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New Type 1 Diabetes Treatment Eliminates Need for Insulin

Key takeaways.

• The FDA has approved a new drug called Lantidra to manage low blood sugar in people with type 1 diabetes.
• The drug helps control blood sugar levels through an infusion of donor pancreatic cells that create insulin in the body so that patients no longer need to take external insulin.
• This drug is for people with severe and recurrent hypoglycemia who are unable to achieve target blood sugar levels.

In June, the FDA approved Lantidra—the first donor cell therapy for people with type 1 diabetes who struggle with severe and recurrent low blood sugar. The drug eliminates the need for external insulin, and avoids something as invasive as an islet cell transplant.

Lantidra (donislecel-jujn) is for people who have trouble managing their blood sugar and suffer from hypoglycemia, or for people who have hypoglycemia unawareness—a condition where patients are unable to detect their dropping blood sugar and might not be able to treat it before it drops to potentially dangerous levels. This can be a life-threatening condition that is not easily treatable with medication.

“Severe hypoglycemia is a dangerous condition that can lead to injuries resulting from loss of consciousness or seizures,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a FDA press release about Lantidra. “Today’s approval, the first-ever cell therapy to treat patients with type 1 diabetes, provides individuals living with type 1 diabetes and recurrent severe hypoglycemia an additional treatment option to help achieve target blood glucose levels.”

Developed by CellTrans, Lantidra is an infusion of islet cells from a deceased donor into the liver portal vein of the diabetic patient. Because the infused cells restore functional pancreatic islet cells in people with type 1 diabetes, external insulin is no longer necessary.

Small—But Successful—Clinical Trials Led to Approval

Lantidra’s safety was studied in two non-randomized trials with 30 participants who live with type 1 diabetes and hypoglycemic unawareness. The patients received at least one Lantidra infusion and a maximum of three infusions, the FDA said in its press release.

After their infusions, 21 patients did not need to take insulin for a year or more. Eleven patients did not need insulin for one to five years and 10 participants did not need insulin for more than five years. Five patients required external insulin after the infusions, and did not achieve any insulin independence.

During the trials there were two deaths—one from multiorgan failure with sepsis about one-and-a-half years after the first infusion, and one from progressive confusion, global atrophy and micro-ischemic disease almost 10 years after the first dose. Both subjects were on immunosuppression at the time.

What to Know About Lantidra

This drug was specifically approved to tackle ongoing and severe low blood sugar in patients with type 1 diabetes who are unable to reach target blood sugar levels despite intensive diabetes management and education.

Type 1 diabetes is a disease where the body's own immune system starts attacking the insulin producing cells of the pancreas, Omid Veiseh, PhD , an associate professor of bioengineering at Rice University, told Verywell. Once those cells are killed off, the patient can no longer regulate their blood glucose, meaning they need to rely on external insulin.

“This new drug gets those insulin producing cells from deceased donors…then they’re purified to be safe in terms of pathogens and whatnot—and then they’re infused into type 1 diabetic recipients,” Veiseh said. “But because the disease is autoimmune mediated, and the cells are from a donor, the patient will receive immunosuppression [medication]. The immune suppression basically protects the cells from the host’s immune response.”

Up until now, patients with recurrent and severe hypoglycemia have had to work with their endocrinologist to manage blood sugar as best as they can through the dosing of their insulin as well as diet and exercise. In severe cases, the use of glucagon , which helps rescue patients from an episode of hypoglycemia, is used, said Fernando Ovalle, MD , director of the Division of Endocrinology, Diabetes and Metabolism at the University of Alabama at Birmingham School of Medicine.

“You don’t want to have hypoglycemia, especially severe or repeated,” Ovalle told Verywell, explaining that a severe low blood sugar can result in incidents like falling and hitting your head, cardiac arrest, or seizures.

For patients for whom ongoing hypoglycemia poses a great threat to their health, including death, an islet cell transplant might be considered. During this procedure, islets are taken from the pancreas of a deceased organ donor, then transferred into a patient with type 1 diabetes. Once the cells are implanted in the liver, they are able to make insulin.  

Lantidra introduces healthy islet cells without requiring a transplant procedure.

Veiseh said advancements like Lantidra are giving hope to the medical and type 1 diabetes community. In the future, advancements will likely include replaceable cell types that can be lab-grown—so you don’t have to rely on donors—as well as localized immunosuppression strategies. This means that only the site that cells are infused into will need to be immunosuppressed, not the entire body.

“I think, in the next five or 10 years, we’re going to see a lot more of these islet replacement therapies, on the market,” Veiseh said. “And it’s going to be great for patients, because the cure is to replace those missing cells that have been killed off.”

How Lantidra Is Administered

Lantidra is a prescription medication that is administered by a healthcare professional via infusion into the liver. The recommended minimum dose is 5,000 equivalent islet number (EIN) per kg for the first infusion, and 4,500 EIN/kg for subsequent infusions, the drugmaker said.

The drug is currently only recommended for people who experience recurrent and severe hypoglycemia or have hypoglycemia unawareness. It is not for all people with type 1 diabetes, or for people with type 2 diabetes. It’s best for any patient considering the drug to first consult with their healthcare provider to see if they are the right candidate.

Lantidra is given in a single infusion dose. An additional dose or two may be necessary depending on whether the patient responds to the first infusion and achieves independence from external insulin within one year. In other words, if the first infusion is not successful, another dose might be needed. There is currently no data on the effectiveness or safety for patients who have more than three infusions.

How Does Lantidra Work?

Lantidra is an infusion of islet cells from a deceased donor into the liver portal vein of the diabetic patient. The infused cells restore functional pancreatic islet cells in people with type 1 diabetes, removing the need for external insulin.

Known Side Effects

In clinical trials, there were a series of adverse reactions associated with Lantidra. The drugmaker said these varied with each participant and depended on the number of infusions they received. 

Ninety percent of trial participants had at least one serious adverse reaction, and the major causes were attributed to the infusion procedure and immunosuppression drugs. Some of these side effects meant that the patient needed to stop taking the immunosuppressants, which stopped the drug from working.

Some of the most common reactions were nausea, fatigue, anemia, diarrhea, and abdominal pain.  

Aside from the side effects of Lantidra itself, there are risks with taking immunosuppressants for a long period of time, including risk of infections, lymphomas and anemia.

“These adverse events should be considered when assessing the benefits and risks of Lantidra for each patient,” the FDA said in its press release.

While the safety of taking Lantidra while pregnant has not been assessed, there are known risks for being on immunosuppressants while expecting. Fetal malformations are associated with some of the suppression drugs, therefore the drugmaker warns patients should have a confirmed negative pregnancy test before starting Lantidra.

How to Get Lantidra

Veiseh said because Lantidra relies on donor cells, CellTrans has a limited supply of the drug.

“You’re sort of at the mercy of donors being available,” he said. “I think the best estimates put this at 2,000 to 4,000 patients per year that you could treat just because of the limitation of organ availability.”

However, Veiseh said Lantidra is a step in the right direction for patients with type 1 diabetes who suffer from severe, ongoing low blood sugar. It is giving them another option instead of an islet cell transplant—a procedure that is only available in certain healthcare settings.

“In other countries, this kind of therapy has been available and reimbursed by insurance for years, but in the U.S., it was sort of a patchwork system of various surgeons that did it but it wasn’t really available to everyone,” said Veiseh. The National Institute of Diabetes and Digestive and Kidney Diseases has said that islet transplantation is considered an experimental procedure, and until it’s approved as a treatment for type 1 diabetes, it can only be performed for research purposes through clinical trials and is generally not covered by insurance.

“I think this is really a big step forward towards making this a potential solution that is uniformly available to all the patients as opposed to just certain ones,” Veiseh said.

University of California San Francisco Department of Surgery. Islet transplant for type 1 diabetes . 

Food and Drug Administration. FDA approves first cellular therapy to treat patients with type 1 diabetes .

Food and Drug Administration. Lantidra [drug label].

By Laura Hensley Hensley is an award-winning health and lifestyle journalist based in Canada. Her work has appeared in various outlets, including Best Health Magazine, Refinery29, Global News, and the National Post.

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FDA Approves First Cellular Therapy to Treat Patients with Type 1 Diabetes

FDA News Release

Today, the U.S. Food and Drug Administration approved Lantidra, the first allogeneic (donor) pancreatic islet cellular therapy made from deceased donor pancreatic cells for the treatment of type 1 diabetes. Lantidra is approved for the treatment of adults with type 1 diabetes who are unable to approach target glycated hemoglobin (average blood glucose levels) because of current repeated episodes of severe hypoglycemia (low blood sugar) despite intensive diabetes management and education.

“Severe hypoglycemia is a dangerous condition that can lead to injuries resulting from loss of consciousness or seizures,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval, the first-ever cell therapy to treat patients with type 1 diabetes, provides individuals living with type 1 diabetes and recurrent severe hypoglycemia an additional treatment option to help achieve target blood glucose levels.”

Type 1 diabetes is a chronic autoimmune disease that requires lifelong care including requiring insulin, either through multiple daily injections or continuous infusion using a pump, every day to live. People with type 1 diabetes also perform blood glucose checks several times a day to guide the management of their diabetes. 

Some people with type 1 diabetes have trouble managing the amount of insulin needed every day to prevent hyperglycemia (high blood sugar) without causing hypoglycemia. They may also develop hypoglycemia unawareness, where they are unable to detect their blood glucose is dropping and may not have a chance to treat themselves to prevent their blood glucose from further dropping. This makes it difficult to dose insulin. Lantidra provides a potential treatment option for these patients.

The primary mechanism of action of Lantidra is believed to be the secretion of insulin by the infused allogeneic islet beta cells. In some patients with type 1 diabetes, these infused cells can produce enough insulin, so the patient no longer needs to take insulin (by injections or pump) to control their blood sugar levels. Lantidra is administered as a single infusion into the hepatic (liver) portal vein. An additional infusion of Lantidra may be performed depending on the patient’s response to the initial dose. 

The safety and effectiveness of Lantidra was evaluated in two non-randomized, single-arm studies in which a total of 30 participants with type 1 diabetes and hypoglycemic unawareness received at least one infusion and a maximum of three infusions. Overall, 21 participants did not need to take insulin for a year or more, with 11 participants not needing insulin for one to five years and 10 participants not needing insulin for more than five years. Five participants did not achieve any days of insulin independence.

Adverse reactions associated with Lantidra varied with each participant depending on the number of infusions they received and the length of time they were followed and may not reflect the rates observed in practice The most common adverse reactions included nausea, fatigue, anemia, diarrhea and abdominal pain. A majority of participants experienced at least one serious adverse reaction related to the procedure for infusing Lantidra into the hepatic portal vein and the use of immunosuppressive medications needed to maintain the islet cell viability.  Some serious adverse reactions required discontinuation of immunosuppressive medications, which resulted in the loss of islet cell function and insulin independence. These adverse events should be considered when assessing the benefits and risks of Lantidra for each patient. Lantidra is approved with patient-directed labeling to inform patients with type 1 diabetes about benefits and risks of Lantidra. 

The FDA granted approval of Lantidra to CellTrans Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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New advances in type 1 diabetes

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• Peer review
• Savitha Subramanian , professor of medicine ,
• Farah Khan , clinical associate professor of medicine ,
• Irl B Hirsch , professor of medicine
• University of Washington Diabetes Institute, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
• Correspondence to: I B Hirsch ihirsch{at}uw.edu

Type 1 diabetes is an autoimmune condition resulting in insulin deficiency and eventual loss of pancreatic β cell function requiring lifelong insulin therapy. Since the discovery of insulin more than 100 years ago, vast advances in treatments have improved care for many people with type 1 diabetes. Ongoing research on the genetics and immunology of type 1 diabetes and on interventions to modify disease course and preserve β cell function have expanded our broad understanding of this condition. Biomarkers of type 1 diabetes are detectable months to years before development of overt disease, and three stages of diabetes are now recognized. The advent of continuous glucose monitoring and the newer automated insulin delivery systems have changed the landscape of type 1 diabetes management and are associated with improved glycated hemoglobin and decreased hypoglycemia. Adjunctive therapies such as sodium glucose cotransporter-1 inhibitors and glucagon-like peptide 1 receptor agonists may find use in management in the future. Despite these rapid advances in the field, people living in under-resourced parts of the world struggle to obtain necessities such as insulin, syringes, and blood glucose monitoring essential for managing this condition. This review covers recent developments in diagnosis and treatment and future directions in the broad field of type 1 diabetes.

Introduction

Type 1 diabetes is an autoimmune condition that occurs as a result of destruction of the insulin producing β cells of the pancreatic islets, usually leading to severe endogenous insulin deficiency. 1 Without treatment, diabetic ketoacidosis will develop and eventually death will follow; thus, lifelong insulin therapy is needed for survival. Type 1 diabetes represents 5-10% of all diabetes, and diagnosis classically occurs in children but can also occur in adulthood. The burden of type 1 diabetes is expansive; it can result in long term complications, decreased life expectancy, and reduced quality of life and can add significant financial burden. Despite vast improvements in insulin, insulin delivery, and glucose monitoring technology, a large proportion of people with type 1 diabetes do not achieve glycemic goals. The massive burden of type 1 diabetes for patients and their families needs to be appreciated. The calculation and timing of prandial insulin dosing, often from food with unknown carbohydrate content, appropriate food and insulin dosing when exercising, and cost of therapy are all major challenges. The psychological realities of both acute management and the prospect of chronic complications add to the burden. Education programs and consistent surveillance for “diabetes burnout” are ideally available to everyone with type 1 diabetes.

In this review, we discuss recent developments in the rapidly changing landscape of type 1 diabetes and highlight aspects of current epidemiology and advances in diagnosis, technology, and management. We do not cover the breadth of complications of diabetes or certain unique scenarios including psychosocial aspects of type 1 diabetes management, management aspects specific to older adults, and β cell replacement therapies. Our review is intended for the clinical reader, including general internists, family practitioners, and endocrinologists, but we acknowledge the critical role that people living with type 1 diabetes and their families play in the ongoing efforts to understand this lifelong condition.

Sources and selection criteria

We did individual searches for studies on PubMed by using terms relevant to the specific topics covered in this review pertaining to type 1 diabetes. Search terms used included “type 1 diabetes” and each individual topic—diagnosis, autoantibodies, adjuvant therapies, continuous glucose monitoring, automated insulin delivery, immunotherapies, diabetic ketoacidosis, hypoglycemia, and under-resourced settings. We considered all studies published in the English language between 1 January 2001 and 31 January 2023. We selected publications outside of this timeline on the basis of relevance to each topic. We also supplemented our search strategy by a hand search of the references of key articles. We prioritized studies on each highlighted topic according to the level of evidence (randomized controlled trials (RCTs), systematic reviews and meta-analyses, consensus statements, and high quality observational studies), study size (we prioritized studies with at least 50 participants when available), and time of publication (we prioritized studies published since 2003 except for the landmark Diabetes Control and Complications Trial and a historical paper by Tuomi on diabetes autoantibodies, both from 1993). For topics on which evidence from RCTs was unavailable, we included other study types of the highest level of evidence available. To cover all important clinical aspects of the broad array of topics covered in this review, we included additional publications such as clinical reviews as appropriate on the basis of clinical relevance to both patients and clinicians in our opinion.

