of a large number of other genetic variants that are involved in the development of the disease[ 152 ]. Two similar studies from the Finns and Swedish populations and the United States resulted in the identification of similar single nucleotide variants[ 153 ] that are linked to the risk of acquiring type 2 diabetes[ 154 , 155 ]. The study in the United States population included in addition to type 2 diabetes, the association of the identified SNPs with the level of triglycerides in the tested subjects[ 155 ]. These SNPs are located near several candidate genes including IGFBP2 and CDKAL1 and other genes in addition to several other variants that are located near or in genes firmly associated with the risk of acquiring type 2 diabetes. Other GWAS analysis studies were performed in the Chinese, Malays, and Asian-Indian populations which are distinct from the European and United States populations in addition to meta-analysis of data from other populations in the region revealed relevant findings among patients with European ancestry[ 156 ]. The results of the combined analysis showed significant association of SNPs in the CDKAL1 , CDKN2A/B , HHEX , KCNQ1 and SLC30A8 genes after adjustment with gender and body mass index. More recently, meta-analysis of GWAS data involving African American type 2 diabetes patients identified similar loci to the previous studies with the addition of two novel loci, HLA-B and INS-IGF[ 157 ]. These results provide strong evidence of common genetic determinants including common specific genes that are linked to diabetes. A small list of specific genetic markers seem strongly associated with the risk of developing type 2 diabetes including the TCF7L2 [ 158 ] and CAPN10 [ 159 , 160 ] genes which also play a significant role in the risk and pathogenesis of the disease[ 158 , 159 ]. The association of TCF7L2 gene variants with type 2 diabetes and its mechanism of action received special attention by several investigators[ 161 , 162 ]. Over expression of the protein was shown to decrease the sensitivity of beta islet cells to secrete insulin[ 163 , 164 ] and was more precisely involved in the regulation of secretary granule fusion that constitute a late event in insulin secretion pathway[ 165 ]. The role of TCF7L2 in insulin secretion was partially clarified[ 166 ] that involves modifying the effect of incretins on insulin secretion by lowering the sensitivity of beta cells to incretins. Several other genes have been found to be significantly associated with the risk of developing type 2 diabetes including a specific SNP in a hematopoietically-expressed homeobox ( HHEX ) gene[ 167 ]. The islet zinc transporter protein (SLC30A8)[ 168 ] showed positive correlation with the risk of developing type 2 diabetes where variant mutations in this gene seem protective against the disease which provides a potential tool for therapy[ 169 ]. More recently, a low frequency variant of the HNF1A identified by whole exome sequencing was associated with the risk of developing type 2 diabetes among the Latino population and potentially may serve as a screening tool[ 170 ]. Genetic variants and specific combined polymorphisms in the interleukin and related genes including interlukin-6 ( IL-6 ), tumor necrosis factor-α and IL-10 genes were found to be associated with greater risk of developing type 2 diabetes[ 171 ], in addition to genetic variants in the genes for IL12B , IL23R and IL23A genes[ 172 ]. In a study involving the hormone sensitive lipase responsible for lipolysis in adipose tissues, a deletion null mutation, which resulted in the absence of the protein from adipocytes, was reported to be associated with diabetes[ 173 ]. Nine specific rare variants in the peroxisome proliferator-activated receptor gamma ( PPARG ) gene that resulted in loss of the function of the protein in adipocytes differentiation, were significantly associated with the risk of developing type 2 diabetes[ 174 ]. In addition, certain SNPs in the alpha 2A adrenergic receptor ( ADRA2A ) gene, involved in the sympathetic nervous system control of insulin secretion and lipolysis, were found to be associated with obesity and type 2 diabetes[ 175 ]. Link analysis between the melatonin MT2 receptor ( MTNR1B ) gene, a G-protein coupled receptor, identified 14 mutant variants from 40 known variants revealed by exome sequencing, to be positively linked with type 2 diabetes[ 176 ]. The authors suggested that mutations in the MT2 gene could provide a tool with other related genes in modifying therapy for type 2 diabetes patients based on their specific genetic background to formulate personalized therapies which potentially may ensures the optimum response. Interestingly, mutations in the clock[ 177 , 178 ] and Bmal1 [ 179 ] transcription factor genes which are involved in beta cells biological clock affecting growth, survival and synaptic vesicle assembly in these cells, resulted in reduced insulin secretion and diabetes. Evidently, prominent metabolic functions involve the production of specific reactive metabolites, leading to oxidative stress, which affect lipids, proteins and other biological compounds leading to serious damage in various tissues and organs. Mutations and SNPs in the antioxidant genes, including superoxide dismutase, catalase and glutathione peroxidase, that decrease their activity are implicated in the risk and pathogenesis of type 2 diabetes[ 180 ]. The metabolic syndrome was shown to be associated with the development of type 2 diabetes in a population that is described as highly endogenous especially in individuals over 45 years of age[ 181 ]. Since consanguinity marriages is high in this population, screening for this syndrome among families could provide an informative marker on the risk of developing type 2 diabetes[ 181 ].