Epidemiology

The incidence of type 1 diabetes is rising worldwide, possibly owing to epigenetic and environmental factors. Globally in 2020 an estimated 8.7 million people were living with type 1 diabetes, of whom approximately 1.5 million were under 20 years of age. 2 This number is expected to rise to more than 17 million by 2040 ( https://www.t1dindex.org/#global ). The International Diabetes Federation estimates the global prevalence of type 1 diabetes at 0.1%, and this is likely an underestimation as diagnoses of type 1 diabetes in adults are often not accounted for. The incidence of adult onset type 1 diabetes is higher in Europe, especially in Nordic countries, and lowest in Asian countries. 3 Adult onset type 1 diabetes is also more prevalent in men than in women. An increase in prevalence in people under 20 years of age has been observed in several western cohorts including the US, 4 5 Netherlands, 6 Canada, 7 Hungary, 8 and Germany. 9

Classically, type 1 diabetes presents over the course of days or weeks in children and adolescents with polyuria, polydipsia, and weight loss due to glycosuria. The diagnosis is usually straightforward, with profound hyperglycemia (often >300 mg/dL) usually with ketonuria with or without ketoacidemia. Usually, more than one autoantibody is present at diagnosis ( table 1 ). 10 The number of islet autoantibodies combined with parameters of glucose tolerance now forms the basis of risk prediction for type 1 diabetes, with stage 3 being clinical disease ( fig 1 ). 11 The originally discovered autoantibody, islet cell antibody, is no longer used clinically owing to variability of the assay despite standardisation. 12

Autoantibody characteristics associated with increased risk of type 1 diabetes 10

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Natural history of type 1 diabetes. Adapted with permission from Insel RA, et al. Diabetes Care 2015;38:1964-74 11

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Half of all new cases of type 1 diabetes are now recognized as occurring in adults. 13 Misclassification due to misdiagnosis (commonly as type 2 diabetes) occurs in nearly 40% of people. 14 As opposed to typical childhood onset type 1 diabetes, progression to severe insulin deficiency, and therefore its clinical presentation in adults, is variable. The term latent autoimmune diabetes of adults (LADA) was introduced 30 years ago to identify adults who developed immune mediated diabetes. 15 An international consensus defined the diagnostic criteria for LADA as age >30 years, lack of need for insulin use for at least six months, and presence of islet cell autoantibodies. 16 However, debate as to whether the term LADA should even be used as a diagnostic term persists. The American Diabetes Association (ADA) Standards of Care note that for the purpose of classification, all forms of diabetes mediated by autoimmune β cell destruction are included in the classification of type 1 diabetes. 17 Nevertheless, they note that use of the term LADA is acceptable owing to the practical effect of heightening awareness of adults likely to have progressive autoimmune β cell destruction and thereby accelerating insulin initiation by clinicians to prevent diabetic ketoacidosis.

The investigation of adults with suspected type 1 diabetes is not always straightforward ( fig 2 ). 18 Islet cell autoantibodies such as glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase IA2 antibody, and zinc transporter isoform 8 autoantibody act as markers of immune activity and can be detected in the blood with standardized assays ( table 1 ). The presence of one or more antibodies in adults with diabetes could mark the progression to severe insulin deficiency; these individuals should be considered to have type 1 diabetes. 1 Autoantibodies, especially GADA, should be measured only in people with clinically suspected type 1 diabetes, as low concentrations of GADA can be seen in type 2 diabetes and thus false positive measurements are a concern. 19 That 5-10% of cases of type 1 diabetes may occur without diabetes autoantibodies is also now clear, 20 and that the diabetes autoantibodies disappear over time is also well appreciated. 21

Flowchart for investigation of suspected type 1 diabetes in adults, based on data from white European populations. No single clinical feature in isolation confirms type 1 diabetes. The most discriminative feature is younger age at diagnosis (<35 years), with lower body mass index (<25), unintentional weight loss, ketoacidosis, and glucose >360 mg/dL at presentation. Adapted with permission from Holt RIG, et al. Diabetes Care 2021;44:2589-625 1

Genetic risk scoring (GRS) for type 1 diabetes has received attention to differentiate people whose classification is unclear. 22 23 24 Developed in 2019, the T1D-GRS2 uses 67 single nucleotide polymorphisms from known autoimmune loci and can predict type 1 diabetes in children of European and African ancestry. Although GRS is not available for routine clinical use, it may allow prediction of future cases of type 1 diabetes to allow prevention strategies with immune intervention (see below).

A major change in the type 1 diabetes phenotype has occurred over the past few decades, with an increase in obesity; the reasons for this are complex. In the general population, including people with type 1 diabetes, an epidemic of sedentary lifestyles and the “westernized diet” consisting of increased processed foods, refined sugars, and saturated fat is occurring. In people with type 1 diabetes, the overall improvement in glycemic control since the report of the Diabetes Control and Complications Trial (DCCT) in 1993 (when one or two insulin injections a day was standard therapy) has resulted in less glycosuria so that the typical patient with lower body weight is uncommon in high income countries. In the US T1D Exchange, more than two thirds of the adult population were overweight or obese. 25

Similarly, obesity in young people with type 1 diabetes has also increased over the decades. 26 The combination of autoimmune insulin deficiency with obesity and insulin resistance has received several descriptive names over the years, with this phenotype being described as double diabetes and hybrid diabetes, among others, 26 27 but no formal nomenclature in the diabetes classification exists. Many of these patients have family members with type 2 diabetes, and some patients probably do have both types of diabetes. Clinically, minimal research has been done into how this specific population responds to certain antihyperglycemic oral agents, such as glucagon-like peptide 1 (GLP-1) receptor agonists, given the glycemic, weight loss, and cardiovascular benefits seen with these agents. 28 These patients are common in most adult diabetes practices, and weight management in the presence of insulin resistance and insulin deficiency remains unclear.

Advances in monitoring

The introduction of home blood glucose monitoring (BGM) more than 45 years ago was met with much skepticism until the report of the DCCT. 29 Since then, home BGM has improved in accuracy, precision, and ease of use. 30 Today, in many parts of the world, home BGM, a static measurement of blood glucose, has been replaced by continuous glucose monitoring (CGM), a dynamic view of glycemia. CGM is superior to home BGM for glycemic control, as confirmed in a meta-analysis of 21 studies and 2149 participants with type 1 diabetes in which CGM use significantly decreased glycated hemoglobin (HbA 1c ) concentrations compared with BGM (mean difference −0.23%, 95% confidence interval −3.83 to −1.08; P<0.001), with a greater benefit if baseline HbA 1c was >8% (mean difference −0.43%, −6.04 to −3.30; P<0.001). 31 This newer technology has also evolved into a critical component of automated insulin delivery. 32

CGM is the standard for glucose monitoring for most adults with type 1 diabetes. 1 This technology uses interstitial fluid glucose concentrations to estimate blood glucose. Two types of CGM are available. The first type, called “real time CGM”, provides a continuous stream of glucose data to a receiver, mobile application, smartwatch, or pump. The second type, “intermittently scanned CGM,” needs to be scanned by a reader device or smartphone. Both of these technologies have shown improvements in HbA 1c and amount of time spent in the hypoglycemic range compared with home BGM when used in conjunction with multiple daily injections or “open loop” insulin pump therapy. 33 34 Real time CGM has also been shown to reduce hypoglycemic burden in older adults with type 1 diabetes ( table 2 ). 36 Alerts that predict or alarm with both hypoglycemia and hyperglycemia can be customized for the patient’s situation (for example, a person with unawareness of hypoglycemia would have an alert at a higher glucose concentration). Family members can also remotely monitor glycemia and be alerted when appropriate. The accuracy of these devices has improved since their introduction in 2006, so that currently available sensors can be used without a confirmation glucose concentration to make a treatment decision with insulin. However, some situations require home BGM, especially when concerns exist that the CGM does not match symptoms of hypoglycemia.

Summary of trials for each topic covered

Analysis of CGM reports retrospectively can assist therapeutic decision making both for the provider and the patient. Importantly, assessing the retrospective reports and watching the CGM in real time together offer insight to the patient with regard to insulin dosing, food choices, and exercise. Patients should be encouraged to assess their data on a regular basis to better understand their diabetes self-management. Table 3 shows standard metrics and targets for CGM data. 52 Figure 3 shows an ambulatory glucose profile.

Standardized continuous glucose monitoring metrics for adults with diabetes 52

Example of ambulatory glucose profile of 52 year old woman with type 1 diabetes and fear of hypoglycemia. CGM=continuous glucose monitoring; GMI=glucose management indicator

Improvements in technology and evidence for CGM resulting in international recommendations for its widespread use have resulted in greater uptake by people with type 1 diabetes across the globe where available and accessible. Despite this, not everyone wishes to use it; some people find wearing any device too intrusive, and for many the cost is prohibitive. These people need at the very least before meal and bedtime home BGM.

A next generation implantable CGM device (Sensionics), with an improved calibration algorithm that lasts 180 days after insertion by a healthcare professional, is available in both the EU and US. Although fingerstick glucose calibration is needed, the accuracy is comparable to that of other available devices. 53

Advances in treatments

The discovery of insulin in 1921, resulting in a Nobel Prize, was considered one of the greatest scientific achievements of the 20th century. The development of purified animal insulins in the late 1970s, followed by human insulin in the early 1980s, resulted in dramatic reductions in allergic reactions and lipoatrophy. Introduction of the first generation of insulin analogs, insulin lispro in the mid-1990s followed by insulin glargine in the early 2000s, was an important advance for the treatment of type 1 diabetes. 54 We review the next generation of insulin analogs here. Table 4 provides details on available insulins.

Pharmacokinetics of commonly used insulin preparations

Ultra-long acting basal insulins

Insulin degludec was developed with the intention of improving the duration of action and achieving a flatter profile compared with the original long acting insulin analogs, insulin glargine and insulin detemir. Its duration of action of 42 hours at steady state means that the profile is generally flat without significant day-to-day variability, resulting in less hypoglycemia compared with U-100 glargine. 39 55

When U-100 insulin glargine is concentrated threefold, its action is prolonged. 56 U-300 glargine has a different kinetic profile and is delivered in one third of the volume of U-100 glargine, with longer and flatter effects. The smaller volume of U-300 glargine results in slower and more gradual release of insulin monomers owing to reduced surface area in the subcutaneous space. 57 U-300 glargine also results in lesser hypoglycemia compared with U-100 glargine. 58

Ultra-rapid acting prandial insulins

Rapid acting insulin analogs include insulin lispro, aspart, and glulisine. With availability of insulin lispro, the hope was for a prandial insulin that better matched food absorption. However, these newer insulins are too slow to control the glucose spike seen with ingestion of a high carbohydrate load, leading to the development of insulins with even faster onset of action.

The first available ultra-rapid prandial insulin was fast acting insulin aspart. This insulin has an onset of appearance approximately twice as fast (~5 min earlier) as insulin aspart, whereas dose-concentration and dose-response relations are comparable between the two insulins ( table 4 ). 59 In adults with type 1 diabetes, mealtime and post-meal fast acting aspart led to non-inferior glycemic control compared with mealtime aspart, in combination with basal insulin. 60 Mean HbA 1c was 7.3%, 7.3%, and 7.4% in the mealtime faster aspart, mealtime aspart, and post‐meal faster aspart arms, respectively (P<0.001 for non-inferiority).

Insulin lispro-aabc is the second ultra-rapid prandial insulin. In early kinetic studies, insulin lispro-aabc appeared in the serum five minutes faster with 6.4-fold greater exposure in the first 15 minutes compared with insulin lispro. 61 The duration of exposure of the insulin concentrations in this study was 51 minutes faster with lispro-aabc. Overall insulin exposure was similar between the two groups. Clinically, lispro-aabc is non-inferior to insulin lispro, but postprandial hyperglycemia is lower with the faster acting analog. 62 Lispro-aabc given at mealtime resulted in greater improvement in post-prandial glucose (two hour post-prandial glucose −31.1 mg/dL, 95% confidence interval −41.0 to −21.2; P<0.001).

Both ultra-rapid acting insulins can be used in insulin pumps. Lispro-aabc tends to have more insertion site reactions than insulin lispro. 63 A meta-analysis including nine studies and 1156 participants reported increased infusion set changes on rapid acting insulin analogs (odds ratio 1.60, 95% confidence interval 1.26 to 2.03). 64

Pulmonary inhaled insulin

The quickest acting insulin is pulmonary inhaled insulin, with an onset of action of 12 minutes and a duration of 1.5-3 hours. 65 When used with postprandial supplemental dosing, glucose control is improved without an increase in hypoglycemia. 66

Insulin delivery systems

Approved automated insulin delivery systems.

CGM systems and insulin pumps have shown improvement in glycemic control and decreased risk of severe hypoglycemia compared with use of self-monitoring of blood glucose and multiple daily insulin injections in type 1 diabetes. 67 68 69 Using CGM and insulin pump together (referred to as sensor augmented pump therapy) only modestly improves HbA 1c in patients who have high sensor wear time, 70 71 but the management burden of diabetes does not decrease as frequent user input is necessary. Thus emerged the concept of glucose responsive automated insulin delivery (AID), in which data from CGM can inform and allow adjustment of insulin delivery.

In the past decade, exponential improvements in CGM technologies and refined insulin dosing pump algorithms have led to the development of AID systems that allow for minimization of insulin delivery burden. The early AID systems reduced hypoglycemia risk by automatically suspending insulin delivery when glucose concentrations dropped to below a pre-specified threshold but did not account for high glucose concentrations. More complex algorithms adjusting insulin delivery up and down automatically in response to real time sensor glucose concentrations now allow close replication of normal endocrine pancreatic physiology.

AID systems (also called closed loop or artificial pancreas systems) include three components—an insulin pump that continuously delivers rapid acting insulin, a continuous glucose sensor that measures interstitial fluid glucose at frequent intervals, and a control algorithm that continuously adjusts insulin delivery that resides in the insulin pump or a smartphone application or handheld device ( fig 4 ). All AID systems that are available today are referred to as “hybrid” closed loop (HCL) systems, as users are required to manually enter prandial insulin boluses and signal exercise, but insulin delivery is automated at night time and between meals. AID systems, regardless of the type used, have shown benefit in glycemic control and cost effectiveness, improve quality of life by improving sleep quality, and decrease anxiety and diabetes burden in adults and children. 72 73 74 Limitations to today’s HCL systems are primarily related to pharmacokinetics and pharmacodynamics of available analog insulins and accuracy of CGM in extremes of blood glucose values. The iLet bionic pancreas, cleared by the US Food and Drug Administration (FDA) in May 2023, is an AID system that determines all therapeutic insulin doses for an individual on the basis of body weight, eliminating the need for calculation of basal rates, insulin to carbohydrate ratios, blood glucose corrections, and bolus dose. The control algorithms adapt continuously and autonomously to the individual’s insulin needs. 38 Table 5 lists available AID systems.

Schematic of closed loop insulin pump technology. The continuous glucose monitor senses interstitial glucose concentrations and sends the information via Bluetooth to a control algorithm hosted on an insulin pump (or smartphone). The algorithm calculates the amount of insulin required, and the insulin pump delivers rapid acting insulin subcutaneously

Comparison of commercially available hybrid closed loop systems 75

Unapproved systems

Do-it-yourself (DIY) closed loop systems—DIY open artificial pancreas systems—have been developed by people with type 1 diabetes with the goal of self-adjusting insulin by modifying their individually owned devices. 76 These systems are built by the individual using an open source code widely available to anyone with compatible medical devices who is willing and able to build their own system. DIY systems are used by several thousand people across the globe but are not approved by regulatory bodies; they are patient-driven and considered “off-label” use of technology with the patient assuming full responsibility for their use. Clinicians caring for these patients should ensure basic diabetes skills, including pump site maintenance, a knowledge of how the chosen system works, and knowing when to switch to “manual mode” for patients using an artificial pancreas system of any kind. 76 The small body of studies on DIY looping suggests improvement in HbA 1c , increased time in range, decreased hypoglycemia and glucose variability, improvement in night time blood glucose concentrations, and reduced mental burden of diabetes management. 77 78 79 Although actively prescribing or initiating these options is not recommended, these patients should be supported by clinical teams; insulin prescription should not be withheld, and, if initiated by the patient, unregulated DIY options should be openly discussed to ensure open and transparent relationships. 78

In January 2023, the US FDA cleared the Tidepool Loop app, a DIY AID system. This software will connect the CGM, insulin pump, and Loop algorithm, but no RCTs using this method are available.

β cell replacement therapies

For patients with type 1 diabetes who meet specific clinical criteria, β cell replacement therapy using whole pancreas or pancreatic islet transplantation can be considered. Benefits of transplantation include immediate cessation of insulin therapy, attainment of euglycemia, and avoidance of hypoglycemia. Additional benefits include improved quality of life and stabilization of complications. 80 Chronic immunosuppression is needed to prevent graft rejection after transplantation.

Pancreas transplantation

Whole pancreas transplantation, first performed in 1966, involves complex abdominal surgery and lifelong immunosuppressive therapy and is limited by organ donor availability. Today, pancreas transplants are usually performed simultaneously using two organs from the same donor (simultaneous pancreas-kidney transplant (SPKT)), sequentially if the candidate has a living donor for renal transplantation (pancreas after kidney transplant (PAKT)) or on its own (pancreas transplantation alone). Most whole pancreas transplants are performed with kidney transplantation for end stage diabetic kidney disease. Pancreas graft survival at five years after SPKT is 80% and is superior to that with pancreas transplants alone (62%) or PAKT (67%). 81 Studies from large centers where SPKT is performed show that recipients can expect metabolic improvements including amelioration of problematic hypoglycemia for at least five years. 81 The number of pancreas transplantations has steadily decreased in the past two decades.

Islet transplantation

Islet transplantation can be pursued in selected patients with type 1 diabetes marked by unawareness of hypoglycemia and severe hypoglycemic episodes, to help restore the α cell response critical for responding to hypoglycemia. 82 83 Islet transplantation involves donor pancreas procurement with subsequent steps to isolate, purify, culture, and infuse the islets. Multiple donors are needed to provide enough islet cells to overcome islet cell loss during transplantation. Survival of the islet grafts, limited donor supply, and lifelong need for immunosuppressant therapy remain some of the biggest challenges. 84 Islet transplantation remains experimental in the US and is offered in a few specialized centers in North America, some parts of Europe, and Australia. 85

Disease modifying treatments for β cell preservation

Therapies targeting T cells, B cells, and cytokines that find use in a variety of autoimmune diseases have also been applied to type 1 diabetes. The overarching goal of immune therapies in type 1 diabetes is to prevent or delay the loss of functional β cell mass. Studies thus far in early type 1 diabetes have not yet successfully shown reversal of loss of C peptide or maintenance of concentrations after diagnosis, although some have shown preservation or slowing of loss of β cells. This suggests that a critical time window of opportunity exists for starting treatment depending on the stage of type 1 diabetes ( fig 1 ).

Teplizumab is a humanized monoclonal antibody against the CD3 molecule on T cells; it is thought to modify CD8 positive T lymphocytes, key effector cells that mediate β cell death and preserves regulatory T cells. 86 Teplizumab, when administered to patients with new onset of type 1 diabetes, was unable to restore glycemia despite C peptide preservation. 87 However, in its phase II prevention study of early intervention in susceptible individuals (at least two positive autoantibodies and an abnormal oral glucose tolerance test at trial entry), a single course of teplizumab delayed progression to clinical type 1 diabetes by about two years ( table 2 ). 43 On the basis of these results, teplizumab received approval in the US for people at high risk of type 1 diabetes in November 2022. 88 A phase III trial (PROTECT; NCT03875729 ) to evaluate the efficacy and safety of teplizumab versus placebo in children and adolescents with new diagnosis of type 1 diabetes (within six weeks) is ongoing. 89

Thus far, targeting various components of the immune response has been attempted in early type 1 diabetes without any long term beneficial effects on C peptide preservation. Co-stimulation blockade using CTLA4-Ig abatacept, a fusion protein that interferes with co-stimulation needed in the early phases of T cell activation that occurs in type 1 diabetes, is being tested for efficacy in prevention of type 1 diabetes ( NCT01773707 ). 90 Similarly, several cytokine directed anti-inflammatory targets (interleukin 6 receptor, interleukin 1β, tumor necrosis factor ɑ) have not shown any benefit.

Non-immunomodulatory adjunctive therapies

Adjunctive therapies for type 1 diabetes have been long entertained owing to problems surrounding insulin delivery, adequacy of glycemic management, and side effects associated with insulin, especially weight gain and hypoglycemia. At least 50% of adults with type 1 diabetes are overweight or obese, presenting an unmet need for weight management in these people. Increased cardiovascular risk in these people despite good glycemic management presents additional challenges. Thus, use of adjuvant therapies may tackle these problems.

Metformin, by decreasing hepatic glucose production, could potentially decrease fasting glucose concentrations. 91 It has shown benefit in reducing insulin doses and possibly improving metabolic control in obese/overweight people with type 1 diabetes. A meta-analysis of 19 RCTs suggests short term improvement in HbA 1c that is not sustained after three months and is associated with higher incidence of gastrointestinal side effects. 92 No evidence shows that metformin decreases cardiovascular morbidity in type 1 diabetes. Therefore, owing to lack of conclusive benefit, addition of metformin to treatment regimens is not recommended in consensus guidelines.

Glucagon-like peptide receptor agonists

Endogenous GLP-1 is an incretin hormone secreted from intestinal L cells in response to nutrient ingestion and enhances glucose induced insulin secretion, suppresses glucagon secretion, delays gastric emptying, and induces satiety. 93 GLP-1 promotes β cell proliferation and inhibits apoptosis, leading to expansion of β cell mass. GLP-1 secretion in patients with type 1 diabetes is similar to that seen in people without diabetes. Early RCTs of liraglutide in type 1 diabetes resulted in weight loss and modest lowering of HbA 1c ( table 2 ). 49 50 Liraglutide 1.8 mg in people with type 1 diabetes and higher body mass index decreased HbA 1c , weight, and insulin requirements with no increased hypoglycemia risk. 94 However, on the basis of results from a study of weekly exenatide that showed similar results, these effects may not be sustained. 51 A meta-analysis of 24 studies including 3377 participants showed that the average HbA 1c decrease from GLP-1 receptor agonists compared with placebo was highest for liraglutide 1.8 mg daily (−0.28%, 95% confidence interval −0.38% to−0.19%) and exenatide (−0.17%, −0.28% to 0.02%). The estimated weight loss from GLP-1 receptor agonists compared with placebo was −4.89 (−5.33 to−4.45)  kg for liraglutide 1.8 mg and −4.06  (−5.33 to−2.79) kg for exenatide. 95 No increase in severe hypoglycemia was seen (odds ratio 0.67, 0.43 to 1.04) but therapy was associated with higher levels of nausea. GLP-1 receptor agonist use may be beneficial for weight loss and reducing insulin doses in a subset of patients with type 1 diabetes. GLP-1 receptor agonists are not a recommended treatment option in type 1 diabetes. Semaglutide is being studied in type 1 diabetes in two clinical trials ( NCT05819138 ; NCT05822609 ).

Sodium-glucose cotransporter inhibitors

Sodium-glucose cotransporter 2 (SGLT-2), a protein expressed in the proximal convoluted tubule of the kidney, reabsorbs filtered glucose; its inhibition prevents glucose reabsorption in the tubule and increases glucose excretion by the kidney. Notably, the action of these agents is independent of insulin, so this class of drugs has potential as adjunctive therapy for type 1 diabetes. Clinical trials have shown significant benefit in cardiovascular and renal outcomes in type 2 diabetes; therefore, significant interest exists for use in type 1 diabetes. Several available SGLT-2 inhibitors have been studied in type 1 diabetes and have shown promising results with evidence of decreased total daily insulin dosage, improvement in HbA 1c , lower rates of hypoglycemia, and decrease in body weight; however, these effects do not seem to be sustained at one year in clinical trials and seem to wane with time. Despite beneficial effects, increased incidence of diabetic ketoacidosis has been observed in all trials, is a major concern, and is persistent despite educational efforts. 96 97 98 Low dose empagliflozin (2.5 mg) has shown lower rates of diabetic ketoacidosis in clinical trials ( table 2 ). 47 Favorable risk profiles have been noted in Japan, the only market where SGLT-2 inhibitors are approved for adjunctive use in type 1 diabetes. 99 In the US, SGLT-2 inhibitors are approved for use in type 2 diabetes only. In Europe, although dapagliflozin was approved for use as adjunct therapy to insulin in adults with type 1 diabetes, the manufacturer voluntarily withdrew the indication for the drug in 2021. 100 Sotagliflozin is a dual SGLT-1 and SGLT-2 inhibitor that decreases renal glucose reabsorption through systemic inhibition of SGLT-2 and decreases glucose absorption in the proximal intestine by SGLT-1 inhibition, blunting and delaying postprandial hyperglycemia. 101 Studies of sotagliflozin in type 1 diabetes have shown sustained HbA 1c reduction, weight loss, lower insulin requirements, lesser hypoglycemia, and more diabetic ketoacidosis relative to placebo. 102 103 104 The drug received authorization in the EU for use in type 1 diabetes, but it is not marketed there. Although SGLT inhibitors are efficacious in type 1 diabetes management, the risk of diabetic ketoacidosis is a major limitation to widespread use of these agents.

Updates in acute complications of type 1 diabetes

Diabetic ketoacidosis.

Diabetic ketoacidosis is a serious and potentially fatal hyperglycemic emergency accompanied by significant rates of mortality and morbidity as well as high financial burden for healthcare systems and societies. In the past decade, increasing rates of diabetic ketoacidosis in adults have been observed in the US and Europe. 105 106 This may be related to changes in the definition of diabetic ketoacidosis, use of medications associated with higher risk, and admission of patients at lower risk. 107 In a US report of hospital admissions with diabetic ketoacidosis, 53% of those admitted were between the ages of 18 and 44, with higher rates in men than in women. 108 Overall, although mortality from diabetic ketoacidosis in developed countries remains low, rates have risen in people aged >60 and in those with coexisting life threatening illnesses. 109 110 Recurrent diabetic ketoacidosis is associated with a substantial mortality rate. 111 Frequency of diabetic ketoacidosis increases with higher HbA 1c concentrations and with lower socioeconomic status. 112 Common precipitating factors include newly diagnosed type 1 diabetes, infection, poor adherence to insulin, and an acute cardiovascular event. 109

Euglycemic diabetic ketoacidosis refers to the clinical picture of an increased anion gap metabolic acidosis, ketonemia, or significant ketonuria in a person with diabetes without significant glucose elevation. This can be seen with concomitant use of SGLT-2 inhibitors (currently not indicated in type 1 diabetes), heavy alcohol use, cocaine use, pancreatitis, sepsis, and chronic liver disease and in pregnancy 113 Treatment is similar to that for hyperglycemic diabetic ketoacidosis but can require earlier use and greater concentrations of a dextrose containing fluid for the insulin infusion in addition to 0.9% normal saline resuscitation fluid. 114

The diagnosis of diabetic ketoacidosis has evolved from a gluco-centric diagnosis to one requiring hyperketonemia. By definition, independent of blood glucose, a β-hydroxybutyrate concentration >3 mmol/L is required for diagnosis. 115 However, the use of this ketone for assessment of the severity of the diabetic ketoacidosis is controversial. 116 Bedside β-hydroxybutyrate testing during treatment is standard of care in many parts of the world (such as the UK) but not others (such as the US). Concerns have been raised about accuracy of bedside β-hydroxybutyrate meters, but this is related to concentrations above the threshold for diabetic ketoacidosis. 116

Goals for management of diabetic ketoacidosis include restoration of circulatory volume, correction of electrolyte imbalances, and treatment of hyperglycemia. Intravenous regular insulin infusion is the standard of care for treatment worldwide owing to rapidity of onset of action and rapid resolution of ketonemia and hyperglycemia. As hypoglycemia and hypokalemia are more common during treatment, insulin doses are now recommended to be reduced from 0.1 u/kg/h to 0.05 u/kg/h when glucose concentrations drop below 250 mg/dL or 14 mM. 115 Subcutaneous rapid acting insulin protocols have emerged as alternative treatments for mild to moderate diabetic ketoacidosis. 117 Such regimens seem to be safe and have the advantages of not requiring admission to intensive care, having lower rates of complications related to intravenous therapy, and requiring fewer resources. 117 118 Ketonemia and acidosis resolve within 24 hours in most people. 115 To prevent rebound hyperglycemia, the transition off an intravenous insulin drip must overlap subcutaneous insulin by at least two to four hours. 115

Hypoglycemia

Hypoglycemia, a common occurrence in people with type 1 diabetes, is a well appreciated effect of insulin treatment and occurs when blood glucose falls below the normal range. Increased susceptibility to hypoglycemia from exogenous insulin use in people with type 1 diabetes results from multiple factors, including imperfect subcutaneous insulin delivery tools, loss of glucagon within a few years of diagnosis, progressive impairment of the sympatho-adrenal response with repeated hypoglycemic episodes, and eventual development of impaired awareness. In 2017 the International Hypoglycemia Study Group developed guidance for definitions of hypoglycemia; on the basis of this, a glucose concentration of 3.0-3.9 mmol/L (54-70 mg/dL) was designated as level 1 hypoglycemia, signifying impending development of level 2 hypoglycemia—a glucose concentration <3 mmol/L (54 mg/dL). 119 120 At approximately 54 mg/dL, neuroglycopenic hypoglycemia symptoms, including vision and behavior changes, seizures, and loss of consciousness, begin to occur as a result of glucose deprivation of neurons in the central nervous system. This can eventually lead to cerebral dysfunction at concentrations <50 mg/dL. 121 Severe hypoglycemia (level 3), denoting severe cognitive and/or physical impairment and needing external assistance for recovery, is a common reason for emergency department visits and is more likely to occur in people with lower socioeconomic status and with the longest duration of diabetes. 112 Prevalence of self-reported severe hypoglycemia is very high according to a global population study that included more than 8000 people with type 1 diabetes. 122 Severe hypoglycemia occurred commonly in younger people with suboptimal glycemia according to a large electronic health record database study in the US. 123 Self- reported severe hypoglycemia is associated with a 3.4-fold increase in mortality. 124 125

Acute consequences of hypoglycemia include impaired cognitive function, temporary focal deficits including stroke-like symptoms, and memory deficits. 126 Cardiovascular effects including tachycardia, arrhythmias, QT prolongation, and bradycardia can occur. 127 Hypoglycemia can impair many activities of daily living, including motor vehicle safety. 128 In a survey of adults with type 1 diabetes who drive a vehicle at least once a week, 72% of respondents reported having hypoglycemia while driving, with around 5% reporting a motor vehicle accident due to hypoglycemia in the previous two years. 129 This contributes to the stress and fear that many patients face while grappling with the difficulties of ongoing hypoglycemia. 130

Glucagon is highly efficacious for the primary treatment of severe hypoglycemia when a patient is unable to ingest carbohydrate safely, but it is unfortunately under-prescribed and underused. 131 132 Availability of nasal, ready to inject, and shelf-stable liquid glucagon formulations have superseded the need for reconstituting older injectable glucagon preparations before administration and are now preferred. 133 134 Real time CGM studies have shown a decreased hypoglycemic exposure in people with impaired awareness without a change in HbA 1c . 34 135 136 137 138 CGM has shown benefit in decreasing hypoglycemia across the lifespan, including in teens, young adults, and older people. 36 139 Although CGM reduces the burden of hypoglycemia including severe hypoglycemia, it does not eliminate it; overall, such severe level 3 hypoglycemia rates in clinical trials are very low and hard to decipher in the real world. HCL insulin delivery systems integrated with CGM have been shown to decrease hypoglycemia. Among available rapid acting insulins, ultra-rapid acting lispro (lispro-aabc) seems to be associated with less frequent hypoglycemia in type 1 diabetes. 140 141

As prevention of hypoglycemia is a crucial aspect of diabetes management, formal training programs to increase awareness and education on avoidance of hypoglycemia, such as the UK’s Dose Adjustment for Normal Eating (DAFNE), have been developed. 142 143 This program has shown fewer severe hypoglycemia (mean 1.7 (standard deviation 8.5) episodes per person per year before training to 0.6 (3.7) episodes one year after training) and restoration of recognition of hypoglycemia in 43% of people reporting unawareness. Clinically relevant anxiety and depression fell from 24.4% to 18.0% and from 20.9% to 15.5%, respectively. A structured education program with cognitive and psychotherapeutic aspects for changing hypoglycemia related behaviors, called the Hypoglycemia Awareness Restoration Program despite optimized self-care (HARPdoc), showed a positive effect on changing unhelpful beliefs around hypoglycemia and improved diabetes related and general distress and anxiety scores. 144

Management in under-resourced settings

According to a recent estimate from the International Diabetes Federation, 1.8 million people with type 1 diabetes live in low and middle income countries (LMICs). 2 In many LMICs, the actual burden of type 1 diabetes remains unknown and material resources needed to manage type 1 diabetes are lacking. 145 146 Health systems in these settings are underequipped to tackle the complex chronic disease that is type 1 diabetes. Few diabetes and endocrinology specialist physicians are available owing to lack of specific postgraduate training programs in many LMICs; general practitioners with little to no clinical experience in managing type 1 diabetes care for these patients. 146 This, along with poor availability and affordability of insulin and lack of access to technology, results in high mortality rates. 147 148 149 In developed nations, low socioeconomic status is associated with higher levels of mortality and morbidity for adults with type 1 diabetes despite access to a universal healthcare system. 150 Although global governments have committed to universal health coverage and therefore widespread availability of insulin, it remains very far from realization in most LMICs. 151

Access to technology is patchy and varies globally. In the UST1DX, CGM use was least in the lowest fifth of socioeconomic status. 152 Even where technology is available, successful engagement does not always occur. 153 In a US cohort, lower CGM use was seen in non-Hispanic Black children owing to lower rates of device initiation and higher rates of discontinuation. 154 In many LMICs, blood glucose testing strips are not readily available and cost more than insulin. 151 In resource limited settings, where even diagnosis, basic treatments including insulin, syringes, and diabetes education are limited, use of CGM adds additional burden to patients. Need for support services and the time/resources needed to download and interpret data are limiting factors from a clinician’s perspective. Current rates of CGM use in many LMICs are unknown.