Molecular genetics of type 1 diabetes

Even though type 1 diabetes is basically described as an autoimmune disease that results in the destruction of pancreatic beta cells, however, single gene mutations and SNPs have been found to be associated with the susceptibility to this type of diabetes. Initially, two gene mutations were linked to the development of type 1 diabetes including the autoimmune regulator ( AIRE ) gene which affect the immune tolerance to self antigens leading to autoimmunity[ 182 ] and the FOXP3 gene which results in defective regulatory T cells[ 183 ]. In addition, a mutation in the histone deacetylase SIRTI gene predominantly expressed in beta cells involved in the regulation of insulin secretion[ 184 ] and played a role in modulating the sensitivity of peripheral tissues to insulin[ 185 ] was detected in type 1 diabetes patients[ 186 ]. Recently, additional mutations and SNPs in the CTLA-4 +49A/G and HLA-DQB1 and INS gene VNTR alleles were found to be associated with type 1 diabetes, which have the advantage of differentiating between Latent autoimmune type 1 diabetes and type 2 diabetes[ 187 ]. The HLA-DQB1, in combination with HLA-DR alleles and a polymorphism in PTPN22 gene seem to be associated with the age onset of late type 1 diabetes[ 188 , 189 ]. Two specific polymorphisms in the promoter region of a transmembrane protein (DC-SIGN) gene expressed in macrophages and played an important role of T- cell activation and inflammation were found to be protective against type 1 diabetes[ 190 ]. An innovative non-parametric SNP enrichment tool using summary GWAS DATA allowed the identification of association between several transcription factors and type 1 diabetes and are located in a type 1 diabetes susceptibility region[ 191 ]. Nine SNP variants in several genes associated with type 1 diabetes, not including the major histocompatibility gene region, were identified using extensive GWAS analysis[ 192 ]. Furthermore, several novel SNPs in a region in chromosome 16 located in the CLEC16A gene were shown to be associated with type 1 diabetes and seem to function through the reduced expression of DEX1 in B lymphoblastoid cells[ 193 ]. Since more than 40 regions in the human genome were identified to be associated with the susceptibility to type 1 diabetes[ 194 - 196 ], a weighted risk model was developed utilizing selected genes SNPs could be used for testing infants for these genetic markers that could provide insights in the susceptibility to type 1 diabetes development or safe prevention of the disease among young children[ 197 ].

Molecular genetics of monogenic diabetes

A large array of genes were identified to be involved in the development of monogenic diabetes[ 80 ] which represent about 2%-5% of diabetes patients. Monogenic diabetes results primarily from gene defects that lead to a decrease in beta cell number or function. Monogenic diabetes genes were identified using linkage studies or code for proteins that directly affected glucose homeostasis. The majority of genes responsible for monogenetic diabetes code for either transcription factors that participate in the control of nuclear gene expression or proteins that are located on the cell membrane, cytoplasm and endoplasmic reticulum, proteins involved in insulin synthesis and secretion, exocrine pancreatic proteins and autoimmune diabetes proteins[ 80 ]. The collective function of these proteins is their participation in glucose metabolism at different levels. Evidently, the hierarchy of a specific gene in the overall glucose metabolism pathway determines the onset of diabetes in the patient and whether it is neonataly expressed or have late onset expression (adulthood). Consequently, molecular defects in the structure and function of these genes lead to the disturbance of plasma glucose level, the primary pathological sign of diabetes. The molecular mechanism of permanent neonatal diabetes mellitus (PNDP) in addition to MODY explains the observed phenotype of monogenetic diabetes that involves loss of function of the expressed mutant protein. The first gene implicated in monogenic diabetes was the glucokinase ( GCK ) gene[ 198 ] which functions as a pancreatic sensor for blood glucose where more than 70 mutations in the gene were identified that affected its activity[ 199 ]. A recent study on GCK gene mutations causing neonatal and childhood diabetes showed that the majority of mutations resulted in the loss of the enzyme function primarily due to protein instability[ 148 , 150 ]. Two hepatocytes nuclear factor genes that code for the HNF4A and HNF1A transcription factors were closely associated with MODY1 and MODY2[ 148 , 149 ]. Definitely, a whole list of other genes involved in monogenic diabetes are either overlooked or included in the genetic determinants of type 1 and type 2 diabetes which will be identified and clarified through more careful future studies.

MOLECULAR GENETICS OF DIABETES COMPLICATIONS

In addition to the genetic determinants of diabetes, several gene mutations and polymorphisms have been associated with the clinical complications of diabetes. The cumulative data on diabetes patients with a variety of micro- and macrovascular complications support the presence of strong genetic factors involved in the development of various complications[ 200 ]. A list of genes have been reported that are associated with diabetes complications including ACE and AKR1B1 in nephropathy, VEGF and AKRB1 in retinopathy and ADIPOQ and GLUL in cardiovascular diseases[ 200 ]. A study on Chinese patients revealed a single SNP in the promoter region of the smooth muscle actin ( ACTA2 ) gene correlates with the degree of coronary artery stenosis in type 2 diabetes patients[ 201 ]. Furthermore, the alpha kinase 1 gene ( ALPK1 ) identified as a susceptibility gene for chronic kidney disease by GWAS[ 202 ], was demonstrated in type 2 diabetes patients[ 203 ]. Three additional genes have been strongly correlated with this risk of diabetic retinopathy (DR) including the vascular endothelial growth receptor, aldose reductase and the receptor for advanced glycation products genes[ 204 ] where specific polymorphisms in these genes seem to increase the risk of DR development in diabetes patients[ 204 ]. A significant differential proteome (involving 56 out of 252 proteins) is evident that characterizes vitreous samples obtained from diabetes patients with the complication in comparison to diabetes patients without the complication and control individuals[ 205 ]. Interestingly, a large portion of these proteins (30 proteins) belong to the kallikrein-kinin, coagulation and complement systems including complement C3, complement factor 1, prothrombin, alpha-1-antitrypsin and antithrombin III that are elevated in diabetic patients with retinopathy[ 205 ]. In addition, 2 single nucleotides polymorphisms in the human related B7-I gene seem to mediate podocyte injury in diabetic nephropathy[ 206 ]. Furthermore, increased concentration of the ligand of B7-1 correlates with the progression of end-stage renal disease (ESRD) in diabetes patients[ 206 ]. These results indicate that B7-I inhibition may serve as a potential target for diabetes nephropathy prevention and/or treatment. Recently, it was shown that direct correlation is evident between circulating levels of tumor necrosis factors 1 and 2 and increased risk of ESRD in American Indian patients[ 207 ]. The link between diabetes and proper bone development and health is evident. Studies using animal models with major significant reduction in insulin receptor (IR) in osteoprogenitor cells resulted in thin and rod-like weak bones with high risk of fractures[ 208 ]. Similar findings were observed in animal models with bone-specific IR knockdown animals which points to the central role of IR in the proper development of bones[ 208 ]. Type 2 diabetes is also associated with mitochondrial dysfunction in adipose tissues. Using knockout animal models of specific mitochondrial genes led to significant reduction in key electron transport complexes expression and eventually adipocytes death[ 209 ]. These animals exhibited Insulin resistance in addition to other complications that can potentially lead to cardiovascular disease[ 209 ].

Diabetes mellitus is the epidemic of the century and without effective diagnostic methods at an early stage, diabetes will continue to rise. This review focuses on the types of diabetes and the effective diagnostic methods and criteria to be used for diagnosis of diabetes and prediabetes. Evidently, diabetes is a complex disease with a large pool of genes that are involved in its development. The precise identification of the genetic bases of diabetes potentially provides an essential tool to improve diagnoses, therapy (more towards individualized patient targeted therapy) and better effective genetic counseling. Furthermore, our advanced knowledge of the association between medical genetics and the chronic complications of diabetes, will provide an additional advantage to delay or eradicate these complications that impose an immense pressure on patient’s quality of life and the significantly rising cost of health-care services.

Conflict-of-interest: The authors declare that there is no conflict of interest associated with this manuscript.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: November 23, 2014

First decision: February 7, 2015

Article in press: April 14, 2015

P- Reviewer: Hegardt FG, Surani S, Traub M S- Editor: Gong XM L- Editor: A E- Editor: Wang CH

Prenatal famine exposure tied to higher risk of Type 2 diabetes

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Researchers at Columbia University Mailman School of Public Health, the University of North Carolina at Chapel Hill and at the National Academy of Sciences of Ukraine used the setting of the man-made Ukrainian Holodomor famine of 1932-1933 to examine the relation between prenatal famine and adult Type 2 diabetes mellitus (T2DM). They studied 128,225 Type 2 diabetes cases diagnosed between 2000-2008 among 10,186,016 male and female Ukrainians born between 1930 and 1938.

Individuals who were exposed in early gestation to the famine had a more than two-fold likelihood of developing Type 2 diabetes compared to those unexposed to the famine, according to a study led by Columbia University Mailman School of Public Health. The results are published in the journal Science.

The famine led to 4 million excess deaths in the short-term and losses were concentrated in a 6 month period. The Holodomor far exceeded other famines in terms of its intensity. Life expectancies at birth in 1933 were only 7.2 years for females and 4.3 for males.

The Ukraine setting provided an unusual opportunity to investigate the long-term impact of the Holodomor -- or death by hunger --on Type 2 Diabetes Mellitus (T2DM) cases diagnosed seven decades after prenatal famine exposure. With the famine concentrated in a six-month period in early 1933, we are able to pinpoint the timing of famine together with extreme variations in intensity across provinces." L.H. Lumey, MD, Professor of Epidemiology at Columbia Public Health

This concentration was the result of Stalin's use of famine as a weapon of terror against Ukrainian farmers. When Ukraine could not fulfill its grain procurement quotas to the Soviet Central Government, having not enough for themselves, drastic measures were implemented to fulfill the quotas, under the excuse that counter-revolutionary elements sabotaged grain procurement. A countrywide campaign of searches of peasant's homes looking for "hidden" or "stolen" grain was launched in late 1932 and expanded in early 1933. All or most of the food was confiscated during many of these searches, leaving families without any food for the rest of the winter. In addition, measures were implemented that curtailed Ukrainian peasants' travel in search of food.

These measures created a perfect storm. Many rural families were left without any food; avenues to search for food were closed and grain reserve funds were depleted. Thousands of rural families were condemned to a slow death by starvation in their villages. The result was an extraordinary increase in Holodomor excess deaths between January and June 1933. At the peak of the famine in June 1933, there were, on the average, 28,000 famine-related deaths per day caused by the famine, equivalent to 1,167 deaths per hour or 19 per minute.

"Our study into the long-term health impact of the Holodomor famine offers several critical lessons for addressing health challenges posed by national disasters," observes Lumey. "It underscores the necessity for a comprehensive health care and policy framework that takes into account the lasting effects of early-life adversities on population health and their potential long-term repercussions on chronic diseases and mental health."

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Review Article
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Published: 02 August 2024

Unmet needs in the treatment of type 1 diabetes: why is it so difficult to achieve an improvement in metabolic control?

Francesco Antonio Mazzotta 1 na1 ,
Lorenzo Lucaccini Paoli ORCID: orcid.org/0009-0009-6461-1824 1 na1 ,
Alessandro Rizzi 2 ,
Linda Tartaglione 2 ,
Maria Laura Leo 1 ,
Valentina Popolla 2 ,
Annarita Barberio 3 ,
Luca Viti 2 ,
Mauro Di Leo 2 ,
Alfredo Pontecorvi 1 &
Dario Pitocco 2

Nutrition & Diabetes volume 14 , Article number: 58 ( 2024 ) Cite this article

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Diabetes complications
Type 1 diabetes

The development of advanced diabetes technology has permitted persons with type 1 diabetes mellitus to improve metabolic control significantly, particularly with the development of advanced hybrid closed-loop systems which have improved the quality of life by reducing hypoglycemia, decreasing macroangiopathy and microangiopathy-related complications, ameliorating HbA1c and improving glycemic variability. Despite the progression made over the past few decades, there is still significant margin for improvement to be made in terms of attaining appropriate metabolic control. Various factors are responsible for poor glycemic control including inappropriate carbohydrate counting, repeated bouts of hypoglycemia, hypoglycemia unawareness, cutaneous manifestations due to localized insulin use and prolonged use of diabetes technology, psychosocial comorbidities such as eating disorders or ‘diabulimia’, the coexistence of insulin resistance among people with type 1 diabetes and the inability to mirror physiological endogenous pancreatic insulin secretion appropriately. Hence, the aim of this review is to highlight and overcome the barriers in attaining appropriate metabolic control among people with type 1 diabetes by driving research into adjunctive treatment for coexistent insulin resistance and developing new advanced diabetic technologies to preserve β cell function and mirror as much as possible endogenous pancreatic functions.