Inequities in the availability of and access to certain insulin formulations continue to plague diabetes care. 155 In developed countries such as the US, rising costs have led to insulin rationing by around 25% of people with type 1 diabetes. 156 LMICs have similar trends while also remaining burdened by disproportionate mortality and complications from type 1 diabetes. 155 157 With the inclusion of long acting insulin analogs in the World Health Organization’s Model List of Essential Medicines in 2021, hope has arisen that these will be included as standard of care across the world. 158 In the past, the pricing of long acting analogs has limited their use in resource poor settings 159 ; however, their inclusion in WHO’s list was a major step in improving their affordability. 158 With the introduction of lower cost long acting insulin biosimilars, improved access to these worldwide in the future can be anticipated. 160

Making insulin available is not enough on its own to improve the prognosis for patients with diabetes in resource poor settings. 161 Improved healthcare infrastructure, better availability of diabetes supplies, and trained personnel are all critical to improving type 1 diabetes care in LMICs. 161 Despite awareness of limitations and barriers, a clear understanding of how to implement management strategies in these settings is still lacking. The Global Diabetes Compact was launched in 2021 with the goal of increasing access to treatment and improving outcomes for people with diabetes across the globe. 162

Emerging technologies and treatments

Monitoring systems.

The ability to measure urinary or more recently blood ketone concentrations is an integral part of self-management of type 1 diabetes, especially during acute illness, intermittent fasting, and religious fasts to prevent diabetic ketoacidosis. 163 Many people with type 1 diabetes do not adhere to urine or blood ketone testing, which likely results in unnecessary episodes of diabetic ketoacidosis. 164 Noting that blood and urine ketone testing is not widely available in all countries and settings is important. 1 Regular assessment of patients’ access to ketone testing (blood or urine) is critical for all clinicians. Euglycemic diabetic ketoacidosis in type 1 diabetes is a particular problem with concomitant use of SGLT-2 inhibitors; for this reason, these agents are not approved for use in these patients. For sick day management (and possibly for the future use of SGLT-2 inhibitors in people with type 1 diabetes), it is hoped that continuous ketone monitoring (CKM) can mitigate the risks of diabetic ketoacidosis. 165 Like CGM, the initial CKM device measures interstitial fluid β-hydroxybutyrate instead of glucose. CKM use becomes important in conjunction with a hybrid closed loop insulin pump system and added SGLT-2 inhibitor therapy, where insulin interruptions are common and hyperketonemia is frequent. 166

Perhaps the greatest technological challenge to date has been the development of non-invasive glucose monitoring. Numerous attempts have been made using strategies including optics, microwave, and electrochemistry. 167 Lack of success to date has resulted in healthy skepticism from the medical community. 168 However, active interest in the development of non-invasive technology with either interstitial or blood glucose remains.

Insulin and delivery systems

In the immediate future, two weekly basal insulins, insulin icodec and basal insulin Fc, may become available. 169 Studies of insulin icodec in type 1 diabetes are ongoing (ONWARDS 6; NCT04848480 ). How these insulins will be incorporated in management of type 1 diabetes is not yet clear.

Currently available AID systems use only a single hormone, insulin. Dual hormone AID systems incorporating glucagon are in development. 170 171 Barriers to the use of dual hormone systems include the need for a second chamber in the pump, a lack of stable glucagon formulations approved for long term subcutaneous delivery, lack of demonstrated long term safety, and gastrointestinal side effects from glucagon use. 74 Similarly, co-formulations of insulin and amylin (a hormone co-secreted with insulin and deficient in people with type 1 diabetes) are in development. 172

Immunotherapy for type 1 diabetes

As our understanding of the immunology of type 1 diabetes expands, development of the next generation of immunotherapies is under active pursuit. Antigen specific therapies, peptide immunotherapy, immune tolerance using DNA vaccination, and regulatory T cell based adoptive transfer targeting β cell senescence are all future opportunities for drug development. Combining immunotherapies with metabolic therapies such as GLP-1 receptor agonists to help to improve β cell mass is being actively investigated.

The quest for β cell replacement methods is ongoing. Transplantation of stem cell derived islets offers promise for personalized regenerative therapies as a potentially curative method that does away with the need for donor tissue. Since the first in vivo model of glucose responsive β cells derived from human embryonic stem cells, 173 different approaches have been attempted. Mesenchymal stromal cell treatment and autologous hematopoietic stem cells in newly diagnosed type 1 diabetes may preserve β cell function without any safety signals. 174 175 176 Stem cell transplantation for type 1 diabetes remains investigational. Encapsulation, in which β cells are protected using a physical barrier to prevent immune attack and avoid lifelong immunosuppression, and gene therapy techniques using CRISPR technology also remain in early stages of investigation.

Until recently, no specific guidelines for management of type 1 diabetes existed and management guidance was combined with consensus statements developed for type 2 diabetes. Table 6 summarizes available guidance and statements from various societies. A consensus report for management of type 1 diabetes in adults by the ADA and European Association for the Study of Diabetes became available in 2021; it covers several topics of diagnosis and management of type 1 diabetes, including glucose monitoring, insulin therapy, and acute complications. Similarly, the National Institute for Health and Care Excellence also offers guidance on management of various aspects of type 1 diabetes. Consensus statements for use of CGM, insulin pump, and AID systems are also available.

Guidelines in type 1 diabetes

Conclusions

Type 1 diabetes is a complex chronic condition with increasing worldwide prevalence affecting several million people. Several successes in management of type 1 diabetes have occurred over the years from the serendipitous discovery of insulin in 1921 to blood glucose monitoring, insulin pumps, transplantation, and immunomodulation. The past two decades have seen advancements in diagnosis, treatment, and technology including development of analog insulins, CGM, and advanced insulin delivery systems. Although we have gained a broad understanding on many important aspects of type 1 diabetes, gaps still exist. Pivotal research continues targeting immune targets to prevent or delay onset of type 1 diabetes. Although insulin is likely the oldest of existing modern drugs, no low priced generic supply of insulin exists anywhere in the world. Management of type 1 diabetes in under resourced areas continues to be a multifaceted problem with social, cultural, and political barriers.

Glossary of abbreviations

ADA—American Diabetes Association

AID—automated insulin delivery

BGM—blood glucose monitoring

CGM—continuous glucose monitoring

CKM—continuous ketone monitoring

DCCT—Diabetes Control and Complications Trial

DIY—do-it-yourself

FDA—Food and Drug Administration

GADA—glutamic acid decarboxylase antibody

GLP-1—glucagon-like peptide 1

GRS—genetic risk scoring

HbA1c—glycated hemoglobin

HCL—hybrid closed loop

LADA—latent autoimmune diabetes of adults

LMIC—low and middle income country

PAKT—pancreas after kidney transplant

RCT—randomized controlled trial

SGLT-2—sodium-glucose cotransporter 2

SPKT—simultaneous pancreas-kidney transplant

Questions for future research

What future new technologies can be helpful in management of type 1 diabetes?

How can newer insulin delivery methods benefit people with type 1 diabetes?

What is the role of disease modifying treatments in prevention and delay of type 1 diabetes?

Is there a role for sodium-glucose co-transporter inhibitors or glucagon-like peptide 1 receptor angonists in the management of type 1 diabetes?

As the population with type 1 diabetes ages, how should management of these people be tailored?

How can we better serve people with type 1 diabetes who live in under-resourced settings with limited access to medications and technology?

How patients were involved in the creation of this manuscript

A person with lived experience of type 1 diabetes reviewed a draft of the manuscript and offered input on important aspects of their experience that should be included. This person is involved in large scale education and activism around type 1 diabetes. They offered their views on various aspects of type 1 diabetes, especially the use of adjuvant therapies and the burden of living with diabetes. This person also raised the importance of education of general practitioners on the various stages of type 1 diabetes and the management aspects. On the basis of this feedback, we have highlighted the burden of living with diabetes on a daily basis.

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: SS and IBH contributed to the planning, drafting, and critical review of this manuscript. FNK contributed to the drafting of portions of the manuscript. All three authors are responsible for the overall content as guarantors.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: SS has received an honorarium from Abbott Diabetes Care; IBH has received honorariums from Abbott Diabetes Care, Lifescan, embecta, and Hagar and research support from Dexcom and Insulet.

Provenance and peer review: Commissioned; externally peer reviewed.

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Study unlocks potential breakthrough in type 1 diabetes treatment

by Silvia Cernea Clark, Rice University

For the well over 700 million people around the globe living with type 1 diabetes, getting a host immune system to tolerate the presence of implanted insulin-secreting cells could be life-changing.

Rice University bioengineer Omid Veiseh and collaborators identified new biomaterial formulations that could help turn the page on type 1 diabetes treatment, opening the door to a more sustainable, long-term, self-regulating way to handle the disease.

To do so, they developed a new screening technique that involves tagging each biomaterial formulation in a library of hundreds with a unique "barcode" before implanting them in live subjects.

According to the study in Nature Biomedical Engineering , using one of the alginate formulations to encapsulate human insulin-secreting islet cells provided long-term blood sugar level control in diabetic mice. Catheters coated with two other high-performing materials did not clog up.

"This work was motivated by a major unmet need," said Veiseh, a Rice assistant professor of bioengineering and Cancer Prevention and Research Institute of Texas scholar. "In type 1 diabetes patients , the body's immune system attacks the insulin-producing cells of the pancreas. As those cells are killed off, the patient loses the ability to regulate their blood glucose."

For decades, scientists labored toward what Veiseh called a "'holy grail" goal of housing islet cells inside a porous matrix made out of a protective material that would allow the cells to access oxygen and nutrients without getting clobbered by the host's immune system.

However, materials with optimal biocompatibility proved very hard to find, due in part to screening constraints. On one hand, immune system response to a given implanted biomaterial can only be assessed in a live host.

"The problem is the immune response needs to be investigated inside the body of these diabetic mice, not in a test tube ," said Boram Kim, a graduate student in the Veiseh lab and co-lead author on the study. "That means that if you want to screen these hundreds of alginate molecules, then you need to have hundreds of animal test subjects. Our idea was to screen for hundreds of biomaterials at the same time, in the same test subject."

On the other hand, different biomaterial formulations look the same, making it impossible to identify high-performing ones in the absence of some telltale trait. This made testing more than one biomaterial per host unfeasible.

"They are different materials but they look the same," Veiseh said. "And once they are implanted in the body of a test subject and then taken out again, we cannot distinguish between the materials and we would be unable to identify which material formulation worked best."

To overcome these constraints, Veiseh and collaborators came up with a way to tag each alginate formulation with a unique 'barcode' that allowed them to identify the ones that performed best.

"We paired each modified biomaterial with human umbilical vein endothelial cells (HUVEC) from a different donor," Kim said.

"The HUVEC cells, because they come from unique donors, act as a barcode that allows us to tell what material was used initially," Veiseh added. "The winners are the ones that have live cells in them. Once we found them, we sequenced the genome of those cells and figured out which material was paired with it. That's how we uncovered the greatest hits."

Trials are underway for stem cell-derived islet cell use in diabetic patients. However, current islet treatments require immunosuppression, making it a taxing way to treat type 1 diabetes.

"Currently, in order to use implanted islet cells in diabetic patients, you have to suppress the entire immune system, just as if you were trying to do an organ transplant," Veiseh said. "That comes with a lot of complications for the patient."

"They can develop cancer, they can't fight infections, so, for the vast majority of patients, it's better to actually do the insulin therapy where they inject themselves. With this biomaterial-encapsulation strategy, no immunosuppression is needed."

Placing actual HUVEC cells inside the biomaterial capsules increased the likelihood that the host immune system would detect a foreign presence. This makes the experiment more robust than simply testing for immune response to the biomaterials alone.

"We wanted to test a library of these materials, with the selection pressure of having cells inside the beads that makes it harder for the material to not get noticed by the immune system," Veiseh said. "There's a lot of interest from all the islet cell manufacturers to be able to get rid of immunosuppression and instead use these alginate hydrogel matrices to protect the implanted cells."

The new high-throughput "barcoding" approach can be deployed to screen for other medical applications using fewer live test subjects.

"That actually feeds into a lot of other projects in my lab where we're doing biologic production from cells for other disease indications," Veiseh said. "The same modifications can be applied to all types of materials that go into the body. This is not limited only to cell transplantation. The technology we developed can be paired with a lot of different device concepts."

"For instance, some diabetic patients use automated pump systems to self-administer insulin. The catheters on those pump systems have to be replaced every few days because they get clogged. We were able to show that coating the catheters with these new materials prevented clogging."

"With this new cell-based barcoding technology, biomaterials research just got an unprecedented boost that will accelerate the translation to clinically applicable products, and make it more affordable," said Dr. José Oberholzer, a transplant surgeon and bioengineer at the University of Virginia.

"This is a real paradigm shift. With this method, we can now screen hundreds of biomaterials at once and select those that the human body does not reject. We can protect cellular grafts from the assaults of the immune system, without the need for immunosuppressive medications," Oberholzer added.

Former Rice bioengineering professor and current NuProbe U.S. CEO David Zhang noted that " high-throughput DNA sequencing has revolutionized many biomedical fields."

"I am pleased to work with Omid to enable the development of improved biomaterials using my team's expertise in DNA sequencing," added Zhang, who was a co-investigator on the grant. "These improved biomaterials can enable durable implanted cell therapies to function as living drug factories, and can have a positively disruptive impact on patients with a variety of chronic diseases."

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The Long, Long Wait for a Diabetes Cure

A documentary captures the desperation and frustration of Type 1 diabetes patients in a clinical trial.

Lisa Hepner produced and directed the documentary “The Human Trial” with her husband, Guy Mossman, about people taking part in a clinical trial to treat Type 1 diabetes. Credit... Alex Welsh for The New York Times

Supported by

By Andrew Jacobs

• Published Aug. 9, 2022 Updated Aug. 10, 2022

In the three decades since she was first diagnosed with Type 1 diabetes, Lisa Hepner has clung to a vague promise she often heard from doctors convinced medical science was on the cusp of making her body whole again. “Stay strong,” they would say. “A cure is just five years away.”

But the cure has yet to arrive, and Ms. Hepner, 51, a filmmaker from Los Angeles, remains hobbled by her body’s inability to make insulin, the sugar-regulating hormone produced by the pancreas. “I might look fine to you,” she said, “but I feel crappy 70 percent of the time.”

Staying healthy can be exhausting for many of the 37 million Americans with some form of diabetes. There’s the round-the-clock monitoring of sugar levels; the constant, life-sustaining insulin injections; and the potential threats from diabetes’ diabolical complications: heart disease, blindness, kidney damage and the possibility of losing a gangrenous limb to amputation.

“‘The cure is five years away’ has become a joke in the diabetes community,” Ms. Hepner said. “If it’s so close, then what’s taking so long? And in the meantime, millions of us have died.”