Efficacy and safety of closed-loop control system for type one diabetes in adolescents a meta analysis

Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial

Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review

Introduction.

Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by pancreatic β cells destruction, resulting in absolute insulin secretion deficit with consequent hyperglycemia [ 1 ]. For decades, the gold-standard treatment of T1D was multiple daily injections, however, the development of new diabetes technologies such as continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion, which attempt to mirror endogenous pancreatic insulin secretion in a more physiological manner, has led to a significant amelioration in glycated hemoglobin (HbA1c) and hence are being more widely implemented in clinical practice. In T1D, CGM systems are associated with 0.5–1% reduction in HbA1c without increased risk of hypoglycemia [ 2 ]. Many studies have demonstrated a significant decrease in hypoglycemia and microangiopathy and macroangiopathy-related complications with the use of new technologies [ 3 ]. However, despite such improvements, about 12–14% of people with T1D still display frankly elevated HbA1c, over 75 mmol/mol or 9% [ 3 ].

The development of CGM systems allows physicians to utilize new parameters which provide useful information regarding intra-and inter-day glucose variations [ 4 ]. The introduction of advanced hybrid closed loop (AHCL) systems has permitted an even better improvement of metabolic control compared to the use of CGM and continuous subcutaneous insulin infusion as separate components, with most studies suggesting a 10% increase in Time in Range (TIR) over a 12-month period [ 5 ].

Despite the significant improvement in metabolic control, there is still considerable opportunity for improvement in terms of metabolic control and quality of life among people with T1D. This is highlighted in the recently published T1D Exchange data that demonstrated only 21% of adults and 17% of youth achieve desired HbA1c targets [ 6 ]. Several factors can interfere with the achievement of appropriate metabolic control including incorrect carbohydrate counting [ 7 ], hypoglycemia unawareness [ 8 ], skin complications [ 9 ] and ‘diabulimia’ [ 10 ].

A relatively new concept is that of ‘Double Diabetes’ which refers to people with T1D which also have insulin resistance and constitutes an important barrier in achieving appropriate metabolic control. The increased incidence of overweight and overt obesity among people with T1D has increased the prevalence of this phenomenon. The addition of adjunctive medications used in the treatment of type 2 diabetes (T2D) to intensive insulin therapy in the management of T1D may lead to improved insulin sensitivity, improve HbA1c, decrease total daily insulin dose and ameliorate glycemic control.

Perhaps, the most important hurdle to overcome for attaining metabolic control is the inability to mirror endogenous pancreatic insulin secretion. Exogenously administered insulin does not follow the oscillatory portal-vein hepatic insulin delivery seen in the endogenous pancreas [ 11 ]. New research in diabetes technology is attempting to surmount this barrier, and mimic endogenous pancreatic insulin delivery through the development of new algorithms and dual-hormone pumps containing glucagon. Indeed, the purpose of this review is to comprehensively understand and overcome the barriers in achieving appropriate glycemic control with a particular focus on the role of adjunctive therapies and novel diabetes technology, with the hope to drive research to further improve metabolic control and improve patient quality of life by preserving β cell function.

Concept of metabolic control and glycemic variability

Glycated hemoglobin.

HbA1c remains the current gold standard for the assessment of glycemic control in people affected by diabetes mellitus and can be used as a marker for glycemic control in the last 3–4 months. Therefore, the measurement of HbA1c correlates with metabolic control, where altered values indicating high glycemic fluctuations which correlate with complications including hypoglycemia, macroangiopathies and microangiopathies [ 12 ].

Despite HbA1c remaining the gold standard marker for metabolic control in people with diabetes, there are many conditions which may alter the HbA1c reading including dyslipidemia, hemoglobinopathies such as thalassemia, hemolytic anemia, kidney failure and blood transfusions. Accordingly, extensive research has been conducted to find novel markers or mathematical methods of determining short-term glycemic variability including inter-day and intra-day variability which more closely monitor glycemic variability and hence would be more reliable indicators for hypoglycemia, microangiopathy and macroangiopathy-related complications [ 13 ].

Glycemic variability

Glycemic variability is defined as the fluctuations of glucose which occur throughout or between days, taking into consideration the amplitude, duration and frequency of glycemic excursions and has shown to statistically correlate with diabetes-related complications including hypoglycemia, macroangiopathies and microangiopathies [ 14 ].

Despite the numerous advantages posed by HbA1c for metabolic control in the long-term, it does not play a role in monitoring glycemic variability throughout the day or between days especially considering glycemic variability due to post-prandial peaks. Interestingly, some studies have shown that glycemic variability, and hence transient bouts of hypoglycemia and hyperglycemia cause elevated levels of oxidative stress compared to prolonged persistent hypo/hyperglycemia and thus are responsible for accelerated microangiopathy and macroangiopathy complications. The underlying pathophysiological mechanisms remain to be elucidated, however transient hyperglycemia induces oxidative stress by recruiting pro-inflammatory cytokines, while transient hypoglycemia induces endothelial damage by promoting platelet activation, both of which accelerate microangiopathy and macroangiopathy-related complications. This has stemmed researchers to overlook the mere HbA1c value and attempt to determine inter-day and intra-day variability, especially embraced by the advent of advanced diabetic technology devices such as CGM.

Glucose variability can be measured by performing CGM or self-monitored blood glucose to derive parameters which determine the amplitude and/or the timing of glycemic variability. The preferred approach by physicians of measuring glycemic variability is coefficient of variation defined as the standard deviation divided by the mean, which possesses the advantage of comparing the degree of variation between different data sets, hence is particularly useful in monitoring hypoglycemia [ 15 ].

Major limitations in achieving metabolic control

Incorrect carbohydrate counting.