That attenuated sense of hope drove Ms. Hepner to spend nearly a decade following the fortunes of ViaCyte, a small San Diego biotech company working to create what would essentially be an artificial pancreas. If successful, its stem-cell-derived therapy would eliminate the pin-pricks and insulin injections that circumscribe the lives of the 1.5 million Americans with Type 1 diabetes. Vertex Pharmaceuticals, a Boston biotech company developing a similar therapy, has already made significant headway .

Since its theatrical debut in June, “The Human Trial,” the documentary she produced with her husband, Guy Mossman, has electrified the diabetes community, especially those with Type 1, a disease that the uninitiated often conflate with the more common Type 2.

Unlike Type 2, which tends to emerge slowly in adulthood and can sometimes be reversed early on with exercise and dietary changes, Type 1 is an autoimmune disease that often strikes without warning in childhood or adolescence.

Type 1 is also far less prevalent, affecting roughly 10 percent of those with diabetes. A pancreas transplant can cure the disease, but donated organs are in short supply and the surgery carries substantial risks. In most years, only a thousand transplants are done in the United States. To ensure the body does not reject the implanted pancreas, recipients must take immunosuppressant drugs all their lives, making them more susceptible to infections.

Therapies developed from human embryonic stem cells, many experts say, offer the best hope for a lasting cure. “The Human Trial” offers a rare glimpse into the complexities and challenges of developing new therapies — both for the patients who volunteer for the grueling clinical trials required by the Food and Drug Administration, and for the ViaCyte executives constantly scrambling to raise the money needed to bring a new drug to market. These days, the average cost , including the many failed trials along the way, is a billion dollars.

At a time when the soaring price of insulin and other life-sustaining drugs has tarnished public perceptions of the pharmaceutical industry, the film is also noteworthy for its admiring portrayal of a biotech company whose executives and employees appear genuinely committed to helping humanity. (Limiting the cost of insulin remains politically volatile. On Sunday, during a marathon vote on the Democrats’ climate and health bill, Republicans forced the removal of a provision with a $35 cap on insulin prices for patients with private insurance, though the cap remained in place for Medicare patients.)

“The Human Trial,” which can also be viewed online , has become a rallying cry for Type 1 patients, many of whom believe only greater visibility can unleash the research dollars needed to find a cure.

Those who have seen the film have also been fortified by seeing their own struggles and dashed hopes reflected in the journeys of the film’s two main subjects, Greg Romero and Maren Badger, who became among the first patients to have the experimental cell pouches implanted under their skin.

The despair that drives them to become human guinea pigs can be hard to watch. Mr. Romero — whose father also had the disease, went blind before he was 30 and then died prematurely — confronts his own failing vision while grappling with the pain of diabetes-related nerve damage. “I hate insulin needles, I hate the smell of insulin. I just want this disease to go away,” Mr. Romero, 48, says numbly at one point in the film.

Type 1 can leave patients feeling alienated and alone, in part because of flawed assumptions about the disease. Tim Hone, 30, a medical writer in New York who has been living with Type 1 since he was 15, said friends and acquaintances sometimes suggested that he was responsible for causing his illness. “I’ve had people scold me and say that if I went on a diet and stopped eating Snickers bars I could reverse my disease,” Mr. Hone said.

The stigma often drives people with Type 1 to hide the disease. In his quest to feel “normal” at college, Todd Boudreaux said, he avoided telling friends about his illness, a decision that could have had dangerous ramifications in the event of a seizure brought on by low blood sugar levels.

“I didn’t want to be defined by my illness, and I didn’t want to be seen as weak, but having Type 1 does make you different and it’s important that everyone around knows so they can help if you have severe low blood sugar,” said Mr. Boudreaux, 35, who lives in Monterey, Calif., and works for the nonprofit group Beyond Type 1.

Ms. Hepner, too, has spent much of her life downplaying the disease, even with her husband, Mr. Mossman. She recalled his confusion early in their relationship when he awoke to find her discombobulated and drenched in sweat, the result of hypoglycemia, or low blood sugar. The more Mr. Mossman, a cinematographer, learned about the disease, the more he pressed her to make the film.

For years, Ms. Hepner stood her ground, worried about drawing unwanted attention to her health. “It’s a competitive world out there and I just didn’t want people to think, ‘Oh, she’s not thinking straight because her blood sugar is high,’” she said.

But over time, the ubiquity of pink-ribbon breast cancer awareness campaigns and highly publicized efforts to cure Alzheimer’s made Ms. Hepner realize her filmmaking skills could change public perceptions of Type 1, a disease that is nearly invisible, in part because many people who have it do not look sick.

She hopes to change other misperceptions, including the notion that diabetes is a relatively inconsequential and “manageable” illness, one that has been popularized by Big Pharma’s feel-good drug television commercials that feature self-assured patients playing tennis and basketball and piloting hot air balloons.

In fact, the industry spends a fraction of its research dollars on finding a cure, with the rest directed toward developing medications and devices that make it easier to live with the disease, according to the Juvenile Diabetes Cure Alliance.

The payoff from those investments is undeniable. For those who can afford them, continuous glucose-monitoring devices can obviate the need for self-administered finger-prick testing, and the machines can be paired with iPhone-size insulin pumps that eliminate much of the guesswork over dosing.

Ms. Hepner has profound appreciation for the wonders of insulin: At one point in the film she pays homage to its inventor, Frederick Banting, during a visit to his home in Canada. But she notes that insulin-dependent diabetes is no picnic. Many people without insurance cannot afford the thousands of dollars it costs annually for the drug, forcing some to skimp and ration. And a miscalculated or ill-timed dose can lead to seizures, unconsciousness and even death. Even with all the advances in care, only about 20 percent of adults with Type 1 are able to maintain healthy blood sugar levels, according to a 2019 study . On one occasion, Ms. Hepner woke up in the I.C.U. after her insulin pump failed.

“We need to stop trying to normalize this disease because, let’s face it, having diabetes isn’t normal,” she said. “It’s the other pandemic, one that killed 6.7 million people last year around the world.”

Despite her frustrations, it would be inaccurate to describe Mr. Hepner and her film as pessimistic. At the risk of giving away too much, “The Human Trial” ends on a hopeful note. And despite a number of near-brushes with bankruptcy, ViaCyte succeeded in gaining the funding to keep the laboratory lights burning.

Then there is more recent news that did not make it into the film. Last month, ViaCyte was acquired by Vertex, the competing biotech company that has been developing its own stem-cell treatment. That treatment has shown early success , and last year the company announced that a retired postal worker who took part in clinical trials had been cured of Type 1 diabetes.

After almost a lifetime of hearing a cure was just around the corner, Dr. Aaron Kowalski, chief executive of the JDRF (Juvenile Diabetes Research Foundation), the world’s biggest funder of Type 1 research, counts himself as an optimist. A dozen more drug companies are pursuing a cure than a decade ago, he said, and the organization this year plans to spend $100 million on cure research. “It’s not a matter of if this will happen, it’s a matter of when,” said Dr. Kowalski, who is a scientist and has had the disease since childhood, as has a younger brother. “Our job is to make sure it happens faster.”

Until that day, he added, people with diabetes, both Type 1 and Type 2, could use a little empathy and understanding.

Andrew Jacobs is a health and science reporter, based in New York. He previously reported from Beijing and Brazil and had stints as a metro reporter, Styles writer and national correspondent, covering the American South. More about Andrew Jacobs

What to Know About Diabetes

Diabetes, a condition in which the body has trouble regulating blood sugar, is increasingly common among americans..

Over 37 million Americans have some form of diabetes. Scientists say that medical care  won’t be enough to halt the spread of the disease: Sweeping societal changes are needed .

Insulin resistance can be a precursor to diabetes and pre-diabetes. Here is what to know about the condition and how to know if you have it .

For people with Type 1 diabetes, which often strikes in adolescence, staying healthy can be exhausting . A treatment that can delay the disease’s onset offers some hope .

People who regularly eat red meat may have a higher risk of Type 2 diabetes later in life , according to a new study. Those who often consume processed meats have an even greater risk.

Healthy practices can delay and prevent Type 2 diabetes. Something as simple as going for a 15-minute walk after a meal  could help ward off the disease.

People are claiming that the diabetes medication Ozempic helped them lose weight quickly and easily — but experts say it’s not a miracle drug .

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Type 1 diabetes articles from across Nature Portfolio

Type 1 diabetes (also known as diabetes mellitus) is an autoimmune disease in which immune cells attack and destroy the insulin-producing cells of the pancreas. The loss of insulin leads to the inability to regulate blood sugar levels. Patients are usually treated by insulin-replacement therapy.

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Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes

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Characterization of the gut bacterial and viral microbiota in latent autoimmune diabetes in adults

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Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review

Felton et al. conduct a systematic review to determine the utility of islet autoantibodies as biomarkers of type 1 diabetes heterogeneity. They find that islet autoantibodies are most likely to be useful for patient stratification prior to clinical diagnosis.

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Mujahid et al. develop a type 1 diabetes patient simulator using a conditional sequence-to-sequence deep generative model. Their approach captures causal relationships between insulin, carbohydrates, and blood glucose levels, producing virtual patients with similar responses to real patients in open and closed-loop insulin therapy scenarios.

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Reply to ‘slowly progressive insulin dependent diabetes mellitus in type 1 diabetes endotype 2’.

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Activation of innate immunity has been linked to the progression of type 1 diabetes. A study now shows that overexpression of METTL3, a writer protein of the m 6 A machinery that modifies mRNA, restrains interferon-stimulated genes when expressed in pancreatic β-cells, identifying it as a promising therapeutic target.

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One hundred years after the Nobel prize was bestowed on Banting and McLeod for the ‘discovery’ of insulin, we are again seeing major evolutions in the management of type 1 diabetes mellitus, with the prospect of achieving disease control beyond mere management now becoming real. Here, we discuss the latest, most notable developments.

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Current and future therapies for type 1 diabetes

Bernt johan von scholten.

1 Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark

Frederik F. Kreiner

Stephen c. l. gough, matthias von herrath.

2 Type 1 Diabetes Center, The La Jolla Institute for Immunology, La Jolla, CA USA

Associated Data

Graphical abstract.

In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.

Supplementary Information

The online version contains a slide of the figure for download available at 10.1007/s00125-021-05398-3.

Introduction

In addition to prolonging the life expectancy of people living with type 1 diabetes, the discovery of insulin a century ago revolutionised the management of this chronic autoimmune disease. Today, type 1 diabetes is the most common type of diabetes in children, and estimates suggest that around 100,000 children develop the disease every year [ 1 ]. Unfortunately, despite the availability of advanced insulins, affected individuals remain at high risk of serious complications, including cardiovascular mortality [ 2 – 4 ]. New interventions are, therefore, urgently required to improve the prognosis for the increasing number of people who are diagnosed with type 1 diabetes each year.

The profile of the person with type 1 diabetes is evolving and, with that, our understanding of the disease. The overall pathophysiological feature is loss of functional beta cell mass in the pancreatic islets of Langerhans (Fig. ​ (Fig.1) 1 ) [ 5 ]. Hypotheses suggest that the loss of functional beta cell mass occurs in a chain of events analogous to an ‘assisted suicide’ [ 6 , 7 ], where the demise of the beta cell is likely due to a combination of a dysfunctional beta cell that becomes more visible to the immune system, which, in turn, overreacts and destroys the beta cell.

Hallmarks of the evolving profile of the individual with type 1 diabetes, and current and future options for the prevention of this disease and for the management of its associated complications. a According to some recent evidence [ 124 – 130 ]. This figure is available as a downloadable slide

In its early stage (Stage 1), type 1 diabetes is usually asymptomatic; however, the development of autoimmunity is often detectable in early life, with circulating autoantibodies targeting insulin or other proteins, such as GAD65, insulinoma-associated protein 2 (IA­2) or zinc transporter 8 (ZNT8) [ 5 ]. When a large portion of the beta cell mass has become dysfunctional or lost, asymptomatic dysglycaemia (Stage 2) and, later, symptoms of hyperglycaemia (Stage 3) ensue due to insufficient or absent insulin secretion.

Type 1 diabetes is a polygenic disorder, in which susceptibility loci or genetic variation contributes to disease risk. The HLA region on chromosome 6 is the main susceptibility locus and, in recent years, many other loci across the genome have been associated with an increasing risk of the disease [ 8 ]. However, from studies in monozygotic twins, for whom the onset of type 1 diabetes can vary considerably [ 9 ], it has become evident that non-genetic factors play a major role in triggering or perpetuating overt type 1 diabetes. A multitude of efforts have failed at robustly identifying such factors, strongly indicating that no single pathogen is responsible. Viral infections have been suggested, including enteroviruses and human herpesvirus-6 [ 10 – 13 ]. Of note, however, studies (mainly in animals) have also suggested that several viral infections may prevent the development of type 1 diabetes [ 14 , 15 ], in line with the ‘hygiene hypothesis’ [ 16 , 17 ].

People living with type 1 diabetes remain dependent on exogenous insulins as the cornerstone therapeutic option [ 18 ]. Since the isolation of insulin in 1921, novel and versatile formulations, analogues and delivery vehicles have been introduced [ 19 , 20 ]. Together with much improved glucose monitoring, these advances have contributed to the increases in the survival and life expectancy of individuals with type 1 diabetes [ 21 ]. Still, only a minority of people with type 1 diabetes achieve recommended glycaemic and time-in-range targets [ 22 ], and hyperglycaemia continues to be a risk factor for short-term metabolic and long-term macro- and microvascular complications [ 2 , 23 – 25 ]. Further, the use of exogenous insulins requires unremitting glycaemic monitoring and dose titration to mitigate the risk of hypoglycaemia. The all-cause mortality risk is around threefold higher for the individual with type 1 diabetes than for the general population [ 2 – 4 , 26 ], and type 1 diabetes has been shown to be linked to cardiovascular outcomes more than any other disease, including type 2 diabetes [ 2 ].

As mentioned earlier, novel interventions are needed for the prevention and management of type 1 diabetes. Whilst progress has been limited, the evolving profile of a person with type 1 diabetes suggests that beyond ensuring accurate titration of exogenous insulin, efficient management of the disease should rely on other additional principles. First, there is an obvious need to act early to prevent or delay the destruction of functional beta cell mass by immunomodulatory intervention or other disease-modifying means. Second, stimulating or reprogramming the remaining beta cell mass to secrete insulin in a balanced way is required to avoid major blood glucose excursions with the lowest possible exogenous insulin dose. Third, reducing the risk of long-term complications, such as cardiovascular and renal outcomes, seems increasingly important (Fig. ​ (Fig.1). 1 ). Below we review selected current and in-development interventions meeting these three criteria (Table ​ (Table1 1 ).

Non-insulin agents for the prevention and management of type 1 diabetes

a Including blood glucose levels, body weight, blood lipids, blood pressure and cardiorenal risk

Immune-focused therapies

The overarching goal of immune-focused therapies in type 1 diabetes is to prevent or delay the loss of functional beta cell mass. The traditional understanding of autoimmunity in type 1 diabetes has focused on systemic immune dysregulation and on autoreactive T cells that have evaded thymic selection and migrated to the periphery, where they destroy islets. This view on the pathogenesis of type 1 diabetes has been referred to as T cell-mediated ‘homicide’ [ 6 ]. Thus, recent efforts have concentrated on cell- or cytokine-directed interventions, which have been successful in other autoimmune diseases. Targeting T cells or proinflammatory cytokines remain valid efforts and many agents are in active development; so far, however, these approaches have been only partly successful. This arguably indicates a need to refocus hypotheses, as discussed later in this review (see ‘ Future perspectives ’ section), where we outline how the beta cell itself contributes to its own demise (the ‘assisted suicide’ hypothesis).

Cell-directed interventions

In line with the traditional immune-centric view on the pathogenesis of type 1 diabetes, many immunomodulatory strategies have focused on antibodies targeting T effector cells. The anti-CD3 antibodies teplizumab and otelixizumab have shown some attenuation of loss of beta cell function [ 27 – 30 ]. A Phase II trial with relatives with a high risk of developing type 1 diabetes indicated a more than 50% risk reduction with teplizumab (HR 0.41 vs placebo) and clinical type 1 diabetes diagnosis was delayed by 1.5–2 years [ 31 ]. Accordingly, teplizumab has recently been granted a breakthrough therapy status by the US Food and Drug Administration. An ongoing Phase III trial (PROTECT; ClinicalTrials.gov registration no. {"type":"clinical-trial","attrs":{"text":"NCT03875729","term_id":"NCT03875729"}} NCT03875729 ) aims to evaluate the benefits and safety of teplizumab in children and adolescents with recently diagnosed type 1 diabetes.

The presence of autoantibodies against beta cell antigens, such as GAD65 and insulin, has spurred attempts targeting B cell-related molecules. These efforts have been somewhat successful in animal models [ 32 , 33 ], as well as clinically, most prominently with the B cell-depleting anti-CD20 antibody rituximab. Although rituximab led to detectable protraction of beta cell function [ 34 ], the effect was transient [ 35 ], exemplifying the fact that B cell-directed therapy alone does not appear to sustainably prevent or ameliorate beta cell autoimmunity. So far, however, B cell-directed agents have not been tested in the early disease stage, precluding conclusions regarding the usefulness of such interventions in delaying or even preventing progression to later stages.

In clinical investigations, low-dose anti-thymocyte globulin (ATG) treatment significantly (vs placebo) preserved C-peptide secretion and improved glycaemic control in children, as well as adults, with new-onset type 1 diabetes [ 36 – 38 ]. The potential benefits of ATG appear to depend on the dose level and the age of the recipients, and the clinical utility of the approach remains to be established. ATG in combination with granulocyte colony stimulating factor (GCSF) was also explored based on the hypothesis of a synergistic benefit of the combination of transient T cell depletion via low-dose ATG with the upregulation of activated T regulatory cells and tolerogenic dendritic cells induced by GCSF. However, the combination did not appear to offer a synergistic effect; in contrast to the use of ATG alone, ATG plus GCSF did not appear to be better than placebo in preserving C-peptide secretion [ 37 ].

Tissue-resident memory T effector cells, which likely play a role in many organ-specific autoimmune diseases, such as type 1 diabetes, are very difficult to eliminate. Alefacept, a T cell-depleting fusion protein that targets CD2 and, therefore, memory T effector cells, was tested in adolescents and young adults with Stage 3 type 1 diabetes in the T1DAL trial [ 39 ]. Although the trial did not complete enrolment as planned, it reported a trend for benefits with regard to beta cell preservation, reduced insulin requirements and low risk of hypoglycaemia that persisted throughout the follow-up of 15 months after treatment.

Importantly, whether considering the targeting of the T or B cell in type 1 diabetes, sufficient long-term benefits via systemic cell pool depletion comes with an inherent risk of introducing equally long-term or even irreversible changes to the immune system. Such changes may predispose the patient to a less favourable prognosis for chronic viral infections. For example, reactivation of Epstein-Barr virus (EBV) has been observed after anti-CD3 therapies [ 40 , 41 ]. Mitigating such risks may be achieved using carefully tailored dosing regimens and monitoring; still, the seriousness of the risks may indicate an unfavourable benefit:risks balance. Therefore, non-depleting immunomodulation has been explored. For example, 24-month blockade of CD80 and CD86 via the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-immunoglobulin fusion molecule abatacept markedly prolonged beta cell function in new-onset type 1 diabetes and was accompanied by increased numbers of naive T cells [ 42 , 43 ].

Cytokine-directed interventions

Anti-inflammatory cytokine-specific compounds, which are successfully used, for example, in rheumatic diseases, have been tested as alternatives to directly targeting the T or B cell in type 1 diabetes, as briefly summarised below. In addition, to stimulate an increase in T regulatory cells, low-dose IL-2 treatment has also been tested and the results have been somewhat promising [ 44 – 48 ], with recent developments mitigating earlier caveats, which included an arguably narrow dose range and lack of full specificity for T regulatory cells.

Blockade or antagonism of the central proinflammatory cytokine TNF-α using infliximab, adalimumab or the receptor fusion protein etanercept have shown some potential in type 1 diabetes, with indications of improved glycaemic control and C-peptide secretion [ 49 , 50 ]. More recently, a C-peptide-sparing effect of TNF-α blockade was reported with golimumab use, after 1 year in children and young adults with type 1 diabetes [ 51 ].

IL-6 is another proinflammatory cytokine that has been targeted with success in multiple other autoimmune diseases [ 52 ]. Although its role in type 1 diabetes is not established, IL-6 has been suggested as a target [ 53 ]. Of note, IL-6 has been shown to protect the beta cell from oxidative stress and is constitutively expressed by pancreatic alpha and beta cells, indicating important physiological roles [ 54 ]. In type 1 diabetes, the EXTEND Phase II trial of tocilizumab, a monoclonal antibody against the IL-6 receptor, was recently completed ( ClinicalTrials.gov registration no. {"type":"clinical-trial","attrs":{"text":"NCT02293837","term_id":"NCT02293837"}} NCT02293837 ).

IL-21 has been proposed as an attractive target in type 1 diabetes [ 55 , 56 ]. Physiologically, IL-21 is important not only for the function of T helper (Th) cells (Th17 and T follicular helper cells) but also for the generation and migration of CD8 + T cells. CD8 + T cells are now considered the chief T cell type accumulating in and around islets [ 57 , 58 ] with pre-proinsulin emerging as a pivotal autoantigen driving their infiltration in type 1 diabetes [ 59 ]. IL-21 neutralisation has been shown to prevent diabetes in mice [ 60 ], and a C-peptide-sparing benefit of anti-IL-21 alone or in combination with the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) liraglutide has been observed in a clinical proof-of-concept study [ 61 ], as described further below. Reassuringly, non-clinical models, including a viral type 1 diabetes model, showed a minor impact of IL-21 blockade on the immune repertoire [ 55 ].

Antigen vaccination

With the appeal of having no expected effect on acquired immunity, the overall aim of beta cell antigen vaccination is to induce tolerance by balancing the T cell population between auto-aggressive T effector cells and autoantigen-specific T regulatory cells. Induction of T regulatory cells carries the potential benefit of also downregulating the activity of proinflammatory antigen-presenting cells. The topic has been extensively reviewed in the past [ 62 ]. Briefly, inspired by successes with vaccination against, for example, peanut allergy, tolerisation of T effector cells has been attempted using administration of whole antigens, such as oral insulin, or of peptides. Whilst the concepts are promising and under active investigation, their effectiveness in humans is yet to be proven. For example, in at-risk children, oral insulin administration has previously failed to prevent type 1 diabetes [ 63 , 64 ], speculatively due to a suboptimal dose level or unclear effects across risk-specific subgroups [ 65 , 66 ], including those defined by insulin gene polymorphisms. Similar results and considerations have been reported for immunisation with GAD65 [ 67 ] and for peptide-based therapies [ 68 , 69 ]. Further, the lack of full clarity regarding the mechanisms at play with antigen-based therapies outlines a number of shortcomings, including the fact that no biomarker is currently available to assist in establishing the optimal dose regimen.

Non-immunomodulatory adjunctives

We next focus on selected compounds that have gained attention due to their potential benefits as adjuncts to insulin in type 1 diabetes.

Amylin deficiency is a recognised feature of type 1 diabetes [ 70 ]. As a neuroendocrine hormone, amylin inhibits glucagon secretion and contributes to reducing postprandial glucose variability. As an adjunct to meal-time insulin, the injectable amylin analogue pramlintide is approved only in the USA for the treatment of type 1 and type 2 diabetes alike [ 71 ]. In type 1 diabetes, pramlintide has been shown to improve postprandial glucose levels to some extent [ 72 ]. Its clinical use has been limited, arguably because of the modest efficacy alongside the occurrence of side effects, such as nausea and, most importantly, postprandial hypoglycaemia.

Metformin is a low-cost agent with glucose-lowering effects that mainly occur via decreased hepatic glucose production. It is not a guideline-recommended option in type 1 diabetes. However, partly because of its ameliorating effect on insulin resistance, metformin has been somewhat promising in managing the disease, especially in children and adolescents, as well as in obese people with type 1 diabetes, with studies indicating reduced insulin requirements and body weight reduction [ 73 – 75 ]. In the large REducing With MetfOrmin Vascular Adverse Lesions (REMOVAL) trial, however, metformin did not reduce the long-term insulin needs or improve glycaemic control in people with long-standing type 1 diabetes and multiple cardiovascular risk factors [ 76 ].

Sodium-glucose cotransporter inhibitors

Sodium-glucose cotransporter (SGLT) inhibitors lower blood glucose levels by restraining the absorption of glucose in the small intestine and promoting the renal excretion of glucose [ 77 ]. Results with dapagliflozin, empagliflozin and sotagliflozin have indicated benefits of SGLT inhibition in managing type 1 diabetes when added to insulin [ 78 – 83 ]. Significant benefits included reduced insulin dose requirements, improved glycaemic control and reduced body weight [ 84 ]. So far, sotagliflozin and dapagliflozin are approved in Europe and Japan (but not the USA) as adjuncts to insulin for the management of overweight or obese people with type 1 diabetes when optimally titrated insulin alone does not provide adequate glycaemic control. Importantly, however, data suggest that the use of SGLT inhibitors in type 1 diabetes is associated with markedly increased risk of diabetic ketoacidosis [ 85 – 87 ]; for sotagliflozin, a 5–17-fold risk increase was noted [ 88 ]. These observations prompted the formation of an international consensus on recommendations for the use of SGLT inhibition in type 1 diabetes [ 89 ] as well as a suggestion that treatment should be overseen by specialists [ 88 ].

GLP-1 is a hormone of the incretin system that is secreted upon food intake. A marked uptake has been seen in the use of GLP-1 RAs in type 2 diabetes due to their pleiotropic glucose-dependent effects that improve glycaemic control and reduce body weight [ 90 ]. In contrast, GLP-1 agonism for the treatment of type 1 diabetes remains unproven, with initial results from smaller investigator-conceived studies being inconclusive. Recently, Phase II findings with the short-acting GLP-1 RA exenatide in adults with type 1 diabetes were negative. In two larger Phase III trials (ADJUNCT ONE and ADJUNCT TWO), the GLP-1 analogue liraglutide used as an adjunct to insulin appeared well-tolerated and improved HbA 1c and reduced body weight [ 91 , 92 ]. Both ADJUNCT trials indicated a minor increase in the risk of hypoglycaemia and hyperglycaemia with ketosis with liraglutide use, whereas the risk of diabetic ketoacidosis was negligible. Subsequently, a plethora of investigations have reached similar conclusions [ 93 – 101 ]. Nonetheless, the use of GLP-1 RAs in type 1 diabetes remains potentially useful, as discussed below.

Verapamil is a common calcium-channel blocker used for decades as an anti-hypertensive agent. In mouse models of type 1 diabetes, verapamil promoted survival of functional beta cells via a mechanism that involves reduced expression of the cellular redox regulator thioredoxin-interacting protein [ 102 ]. In a smaller Phase II trial, verapamil was better than placebo for preserving meal-stimulated C-peptide secretion in adults with type 1 diabetes and no safety concerns were identified [ 103 ]. Despite these findings, however, the place for verapamil as a disease-modifying agent in type 1 diabetes remains to be fully established.

Future perspectives

Although research into type 1 diabetes prevention and disease modification continues to produce encouraging data, none of the approaches discussed above appears sufficiently effective alone in preventing or managing type 1 diabetes. Future endeavours will, therefore, require a novel focus, leveraging prior experience with regard to the immunopathophysiology of type 1 diabetes, whilst also exploring the promise of combination therapies that integrate tried or new treatment modalities. In addition, lessons learned from type 2 diabetes with regard to the beneficial effects of certain agents on, for example, body weight and cardiorenal risk may also prove relevant in type 1 diabetes. We review selected future prospects addressing these aspects below.

Of further note, the lack of sufficient efficacy of previously tested therapies may also be related to the fact that type 1 diabetes is a heterogenous disease with diverse disease stages (Stages 1 to 3) and modifiers, such as age of onset or clinical diagnosis. Identifying the optimal timing of each type of intervention relative to the disease stages and the age of the patient is, therefore, important. For example, initiating an immunomodulatory intervention at Stage 1 (i.e. prior to clinical diagnosis) is not a straightforward decision and may be associated with clinical inertia. Moreover, an increased focus on disease endotypes (i.e. different biological processes under the type 1 diabetes umbrella) was recently suggested to ensure a precision-medicine approach to type 1 diabetes research and management [ 104 ].

Immune interventions

It is becoming increasingly clear that autoreactivity to islet antigens is also present in healthy individuals [ 59 ] and autoimmunity recurs after autologous nonmyeloablative haematopoietic stem cell transplantation [ 105 , 106 ]. Thus, in line with the ‘assisted suicide’ theory introduced earlier [ 6 , 7 ], it is also increasingly apparent that the development of type 1 diabetes does not only involve dysfunctional islets, but also beta cells that ‘unmask’ themselves to immune recognition and destruction. This notion supports two central realisations; first, it might explain why, in previous studies, immune therapy alone has failed to protect beta cell function over longer periods of time after onset of diabetes. Second, looking forward, novel type 1 diabetes therapies should pursue the holy grail of type 1 diabetes immune therapy: essentially agents that act locally in the islets, within the pancreas, either targeting the immune cells destroying the beta cell or the beta cell itself. Knowledge gained over the years regarding the beta cell has suggested multiple, yet putative reasons for the ‘unmasking’ of these cells. Potential reasons include the facts that beta cells are especially biosynthetically active and systemically exposed [ 107 ] and, therefore, susceptible to stress-induced production of autoantigenic proteins during, for example, infections [ 108 – 110 ]. Moreover, the beta cell might be vulnerable to both cytokine-mediated destruction [ 111 ] and various types of endoplasmic reticulum stress [ 112 ]. Relieving the beta cell of these burdens may provide an opportunity to save the beta cell without resorting to aggressive immune suppression.

With this in mind, we see the following two promising avenues as deserving increased focus going forward: (1) therapies aimed at inducing tolerance to beta cell antigens; and (2) the use of GLP-1 RAs that directly target the beta cells to enhance their function whilst also protecting them from immune-mediated inflammatory stress.

As discussed above, achieving antigenic tolerance has, so far, proven elusive but carries the crucial potential of leaving the overall capacity of the immune system intact whilst suppressing only the diabetogenic cell populations. Future studies need to establish whether inducing tolerance in humans can be achieved by clonal anergy or clonal deletion of effector cells, or whether antigen-specific regulatory cells may be able to suppress autoreactivity locally. Moreover, it needs to be clarified to what extent tissue-resident memory effector cells can be eliminated.

Recent evidence from rodent models indicates a role for GLP-1 RAs in protecting beta cells from apoptosis and in promoting beta cell replication and mass [ 113 – 117 ]. As such, although this remains to be confirmed, it is conceivable that GLP-1 RAs may offer a way to prevent the ‘unmasking’ of the beta cell to immune effector cells, for example, by downregulating expression of MHC class I proteins. Intriguingly, unpublished non-clinical evidence shows that liraglutide also limits immune cell infiltration into pseudo-islets (M. von Herrath, unpublished results). In addition, studies in NOD mice have shown that GLP-1 RAs administered in combination with various immunomodulatory agents, including anti-CD3 compounds [ 118 ], were more efficient in inducing diabetes remission than when given as monotherapy [ 119 ]. Furthermore, the anti-inflammatory effects of GLP-1 RAs are well-documented, with liraglutide being associated with reduced systemic levels of C-reactive protein and of proinflammatory cytokines, such as TNF-α, IL-1β and IL-6 [ 120 – 123 ]. Whilst these findings have mainly been observed in animal models or in type 2 diabetes, their relevance to (clinical) type 1 diabetes is conceivable but, so far, largely unexplored.

Management of cardiometabolic complications

A person diagnosed with type 1 diabetes faces a high risk of serious complications and of premature death, primarily for cardiovascular causes. This warrants a therapeutic focus on the broad pathophysiology of the disease.