Carbohydrate counting (CC) is a meal planning practice for people with diabetes, focusing on tracking the amount of carbohydrates in grams consumed at meals to manage blood glucose (BG) levels. The correct bolus insulin dosage is determined by the total carbohydrate intake at each meal and the insulin-to-carbohydrate ratio (ICR). These two factors are used to estimate the amount of insulin required for the effective management of BG levels after each meal [ 16 ]. Evidence suggests that CC improves metabolic control and lowers HbA1c levels [ 17 ]. Thus, accurately performing CC is the recommended method to adjust insulin bolus and, consequently, to achieve proper BG regulation [ 18 ]. Indeed, carbohydrates over- and underestimations introduce errors in the bolus insulin that may lead to hypoglycemic and hyperglycemic episodes, respectively. Therefore, CC demands nutritional education and training and implementation of an individualized appropriate ICR [ 19 ].

Physical inactivity

Physical activity is being increasingly recommended as part of the therapeutic regimen for T1D because it helps to manage BG levels by reducing the risk of insulin resistance, weight gain or obesity [ 20 ]. Active adults with T1D demonstrated to achieve better blood pressure levels and lipid profile and to improve body composition, cardiorespiratory fitness, and well-being compared with their inactive counterparts [ 21 ]. Furthermore, in subjects with T1D at risk of diabetic kidney disease (DKD) or with established DKD, regular moderate-to-vigorous physical activity is associated with reduced incidence and progression of DKD, as well as reduced risk of cardiovascular events and mortality [ 22 ]. Physical inactivity can be a significant factor limiting the gain of good metabolic control and, therefore, exercise advice and physical activity assessment should become a routinary integral part of the patient-centered treatment strategy also in T1D [ 23 ]. In people with T1D, physical activity has been shown to reduce total daily insulin dose and HbA1c levels, but it exposes subjects to a greater risk of hypoglycemia. Furthermore, physical activity can make the estimate of the needed insulin dose even more challenging, with an overestimation of bolus after exercise and consequent risk of hypoglycemia [ 24 ].

Insulin physiology

Insulin, released by pancreatic β cells in response to increasing glucose levels, initially travels via the portal vein to the liver, interacting with hepatocytes. The portal vein delivers insulin to the liver in a pulsatile oscillatory pattern, occurring in intervals of approximately five minutes, with lower amplitude in pre-prandial conditions and higher amplitude in post-prandial states. The pulsatile pattern of portal vein-mediated insulin delivery enhances hepatic degradation of insulin and hence contributes to homeostasis, regulating the amount of insulin to maintain euglycemia in physiological states [ 25 ].

Exogenous insulin delivered by an insulin pump or insulin pen is administered subcutaneously and therefore does not undergo hepatic metabolism in the same manner as endogenous insulin, thereby decreasing the amount of insulin degradation. Consequently, exogenous insulin administration results in equal or excessive amount of insulin concentration relative to the portal vein, with consequent insulin activity in the adipose tissue and skeletal muscle rather than the liver, contributing to increased unwanted adverse effects such as weight gain and lipodystrophy. Furthermore, the absorption of insulin subcutaneously is a rate-limiting step of insulin activity since it takes time for insulin to cross into the blood circulation and exerts its metabolic effects in the periphery. The exogenous administration of insulin remains a major hindrance for improving glycemic control among people with T1D, and hence, novel methods of insulin administration should be studied to surmount this major limitation [ 7 ].

Fear of hypoglycemia and hypoglycemic unawareness

Hypoglycemia, defined as a glucose value below 70 mg/dL, poses a significant threat to people with T1D, since excessive repeated episodes of hypoglycemic bouts result in hypoglycemia unawareness, defined as the absence of symptoms with glucose below 70 mg/dL and is caused by a reduction the autonomic nervous system response threshold to further hypoglycemic events [ 8 ].

Such symptoms among individuals with diabetes may result in some subjects developing the so-called fear of hypoglycemia phenomenon, especially if the patient has had multiple episodes of symptomatic recurrent hypoglycemia. The phenomenon is characterized by anxiety and discomfort due to the fear of developing further hypoglycemic symptoms, which may result in somatization typically in the form of dyspnea, tremors, sweating and palpitations. Indeed, the fear of hypoglycemia phenomenon poses a significant threat for subjects since the symptoms mimic overt hypoglycemic symptoms, hence may result in inadequate metabolic control, and contribute to behaviors disproportionate to the actual risk of developing hypoglycemia [ 26 ]. Unfortunately, hypoglycemia is a common phenomenon occurring among people with T1D and constitutes an important barrier in achieving appropriate metabolic control if not appropriately managed [ 27 ].

Cutaneous reactions

Cutaneous reactions are common manifestations among people with diabetes which use insulin pens, insulin pumps and/or CGM. Some of the most reported skin reactions reported by insulin pump users include scar formation/fibrosis, pigmentation changes, erythema, and irritant/contact dermatitis. The dermatological manifestations may occur due to mechanical factors such as long-term cutaneous occlusion beneath the sensor, excessive local sweating, damaged epidermis due to plaster tearing or needle injury with insertion of the cannula. A cross-sectional study of 64 adolescent people with T1D showed how among adolescents with T1D using insulin pump therapy the most common skin complications were pigmentation changes and skin irritation [ 28 ].

Localized lipodystrophy arguably is one of the most common dermatological complications of people with diabetes which utilize insulin. Localized lipodystrophy can be defined as a group of disorders characterized by lipohypertrophy or lipoatrophy, denoting localized increase or retraction of subcutaneous fat respectively, due to insulin interaction with the panniculus. Indeed, subcutaneous insulin administration in sites of lipodystrophy results in poor absorption of insulin, thereby leading to hyperglycemia. Consequently, this typically results in the patient autonomously increasing the dosage of insulin to attempt to contrast the persistently elevated glycemic values. Accordingly, if the patient chooses a different injection site with the increased insulin dosage, then it will cause hypoglycemia and further contribute to poor metabolic control [ 29 ]. Cutaneous manifestations are often under-estimated by physicians and as such may have drastic consequences in acquiring the appropriate TIR, causing excessive glycemic fluctuations resulting in hyperglycemic or hypoglycemic excursions and hence contributing to poor metabolic control [ 9 ].