Further, whilst the exact connections between excess body weight and type 1 diabetes remain debatable [ 124 ], the increased incidence of type 1 diabetes seems to coincide with the rapid rise in the prevalence of obesity [ 125 , 126 ]. Recent evidence suggests that a high BMI may exacerbate the early-stage immune-mediated beta cell destruction in type 1 diabetes, especially in children and adolescents [ 127 ]. Evidence also points to an impact of rapid growth in early childhood [ 128 ], and a positive correlation between the age of type 1 diabetes onset and BMI has been observed [ 129 ]. The ‘accelerator hypothesis’ views high BMI and low insulin sensitivity as triggers for type 1 diabetes onset [ 130 ] and the term ‘double diabetes’ has been suggested to describe an amalgam of type 1 diabetes with parallel and separate pathophysiological processes typically associated with type 2 diabetes, such as obesity and insulin resistance [ 131 ].

Use of SGLT inhibitors or GLP-1 RAs as adjuncts to insulin admittedly holds promise in ameliorating multiple type 1 diabetes complications. For example, evidence suggests that SGLT inhibitors offer cardiorenal protection [ 132 , 133 ], at least in type 2 diabetes, putatively owing to clinically unproven mechanisms of action beyond improved glucose homeostasis [ 134 ]. Moreover, a few GLP-1 RAs (dulaglutide, liraglutide and semaglutide) are now indicated to reduce cardiovascular risk in people with type 2 diabetes and established cardiovascular disease, and a protective effect of GLP-1 RAs on the kidneys is suggested from a range of cardiovascular outcome trials (CVOTs) in type 2 diabetes [ 135 – 138 ]. In addition, both SGLT inhibitors and GLP-1 RAs, especially second-generation GLP-1 RAs (e.g., semaglutide), are associated with a meaningful reducing effect on body weight.

Combination therapies

Combination therapies that work via two mechanistically distinct targets to integrate immune modulation with a beta cell-specific component have been suggested [ 139 – 141 ] and encouraged [ 142 ]. Truly advantageous combination therapies are arguably those in which the components target different pathogenic pathways (for example, systemic vs beta cell-specific pathways), thereby synergising in terms of the beneficial effects. These combination therapies should also be safe and well-tolerated alone and in combination.

Known ongoing efforts are sparse but include the combination of ATG and GCSF (as discussed above) and the combination of targeted immune modulation via an anti-IL-21 antibody in combination with a GLP-1 analogue (liraglutide). In addition to the potential of preserving functional beta cell mass by leveraging the immunomodulatory and anti-inflammatory properties of both the anti-IL-21 antibody and liraglutide, their combination addresses the need to manage the symptoms and complications of established type 1 diabetes, as discussed earlier. As previously mentioned, results from a clinical proof-of-concept trial recently found that anti-IL-21 plus liraglutide was significantly better than placebo in preserving C-peptide secretion over a period of 54 weeks [ 61 ]. The benefits diminished after treatment cessation; however, the treatment appeared safe and well-tolerated.

Stem cell replacement therapy

On the horizon, we approach the promise of stem cell-based therapies [ 143 ], offering a potential cure by replacing or supplementing beta cells that have been lost or have become dysfunctional. Stem cell-derived beta cells, however, also need to be rescued from immune-mediated destruction, suggesting that some degree of immunomodulation will be needed, even in the advent of viable stem cell therapy in type 1 diabetes, unless a fully effective immune-defying capsule is available [ 144 ]. In this context, better prevention or treatment regimens will also be useful for enabling longer-term beta cell graft acceptance.

Closing thoughts

Whilst many intriguing non-insulin therapies have failed to fully meet their potential in the past few decades, hope remains that the knowledge gained has carved out paths towards better options for the prevention and management of type 1 diabetes. Taken together, in our view, stem cell replacement therapies and a refocused development of safe and well-tolerated combination therapies are the most promising emerging preventive or therapeutic avenues. In parallel, reinforced efforts to predict or diagnose type 1 diabetes as soon as possible are equally important in light of the fact that even the best interventions need to be introduced as early as possible to effectively preserve or rescue beta cells in individuals with this condition.

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All authors are employees of Novo Nordisk A/S, Denmark.

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New Startup Develops Potential Cure for Type 1 Diabetes

Nov 03, 2022 — atlanta, ga.

Islets (stained green with viability stain) mixed with microgels presenting FasL (red).

Insulin injections to treat Type 1 diabetes could become a thing of the past, but finding the cure faces many challenges. Although transplanting insulin-producing cells represents a promising approach, this cell therapy requires immunosuppression to prevent rejection. Georgia Tech researchers have developed a new biomaterial called iTOL-100 that could cure Type 1 diabetes by inducing immune acceptance of curative transplanted cells without immunosuppression.

This groundbreaking platform therapy is the basis for the new startup, iTolerance. The company is working to enable implantable tissue, organoid, or cell therapy without the requirement for lifelong immunosuppression. The therapies have the potential to not only cure Type 1 diabetes but also regenerate failing livers.

“Our major goal for two decades has been to come up with approaches to eliminate immunosuppression,” said Andrés García , executive director of the Parker H. Petit  Institute for Bioengineering and Bioscience and member of iTolerance’s scientific advisory board. “Our combined biomaterial is decorated with a potent immunomodulatory protein, so when we transplant it with cells, it trains the immune system to accept the graft as self and not to reject.”

The Insulin Issue

Type 1 diabetes is an autoimmune condition where a person becomes immune to the pancreas’s insulin-producing cells called islets. Without islets, a person cannot regulate blood glucose levels. Although this form of diabetes can be treated with insulin injections, it is far from a cure and can still lead to long-term complications such as heart disease, vision problems, or even premature death.

The best way to manage Type 1 diabetes currently is either insulin injections or, for patients with more severe conditions, isolating islets from cadavers and reinfusing them into the patient. However, this procedure requires immunosuppression to ensure the body doesn’t reject the cells. This is not only toxic but can make a person more susceptible to other diseases.

“We’re going to be able to treat a lot more patients if we use insulin-producing cells derived from stem cells because that would allow us to eliminate the cadaveric donors,” García said. “Eventually this could benefit all Type 1 diabetes patients.”

How iTOL-100 Works

The biomaterial is made of a synthetic hydrogel, a soft material that is 95% water and 5% synthetic polymer, that acts as a fishnet. On the surface is a potent immune system protein, Fas ligand (FasL), that induces immune acceptance and tolerance.

“People in the field thought that you would have to encapsulate the cells in the biomaterial, but when we realized we could simply mix the cells with the biomaterials, it makes it very easy because we can do it at the time of cell transplantation,” García said.

Introducing iTolerance

García started working on this research after receiving a three-year grant from the Juvenile Diabetes Research Foundation to engineer injectable biomaterials. The biomaterial was first researched in a mouse model, but because they have very different immune systems from humans, they also validated in a non-human primate model. The research proved so promising that it was licensed into iTolerance to eventually push the technology to market.

“The data that the scientific founders of iTolerance generated with the iTOL-100 technology were incredibly compelling,” said Anthony Japour, M.D ., CEO of iTolerance. “The opportunity to translate that promising research into the clinic was something we couldn’t pass up. Leveraging the iTOL-100 platform technology not only has the potential to generate a cure for Type 1 diabetes, but also has significant potential to address a number of additional indications using both allogenic pancreatic islets and stem cells that have the potential to cure diseases.”

Currently, iTOL-100 only works with individual cells, making it ideal for diabetes research and even liver failure because they can be treated on a cell-by-cell basis. However, García believes it could be applied to solid organs such as kidneys and hearts.

“The material is really agnostic to what the cell source is,” García said. “It's just a matter of combining the cells with the body materials and transplanting.”

For now, though, iTolerance’s breakthrough could revolutionize the treatment and health of Type 1 diabetes patients.

“Insulin is a way to manage diabetes, but it's not a cure,” García said. “Cell therapy is the cure.”

García has co-founded a company called iTolerance that is developing immunomodulatory biomaterial technology, bringing it further into clinical trials, commercializing it, and ultimately making it available to patients.   

García and several other Georgia Tech researchers are inventors of the immunomodulatory biomaterial used in this study and have ownership interest in iTolerance. They are entitled to royalties derived from iTolerance’s future sales of products related to the research. These potential conflicts of interest have been disclosed and are overseen by Georgia Institute of Technology.  

Executive Director, Parker H. Petit Institute for Bioengineering and Bioscience, The Petit Director's Chair in Bioengineering and Bioscience, Regents' Professor, George Woodruff School of Mechanical Engineering

Executive Director, Parker H. Petit Institute for Bioengineering and Bioscience, The Petit Director's Chair in Bioengineering and Bioscience, Regents' Professor, George Woodruff School of Mechanical Engineering

Tess Malone, Research Writer/Editor 

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Research on a cure for type 1 diabetes

To find a cure for people living with type 1 diabetes , we need to find a way to help people produce their own insulin.   

One solution is islet cell transplants. So, we’ve invested around £2.2 million in the last 10 years.  

What are islet cell transplants?   

• Scientists remove clusters of insulin-making beta cells, called islets, from a donor pancreas  
• Donor cells are transplanted into someone with type 1 diabetes
• Donated beta cells start producing insulin
• This allows people to temporarily make enough of their own to reduce or stop insulin injections, have steadier blood sugar levels, fewer severe hypos and regain hypo awareness.  

In 1989, Diabetes UK scientists, led by Dr Roger James and Dr Stephen Lake, developed a way to collect islets for transplant. Their method is still regarded as the gold standard today.  

Soon after, we launched the UK Islet Transplant Consortium to bring together leading researchers to make sure islet transplants are available to those who could benefit the most.   

In 2005, we then funded teams at King’s College London, the Royal Free Hospital and Oxford to carry out the UK’s first 12 islet transplants.  

Our research then established that islets could successfully be moved around the UK, to reach those who needed them. Thanks to this, by 2008, islet transplants became available on the NHS to people with type 1 with no hypo awareness and who experience severe hypos.  

In 2021, our research showed islet transplants are more effective if people receive two transplants over a short period - changing how islet cell transplants are performed in the UK.  

Rachel Brown lives with type 1 diabetes and received an islet transplant after experiencing life-threatening hypos. She said:  

“You feel as close to a normal person as possible. I was even able to come off insulin and my sugars seemed to be in range almost all of the time. Everything is so much better now, and it just made me feel free.”

Watch Rachel discuss the difference her islet transplant made with our researcher, Professor Shareen Forbes.

Beta cells, a challenge for the future

Donor islets are scarce, which limits the number of people with type 1 diabetes who can benefit. That’s why we’re also investing in research to grow new beta cells in the lab.   

This would give us a steady supply of cells so in the future everyone with type 1 diabetes can benefit from transplants.  

Thanks to the Type 1 Diabetes Grand Challenge , we’re making major investments in research to radically improve how beta cells are grown in the lab and fast-track progress towards rescuing people’s own beta cells.  

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© The British Diabetic Association operating as Diabetes UK, a   charity registered in England and Wales (no. 215199) and in Scotland (no. SC039136). A company limited by guarantee registered in England and Wales with (no.00339181) and registered office at Wells Lawrence House, 126 Back Church Lane London E1 1FH

Melbourne researchers' diabetes breakthrough could reduce need for insulin injections

Diabetes researchers say they have made a breakthrough that could pave the way to eliminating the need for daily insulin injections.

Key points:

• The Monash University team was able to get pancreatic cells to produce insulin
• If the research leads to animal studies then clinical trials, it could reduce the need for insulin injections
• It could be a "game changer" in treatment for the chronic disease, an independent researcher says

The Monash University research, published in the Nature journal  Signal Transduction and Targeted Therapy , could lead to the regeneration of insulin in pancreatic stem cells.

Insulin is a hormone, made by what are known as beta cells in the pancreas, which helps to regulate blood sugar levels. 

Broadly, people with diabetes do not naturally produce enough insulin, or their bodies do not use the hormone as they should. The beta cells in many people with diabetes are unable to produce insulin at all.

"There are different forms of diabetes and it's a disease that requires relentless attention," said Keith Al-Hasani, a Monash University researcher and one of the study's authors.

Type 1 diabetes generally first presents when patients are children, which Dr Al-Hasani said often meant up to five insulin injections per day as young people adjusted to the disease. Adult sufferers can administer up to 100 shots a month to manage the illness.

After the death of a 13-year-old with type 1 diabetes, the researchers studied donated pancreatic cells and used a compound to trigger insulin production.

"We're reprogramming cells that don't generally produce insulin, to express insulin now," researcher and study co-author Ishant Khurana said.

The compound GSK126 is approved for use to treat another condition by the US Food and Drug Administration, but has not been used for diabetes treatment in Australia or elsewhere. 

"This is a big breakthrough in the diabetes realm," Dr Khurana said.

While the researchers studied stem cells, they did not genetically alter the cells to get their results. 

The authors acknowledged there was still a long way to go before the potential treatment could be used in humans.

They next want to collect more pancreatic cell samples from a bigger range of people, then move to animal trials before possibly beginning human clinical trials.

The end goal, Dr Khurana said, was to eliminate the need for daily injections and pancreatic transplants.

It would affect most people with Type 1 diabetes, and the about 30 per cent of people with Type 2 diabetes who are insulin dependent.

According to Diabetes Australia, about 1.8 million Australians have diabetes and it is the fastest-growing illness in the country. About 500 million have the disease worldwide.

Simon McCrudden, 46, has been administering his own insulin since he was seven years old and said removing the burden of daily injections would be "massive".

"I'd have to re-learn just how to just do daily life, but it'd be great," he said.

Associate professor Neale Cohen, the director of diabetes clinical research at the Baker Heart and Diabetes Institute, said the Monash research was still in its early days but showed great potential.

"There are a number of attempts to find ways of replacing beta cells, which are all tremendously important. And if that is possible, what it would mean it would be a cure for people with Type 1 diabetes," he said.

Dr Cohen, who was not involved in the study, said research over a number of decades had found "it seems to be remarkably difficult to reprogram cells to become insulin-producing cells.

"So if you can cure these people from this very difficult chronic condition, that's a game changer," he said.

"People will no longer need to inject insulin, and they won't have the burden of this chronic illness."

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Keyoshi carr.

“We are all in this together. To be able to go to the Walk and see that we are a community makes all the difference to my family,” Carmen Carr, Keyoshi Carr’s mother.

Keyoshi’s family changed forever when her older sibling was diagnosed with T1D. They quickly became active members of the JDRF community, doing school fundraisers, T1D education workshops and starting a JDRF One Walk team.

Six years later, the unimaginable happened again. Keyoshi was diagnosed with T1D. She had been a participant in TrialNet, a JDRF-funded program that offers risk screening for relatives of people with T1D. She had tested positive for antibodies, so her parents we’re watching for the symptoms. They credit TrialNet with potentially saving her life.

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Dan has found he has had to be a strong advocate for himself with healthcare providers. He had made sure to work with clinics and professionals that specialize in T1D and keep up with the latest technology and treatment options. He enjoys mentoring others with T1D and helping them discover a path to staying strong and minimizing complications.

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In 2017, Maddy took part in JDRF Government Day, meeting with her members of Congress. She offered a unique perspective, as she’s seen first-hand how far research has come over the years.

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When Will Stevens complained of aches and pains, the doctor advised his mother, Cassie, to give him a baked potato before basketball practice and to make sure he had plenty of Gatorade to drink. Will’s health went from bad to worse. He lost weight and was tired all the time.

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Ariana Shakibinia decided to study public health in large part because she lives with T1D. She had always been interested in public policy, but she says living with this disease has made her more vested in the healthcare conversation. “ I am living with what is essentially a pre-existing condition. I’m fortunate enough to have good health insurance, but it makes the potential financial burden of T1D management much more visible and relatable.”

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Islet Transplantation for Treating Difficult-to-Manage Type 1 Diabetes in Adults

Decades of research supported by NIDDK and other NIH Institutes recently led to the landmark U.S. Food and Drug Administration (FDA) approval of an entirely new type of therapy for people with type 1 diabetes whose disease cannot be managed using current therapies: islet transplantation. Among its many potential benefits, the procedure may allow someone to go from having difficult-to-manage diabetes to being completely insulin-independent, while substantially lowering the risk of having their glucose (sugar) levels fall dangerously low (hypoglycemia). Before the approval, islet transplantation was only available to people participating in a research study. Now, this therapy is approved for adults with the disease who are unable to approach target hemoglobin A1c levels (a measure of average blood glucose levels over time) because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education.