Diabulimia and eating disorders

Eating disorders are commonly encountered comorbidities among people with diabetes requiring insulin. Eating disorders among people with T1D are classified as overt eating disorders including bulimia nervosa or anorexia nervosa, and disordered eating symptoms which includes abnormal behaviors such as binge eating, excessive exercise, laxative or diuretic use, self-induced vomiting, and insulin therapy omission. These symptoms must be evaluated since may develop into overt eating disorders over time [ 30 ]. Accordingly, ‘diabulimia’ is a colloquial term often used by the media to denote the deliberate omission of insulin therapy to achieve weight loss. The rationale to omit insulin is to prevent weight gain due to the anabolic side effects of insulin and simultaneously achieve weight loss by inducing hyperglycemia which loses glucose calories by glucosuria [ 10 ].

Recent studies have demonstrated that eating disorders correlate with poor metabolic control and hence increased risk of diabetes-related complications. Despite the lack of formal diagnostic criteria, recent studies have suggested that approximately 20% of young women with T1D deliberately omit insulin [ 31 ].

The lack of formal diagnostic criteria and absent clinically validated tools poses a significant problem in screening people with diabetes with comorbid eating disorders or symptoms. Accordingly, physicians should screen for risk factors including female sex, adolescent age, overweight/obese body-mass index, excessive weight fluctuations, drug abuse, anxious personality trait and family history of alimentary disorders [ 32 ].

Double diabetes

Double diabetes was first described by Teupe and Bergin in 1991 and it denotes people with T1D which have concurrent clinical features of insulin resistance. Despite the suggested increasing prevalence of individuals affected by double diabetes, there are no clear-cut defining diagnostic criteria and hence the number of subjects affected globally remains largely unknown [ 33 ]. Nonetheless, double diabetes should be suspected in people with T1D with a family history of T2D, concurrent presence of obesity or metabolic syndrome, and insulin resistance measured by the Homeostatic Model Assessment for Insulin Resistance index, or the estimated glucose disposal rate [ 34 ]. Interestingly, people with double diabetes displayed a marked weight gain over time, a high daily insulin requirement and a positive family history of T2D. In addition, people with T1D with concurrent insulin resistance may have high normal blood pressure (or hypertension) and exhibit a higher cardiovascular risk [ 35 ].

The underlying pathophysiological mechanisms of insulin resistance in T1D remains to be elucidated, however, is thought to be caused by an increased incidence of obesity especially among younger people, due to lack of physical activity and excessive food consumption [ 36 ]. Furthermore, insulin resistance may be secondary to weight gain due to the anabolic effect of excessive subcutaneous insulin administration, that causes peripheral hyperinsulinemia and relative hepatic hypoinsulinemia compared to endogenous insulin [ 35 ].

Indeed, double diabetes constitutes an important obstacle in obtaining appropriate metabolic control especially given the lack of internationally recognized diagnostic criteria. Nonetheless, many studies are being conducted, especially regarding the role of new therapies used in T2D as potential adjuncts to insulin to ameliorate HbA1c, decrease glycemic variability, and decrease total daily insulin dose [ 34 ].

Potential adjunctive treatment in type 1 diabetes

Metformin has long been considered and remains the gold standard first line treatment in people with T2D in conjunction with appropriate nutrition and physical exercise [ 37 ].

The principle of utilizing metformin as an adjunct to insulin therapy in T1D is to decrease glycemic variability especially by reducing post-prandial hyperglycemic excursions and decrease total daily insulin dose, particularly in persons with concurrent insulin resistance. The most important study coined the Reducing with Metformin Vascular Adverse Lesions (REMOVAL) trial, conducted in 2017 was a double-blind placebo-controlled trial which studied the effects of metformin in over 400 people with T1D on insulin therapy over a 3-year period. At the end of the 3 years, there was a total decrease of 0.13% HbA1c compared to baseline. Furthermore, insulin dose was reduced by approximately 0.02U/kg and weight loss of about 1.15 kg was achieved over a three-year period. Interestingly, there was no reported increased risk in ketoacidosis or hypoglycemic episodes, however, drop-out rates due to gastrointestinal symptoms were twice that of placebo and a reported higher incidence of people with vitamin B12 deficiency [ 38 ]. Accordingly, the use of metformin as an adjunctive therapy in people with T1D with concurrent insulin resistance remains unclear due to poor evidence in reducing HbA1c over time, however, it may be considered a useful additional therapy for subjects that require a reduction in total daily insulin dose and for those who are overweight or overtly obese or with other clinical signs of insulin resistance [ 39 ].

Glucagon-like peptide-1 receptor agonists

Glucagon like-peptide 1 receptor agonists (GLP-1-RA) are commonly prescribed treatments for people with T2D and are especially useful as an adjunct to metformin in people with overweight or obesity and are affected by cardiovascular atherosclerotic disease [ 40 ]. Furthermore, GLP-1-RA have been extensively studied in recent years and have been shown to stimulate weight loss, ameliorate insulin sensitivity and exhibit cardioprotective and nephroprotective effects [ 41 ].

The rationale of using GLP-1-RA in T1D may potentially be useful in reducing total daily insulin dose, promoting weight loss, decreasing hypoglycemic events, and lowering glycemic variability by reducing hyperglycemic excursions. Despite the clinical benefits of implementing GLP-1-RA in T2D with insulin therapy, albeit by decreasing HbA1c, decreasing hypoglycemia and inducing weight loss, recent clinical studies generally have not been successful in demonstrating a statistically significant reduction in HbA1c as adjunctive therapy in T1D. Despite the lack of amelioration in HbA1c parameter, recent clinical trials have shown that GLP-1-RA promote weight loss in people with T1D, typically in the range of approximately 4–7 kg compared to placebo over a 12–52-week period. Perhaps the most important randomized control trial analyzing the addition of GLP-1-RA to people with T1D was the Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes (ADJUNCT) study whereby over 1300 people with T1D received Liraglutide or placebo. Consistently, the ADJUNCT trial demonstrated a statistically significant weight loss and concurrent decrease in total daily insulin dose, especially at the higher doses of Liraglutide compared to the placebo. A statistically significant reduction of HbA1c was only demonstrated in the 1.2 mg Liraglutide dose. Furthermore, documented symptomatic hypoglycemic events were increased in Liraglutide at all doses compared to placebo and statistically significant increase in ketoacidosis in subjects treated with the highest dose of Liraglutide [ 42 ]. From the findings of the ADJUNCT trial and other trials, the addition of GLP-1-RA in people with T1D may be particularly useful in promoting weight loss and decreasing total daily insulin dose especially for those with concurrent insulin resistance. However, data is clearly lacking regarding ameliorations to HbA1c, glycemic variability, hypoglycemia risk and the incidence of adverse reactions including gastrointestinal symptoms or pancreatitis [ 43 ].

Sodium/glucose transporter 2 inhibitors

Sodium/Glucose transporter 2 inhibitors (SGLT2i) are relatively new therapeutic options typically used in people affected by T2D and especially indicated for people with concurrent heart failure or chronic kidney disease [ 44 ].

The use of SGLT2i in the management of T2D has been well documented and implemented in international guidelines, however, the use of SGLT2i in people with T1D is less clear. Nonetheless, the rationale of using SGLT2i includes reducing glycemic variability and hence ameliorating the TIR, decreasing the total daily insulin dose, promoting cardioprotective and nephroprotective effects and inducing weight loss, all of which without increasing the risk of hypoglycemic episodes. One of the major trials studying the use of SGLT2i in T1D was the Empaglifozin as Adunctive to Insulin Therapy in Type 1 Diabetes (EASE) trial, involving double-blind placebo-controlled trials comparing the effectiveness of different doses of Empaglifozin and placebo as adjuvant insulin therapy. Rather interestingly, the EASE trial demonstrated that the concurrent use of Empaglifozin with insulin therapy resulted in approximately 0.5% decrease in HbA1c, weight loss of approximately 2kg, and decreased the total daily insulin dose by approximately 0.1 U/kg compared to the placebo group after 28 days. Furthermore, blood pressure was reduced by approximately 4 mmHg systolic and 2 mmHg diastolic, and TIR improved by approximately 2 h per day [ 45 ].

Dapaglifozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes Trial (DEPICT-1) was a randomized placebo-controlled double-blind trial which compared Dapaglifozin at different doses and placebo as an adjunct to insulin therapy in subjects with T1D and inadequate glycemic control. Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in people with T1D, while increasing the risk of diabetic ketoacidosis (DKA) at approximately 4% compared to placebo [ 46 ].

Nonetheless, despite the potential use of Dapaglifozin in the treatment of T1D in addition to insulin therapy, its approval has been withdrawn by the Medicines and Healthcare Products Regulatory Agency (MHRA) and further longer studies are required before implementing SGLT2i with insulin due to the concurrent increased risk of diabetic ketoacidosis [ 47 ].

β cell preservation

Preservation of β cell function is a crucial goal in the management of T1D since it has been shown to promote metabolic control by reducing glycemic variability, decreasing hypoglycemic episodes, reduce risk of diabetic ketoacidosis and decrease the development of microangiopathies. C-peptide measurements is the gold-standard method to quantify residual pancreatic β cell function and correlates with the degree of metabolic control. Given its equimolar concentration with insulin and the longer half-life compared to insulin, it can be used as a reliable marker for residual β cell function among subjects with T1D [ 48 ].

A study conducted during the Diabetes Control and Complications Trial (DCCT) demonstrated the importance of β cell preservation in improving metabolic control, specifically by reducing HbA1c values, lowering the risks of diabetic retinopathy progression and decreasing the risk of severe hypoglycemic episodes. During this study, fasting and stimulated C-peptide following ingestion of a liquid mixed-meal were measured among subjects with a 1–5-year and 5–15-year duration of T1D. Among people with a 1–5-year duration, over an average of 6.5 years follow-up, C-peptide responders with stimulated C-peptide values ≥0.2 nmol/L had significantly lower values of HbA1c and blood glucose, and were receiving lower doses of insulin than the non-responders with C-peptide <0.2 nmol/L. In addition, C-peptide responder subjects assigned to intensive therapy had lower risks of both diabetic retinopathy progression and severe hypoglycemia compared with those receiving conventional treatment. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA1c decreased by 0.07%, insulin dose decreased by 0.0276 units/kg/day and hypoglycemia risk decreased by 8.2%, while the risk of sustained retinopathy was reduced by 25% [ 49 ]. Thus, residual pancreatic β cell function, measured as stimulated C-peptide secretion, is associated with a reduced risk of long-term complications, hence highlighting the need to find new methods to preserve β cell function in newly diagnosed T1D.

A recently conducted randomized control trial has demonstrated that achievement of near-normal glucose levels soon in youths with newly diagnosed T1D has a positive impact on metabolic control, leading to a significant improvement in HbA1c values in the intensive diabetes management group compared with the standard care group. Nevertheless, intensive diabetes management did not affect the decline in pancreatic C-peptide secretion at 52 weeks [ 50 ]. Therefore, it is necessary to evaluate other methods to preserve β cell function in people with T1D either by implementing new diabetes technologies which mirror physiological pancreatic insulin secretion and/or adjunctive therapies to further improve metabolic control (Table 1 ).

Future prospects and conclusion

Appropriate metabolic control is a difficult target to achieve in people with T1D due to the increased incidence of people with concurrent insulin resistance, presence of dermatological manifestations, hypoglycemia/hypoglycemic unawareness with overt fear of recurring hypoglycemia, and comorbidities such as eating disorders. Therefore, it is crucial to develop new screening tools such as clinically validated questionnaires for fear of hypoglycemia, cutaneous reactions and alimentary disorders/symptoms, and internationally recognized indices for evaluating insulin resistance in subjects with T1D.

Nonetheless, perhaps the most important barrier to achieving appropriate metabolic control is the inability to appropriately mimic endogenous insulin secretion and mirror physiological portal vein oscillations. Nonetheless, advanced diabetic technology has attempted to surmount the obstacle with the development of CGM and insulin pumps. In particular, AHCL technology has permitted a significant improvement in metabolic control because it mimics the endogenous pancreas more physiologically compared to basal-bolus regimens, with various studies having demonstrated a significant improvement in glucose variability, ameliorated HbA1c, reduced risk of hypoglycemia, decreased total daily dose of insulin, and fewer microangiopathy and macroangiopathy-related complications. Despite the significant improvement in metabolic control by AHCL systems, there are still numerous barriers to overcome to mirror the physiological pancreas, including overcoming the non-linear relationship of subcutaneous insulin infusion and glycemic excursions particularly post-prandially. Furthermore, the subcutaneous administration of insulin does not resemble the physiological portal vein oscillations and hepatic metabolism, therefore contributes to the development of adverse reactions such as cutaneous manifestations and weight gain, and consequent poor metabolic control [ 7 ].

Various studies are being conducted to attempt to surmount this barrier including the development of new algorithms in insulin pumps, multiple-hormone pumps, and pulsed intravenous insulin therapy, all of which attempt to mirror insulin secretion more physiologically. Pulsed intravenous insulin therapy is still in early trials; however, the rationale is to mimic physiological pancreatic insulin secretion by administering insulin intravenously via a catheter in the portal vein, hence permitting appropriate hepatic first pass and second pass metabolism without the unwanted side effects of subcutaneous insulin. Nonetheless, it remains an invasive technique, and many further studies are required to better understand the benefits and possible side effects of implementing such treatment in daily clinical practice [ 51 ].

Currently utilized algorithms in AHCL pumps function by regulating the delivery of insulin doses based on the value indicated by the CGM. One such algorithm is the Proportional, Integrative, Derivative controller which modulates basal insulin doses based on the deviation from a pre-set target glucose value over a set-time period and calculating the area under the curve, however, lacks the ability to modulate non-linear glycemic kinetics such as post-prandial hyperglycemic peaks [ 52 ]. Another commonly utilized algorithm includes the Model Predictive Control which is an algorithm based on predicted glucose values over a given time range based on insulin doses and takes into consideration insulin stacking [ 53 ]. A recently developed algorithm is the so-called fuzzy logic, which utilizes intermediate metrics in a binary logic, considering glucose trends, current glucose levels, change in basal rate, quantity of insulin previously administered and therefore may be useful in predicting post-prandial hyperglycemic excursions and tardive hypoglycemia. Nonetheless, fuzzy logic controllers are technically difficult to implement, and more studies are required prior to use in clinical practice [ 54 ].

Dual-hormone pumps which potentially utilize other hormones such as glucagon as part of the insulin pump have been studied extensively in recent years. The rationale of utilizing dual-hormone pumps may contribute to better metabolic control by tackling the obstacles of single-pump therapy including post-prandial glycemic excursions and treating hypoglycemia without user intervention. However, glucagon would require a separate cartridge from the insulin pump, with the need to formulate room temperature-stable preparations to avoid fibril precipitation and necessitates extensive studies to fully understand the pharmacokinetics of subcutaneously administered glucagon. Furthermore, new algorithms would have to be implemented, especially considering the effect of different insulin: glucagon ratio on hepatic glucose production [ 53 ]. The development of new algorithms which take into consideration non-linear kinetic glycemic excursions coupled with dual-hormone pumps which can tackle predicted hypoglycemia would significantly improve metabolic control in people with T1D and contribute to an improved quality of life.

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Department of Endocrinology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

Francesco Antonio Mazzotta, Lorenzo Lucaccini Paoli, Maria Laura Leo & Alfredo Pontecorvi

Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

Alessandro Rizzi, Linda Tartaglione, Valentina Popolla, Luca Viti, Mauro Di Leo & Dario Pitocco

Department of Internal Medicine, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

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Mazzotta, F.A., Lucaccini Paoli, L., Rizzi, A. et al. Unmet needs in the treatment of type 1 diabetes: why is it so difficult to achieve an improvement in metabolic control?. Nutr. Diabetes 14 , 58 (2024). https://doi.org/10.1038/s41387-024-00319-w

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By synthesizing current research findings and technological advances so as to effectively control diabetes mellitus and mitigate its far-reaching social and economic impacts. The integration of AI and ML promises to revolutionize diabetes mellitus treatment strategies, offering hope for improved patient outcomes and reduced healthcare burdens ...
Early findings from the NHS Type 2 Diabetes Path to ...
Findings from the NHS T2DR programme show that remission of type 2 diabetes is possible outside of research settings, through at-scale service delivery. However, the rate of remission achieved is lower and the ascertainment of data is more limited with implementation in the real world than in randomised controlled trial settings.
COVID-19 and Incident Diabetes
A meta-analysis 2 of reports from the US, Norway, the UK, Germany, and multisite consortia found an overall 66% increase in the incidence of new-onset diabetes following SARS-CoV-2 infection. Another review 3 showed that 12 of 14 population-based studies found significantly increased incidence of diabetes following COVID-19, with excess cases ...
Diabetes mellitus: The epidemic of the century
Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field.
Prenatal famine exposure tied to higher risk of Type 2 diabetes
The study was supported by Ukraine State complex program Diabetes Mellitus, 0106U000844; the Holodomor Research and Education Consortium in Canada; NIDI-NIAS Fellowship of the Royal Netherlands ...
Unmet needs in the treatment of type 1 diabetes: why is it so ...
The development of advanced diabetes technology has permitted persons with type 1 diabetes mellitus to improve metabolic control significantly, particularly with the development of advanced hybrid ...