Insulin is a life-saving treatment for people with type 1 diabetes, whether taken by injection, insulin pump, or an artificial pancreas device. To estimate how much insulin their body may need, people with the disease must closely monitor their diet, exercise, and daily routine. Despite careful management of diabetes, it is difficult to mimic the exquisite blood glucose control of the pancreas. While taking insulin treats excess glucose in the blood (hyperglycemia), too much insulin can lead to a lack of glucose in the brain and to dangerous situations, including coma and death. Despite vigilant insulin administration, some people have episodes of severe hypoglycemia with memory loss, confusion, altered or irrational behavior, difficulty in awakening, seizures, or loss of consciousness. Such episodes may make activities like driving or caring for young children unsafe. Repeated episodes can lead to impaired awareness of hypoglycemia, where a person does not realize that they have dangerously low blood glucose levels and/or is unable to self-administer treatment, typically by consuming high-sugar foods or drinks or taking a glucose tablet.

To address these challenges, NIDDK vigorously supports research to improve diabetes management. This includes research to advance glucose management technologies, such as artificial pancreas devices that automate insulin delivery in response to blood glucose levels, as well as to develop cell-based approaches, such as islet transplantation, to replace the insulin-producing β (beta) cells that have been destroyed in type 1 diabetes. In islet transplantation, islets (which contain β cells and other cell types) are isolated from donor cadaveric pancreases and transplanted into people with type 1 diabetes. The transplanted islets then start to produce insulin in response to blood glucose levels.

The approval of islet transplantation for people with recurrent severe hypoglycemia is the culmination of decades of collaborative work between NIDDK and the National Institute of Allergy and Infectious Diseases (NIAID), as well as non-governmental organizations and businesses, with oversight and advice from the FDA. The Immune Tolerance Network (ITN), led by NIAID with support from NIDDK and JDRF, tested an approach pioneered in Canada, called the Edmonton Protocol, for injecting transplanted islets into a major vein in the liver and keeping them alive with a novel combination of immunosuppressive drugs. Often, ITN found, the islets survived for months or even years and either reduced the recipient’s need for injected insulin or eliminated it entirely. NIDDK and NIAID continued and built on ITN’s work through the Clinical Islet Transplantation Consortium (CIT) with support from the Special Statutory Funding Program for Type 1 Diabetes Research.

The CIT has achieved remarkable successes, such as documenting the complete elimination of severe hypoglycemic events in the majority of study participants and demonstrating that islet transplantation enabled them to achieve near-normal average blood glucose levels while improving their quality of life—results that paved the way to the recent FDA approval. Notably, ITN and CIT also identified important limitations to islet transplantation procedures. For example, although the surgery itself is less invasive than the transplant of an intact pancreas, complications from the procedure may still occur. More importantly, the medications needed to suppress immune rejection of the islets must be continued for the life of the transplant, and they come with significant risks. Their use increases susceptibility to bacterial and viral infections; can cause fatigue, decreased kidney function, mouth sores, and gastrointestinal problems; and may increase the long-term risk of developing certain cancers. These immunosuppressants are also thought to affect the long-term viability of the transplanted islets, as studies suggest that they are toxic to the islets over time. Thus, an important future research goal is the achievement of “immunological tolerance” for the transplanted cells, meaning that immunosuppression drugs would only be needed for a short time or even not at all.

Because of its current limitations, and because the needed cadaver-derived islets are in short supply, islet transplantation is only appropriate for a small subset of people with type 1 diabetes. NIDDK is currently supporting research to characterize and generate new sources of insulin-producing cells and to eliminate the need for immunosuppressive medicines. For example, in one strategy, called encapsulation, islets (including those from donors as well as progenitor cell-derived islet-like clusters and organoids grown in the laboratory) are coated with a material that protects them from being attacked by the recipient’s immune system and promotes their healthy functioning. To help overcome the shortage of cadaveric islets, research is building on an NIDDK- supported landmark discovery that progenitor cells could be used to produce large quantities of β-like cells in the laboratory. Further development of this breakthrough is being pursued by industry, including the conduct of human clinical trials testing encapsulated and unencapsulated cells. Both the cell source and biomaterials have been developed from fundamental NIDDK-funded research. These industry trials are utilizing clinical trial approaches and experiences developed by NIDDK-supported research on cadaver-derived islet transplantation that led to the FDA licensure, and are expected to benefit from the now established pathway to product licensure made possible by the CIT and the FDA approval.

Overall, this FDA approval is an important milestone in developing a cell-based therapy as a diabetes treatment, helping people with type 1 diabetes who have recurrent hypoglycemia and cannot manage their disease using other approved therapies. This approval also establishes a regulatory framework that future, more broadly applicable cell therapies could follow once they become available. Continued research to identify and test cells and biomaterials, in parallel with research toward generating and preserving sufficient numbers of islets/cells for implantation, will yield knowledge necessary to achieve further progress.

Experimental type 1 diabetes drug shelters pancreas cells from immune system attack

Drug 'hides' insulin-producing beta cells in mice.

Scientists at Johns Hopkins Medicine say that an experimental monoclonal antibody drug called mAb43 appears to prevent and reverse the onset of clinical type 1 diabetes in mice, and in some cases, to lengthen the animals' lifespan.

The drug is unique, according to the researchers, because it targets insulin-making beta cells in the pancreas directly and is designed to shield those cells from attacks by the body's own immune system cells. The drug's specificity for such cells may enable long-term use in humans with few side effects, say the researchers. Monoclonal antibodies are made by cloning, or making identical replicas of, an animal (including human) cell line.

The findings, reported online recently and in the May issue of Diabetes , raise the possibility of a new drug for type 1 diabetes, an autoimmune condition that affects about 2 million American children and adults and has no cure or means of prevention. Unlike type 2 diabetes, in which the pancreas makes too little insulin, in type 1 diabetes, the pancreas makes no insulin because the immune system attacks the pancreatic cells that make it.

The lack of insulin interferes with the body's ability to regulate blood sugar levels.

"People with type 1 diabetes face lifelong injections of insulin and many complications, including stroke and eyesight problems if the condition is not managed properly," says Dax Fu, Ph.D., associate professor of physiology at the Johns Hopkins University School of Medicine and leader of the research team.

Fu says mAb43 binds to a small protein on the surface of beta cells, which dwell in clusters called islets. The drug was designed to provide a kind of shield or cloak to hide beta cells from immune system cells that attack them as "invaders." The researchers used a mouse version of the monoclonal antibody, and will need to develop a humanized version for studies in people.

For the current study, the researchers gave 64 non-obese mice bred to develop type 1 diabetes a weekly dose of mAb43 via intravenous injection when they were 10 weeks old. After 35 weeks, all mice were non-diabetic. One of the mice developed diabetes for a period of time, but it recovered at 35 weeks, and that mouse had early signs of diabetes before the antibody was administered.

In five of the same type of diabetes-prone mice, the researchers held off giving weekly mAb43 doses until they were 14 weeks old, and then continued dosages and monitoring for up to 75 weeks. One of the five in the group developed diabetes, but no adverse events were found, say the researchers.

In the experiments in which mAb43 was given early on, the mice lived for the duration of the monitoring period of 75 weeks, compared with the control group of mice that did not receive the drug and lived about 18-40 weeks.

Next, the researchers, including postdoctoral fellows Devi Kasinathan and Zheng Guo, looked more closely at the mice that received mAb43 and used a biological marker called Ki67 to see if beta cells were multiplying in the pancreas. They said, after treatment with the antibody, immune cells retreated from beta cells, reducing the amount of inflammation in the area. In addition, beta cells slowly began reproducing.

"mAb43 in combination with insulin therapy may have the potential to gradually reduce insulin use while beta cells regenerate, ultimately eliminating the need to use insulin supplementation for glycemic control," says Kasinathan.

The research team found that mAb43 specifically bound to beta cells, which make up about 1% or 2% of pancreas cells.

Another monoclonal antibody drug, teplizumab, was approved by the U.S. Food and Drug Administration in 2022. Teplizumab binds to T cells, making them less harmful to insulin-producing beta cells. The drug has been shown to delay the onset of clinical (stage 3) type 1 diabetes by about two years, giving young children who get the disease time to mature and learn to manage lifelong insulin injections and dietary restrictions.

"It's possible that mAb43 could be used for longer than teplizumab and delay diabetes onset for a much longer time, potentially for as long as it's administered," says Fu.

"In an ongoing effort, we aim to develop a humanized version of the antibody and conduct clinical trials to test its ability to prevent type 1 diabetes, and to learn whether it has any off-target side effects," says Guo.

Other scientists who contributed to the research include Dylan Sarver, G. William Wong and Maria Golson from Johns Hopkins; Shumei Yun from the University of Maryland, Aaron Michels and Liping Yu from the University of Colorado; and Chandan Sona and Matthew Poy from Johns Hopkins All Children's Hospital.

Funding for the research was provided, in part, by the National Institutes of Health (R01DK125746, P30DK116073, R01DK110183, R01 DK135688 and RO1DK084171).

• Immune System
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• Diabetes mellitus type 1
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Story Source:

Materials provided by Johns Hopkins Medicine . Note: Content may be edited for style and length.

Journal Reference :

• Devi Kasinathan, Zheng Guo, Dylan C. Sarver, G. William Wong, Shumei Yun, Aaron W. Michels, Liping Yu, Chandan Sona, Matthew N. Poy, Maria L. Golson, Dax Fu. Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice . Diabetes , 2024; 73 (5): 806 DOI: 10.2337/db23-0568

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‘Need for fast-acting insulin disappeared’: UB professor discovers new way to treat Type 1 diabetes

AMHERST, N.Y. — Dr. Paresh Dandona at the University at Buffalo Jacobs School of Medicine may have discovered a medication that could change the way Type 1 diabetes is treated.

“What I’m talking about right now is far ahead of anyone else in the world in this area today,” Dandona said. “Had I been at Harvard, this would have made massive noise.”

Dandona is the SUNY distinguished professor at the University at Buffalo Jacobs School of Medicine.

His studies have found that treating Type 1 diabetics (who still meet a certain threshold of insulin production) may have a way to reduce their insulin injection amount.

Dandona found that treating these Type 1 diabetics with semaglutide, the drug in products like Ozempic, may drastically reduce or even eliminate their need for injected insulin.

“With all of them, within 6 months, the need for fast acting insulin disappeared,” Dandona said.

There are several types of diabetes:

According to the CDC, the most common and preventable form of diabetes, Type 2, is when your body has insulin, but doesn’t use it well enough to keep blood sugar at normal levels.

Type 1 diabetes is a reaction that stops your body from making insulin altogether, with no prevention or cure.

One of Dr. Dandona’s patients, Ginny Bullock shared her struggles with her Type 1 diagnosis.

A year and half ago, Bullock was diagnosed with Type 1 diabetes. She lives in Colorado and has never been to Buffalo, but her search for help led her to UB.

“The insulin thing is just really complicated,” Bullock said. “I emailed him, I really didn’t think he’d get back to me. Within 10 mins he got back to me, and I spoke on the phone with him, and he got the process rolling.”

Ever since she started using the semaglutide medication, she no longer needs injections every meal.

The treatment reduced her weekly injections by over 90%, to one dose of the medication and one dose of long-acting insulin.

“I’m extremely grateful, I love him,” Bullock said.

“One of the joys of being a physician is to see your patients doing well,” Dandona said.

He is still researching these effects and encourages other diabetics to reach out to him by emailing him at [email protected] .

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Living With Diabetes

Warning signs of diabetes, types of diabetes, type 1 vs type 2 diabetes, type 1 diabetes, type 1 diabetes causes, type 1 diabetes symptoms, is there a cure for type 1 diabetes, type 2 diabetes, type 2 diabetes treatment.

Educate teachers, school personnel and other child care providers about taking care of your child with type 1 diabetes. Download this helpful guide now.

What is Type 1 Diabetes?

Type 1 diabetes is a condition in which the pancreas doesn’t make enough insulin, or stops making it altogether. Insulin is a hormone that helps cells convert sugars from the blood into energy. When you don’t have enough insulin, your body can’t absorb enough blood sugar, and it starts to accumulate in your blood. Over time, this can damage your heart, blood vessels, and other important organs in your body.

Type 1 diabetes can develop at any age, but it is most often diagnosed in people when they are young, which is why it used to be called juvenile diabetes. While there is currently no cure, it can be managed with insulin injections, following a healthy lifestyle, and working with your care team to keep your blood sugar levels under control.

Common symptoms of type 1 diabetes include:

• Extreme thirst
• Increased urination
• Sudden weight loss
• Increased hunger
• Blurry vision
• Mood Changes

What Causes Type 1 Diabetes?

Type 1 diabetes is not caused by a person’s diet or lifestyle. It is an autoimmune disorder, and it’s not known what causes type 1 diabetes. It develops when the body’s immune system starts to attack the cells in the pancreas that create insulin, called beta cells. After months or years of this process, enough beta cells have been destroyed that the pancreas can no longer make insulin.

Risk Factors

There are several possible risk factors for type 1 diabetes:

• Family history. If your parents, siblings, or other members of your family have been diagnosed with type 1 diabetes, you may be at increased risk.
• Genetics. Some people have genes that make them more likely to develop type 1 diabetes.
• Age. People are more likely to develop type 1 diabetes as a child or adolescent. However, you can be diagnosed at any age.
• Race. In the U.S., white people are more likely to develop type 1 diabetes than people from other ethnic backgrounds.

Complications

If type 1 diabetes is not properly managed, blood sugar levels can build up over time. This can damage many different parts of the body, leading to serious complications, or even death. Complications include:

• Cardiovascular disease including heart attack, stroke, coronary artery disease, hypertension, and atherosclerosis (hardening of the arteries)
• Kidney disease or kidney failure
• Neuropathy (nerve damage) including nerve pain, numbness, and tingling
• Gastrointestinal problems including nausea, vomiting, constipation, and diarrhea
• Foot problems caused by poor circulation in the feet, including wounds that are slow to heal, and infections that can lead to amputation
• Eye and vision problems including retina damage, cataracts, glaucoma, and blindness
• Skin and mouth problems including increased risk of skin infections, gum disease, and dry mouth
• Erectile dysfunction

There is currently no known way to prevent type 1 diabetes. However, by managing the disease and keeping blood sugar levels under control with diet, exercise, and insulin, you can prevent complications from developing or getting worse.

Testing for Type 1 Diabetes

There are several tests to diagnose type 1 diabetes. The most common is the glycated hemoglobin test, or the A1C test, which measures your average blood sugar levels over several months. Other tests include a random blood sugar test, in which blood samples are taken at random and repeated over time; and a fasting blood sugar test, in which blood is tested after an overnight fast. If you are diagnosed with diabetes, additional blood and urine tests may be given to determine if you have type 1 or type 2. 

Managing Type 1 Diabetes

Type 1 diabetes can be managed with insulin therapy, getting regular exercise, and eating a healthy diet, including counting and limiting carbohydrates. It’s necessary to continuously monitor blood sugar levels to make sure they’re staying in a safe range. It’s also important to manage stress by getting enough sleep, learning relaxation techniques, and getting emotional support. Patients can work with their doctor and diabetes care team to create a diabetes management plan specific for each individual’s needs.

Hypoglycemia

Hypoglycemia occurs when blood sugar levels get too low, usually because of too much insulin or too long of a wait between meals. It can cause symptoms including a racing heartbeat, shaking, dizziness, confusion, mood swings, and irritability. Hypoglycemia can come on suddenly, so it’s a good idea to closely monitor blood sugars to make sure they’re in a healthy range before driving or operating heavy machinery.

Get Support

In addition to a primary care physician, a diabetes health care team can include an endocrinologist, or a doctor who specializes in diabetes and hormones like insulin; a nurse to help coordinate your care, a dietitian to help with meal planning, and specialists to help with specific concerns, such as problems with the heart, eyes, or feet. It can also include a mental health professional to help with stress. Support groups like the Diabetes Research Institute Foundation’s PEP Squad can provide additional resources.

Curing Diabetes Type 1

There is currently no cure for type 1 diabetes. The Diabetes Research Institute (DRI) is considered by many families to be the best hope for a cure, with researchers studying how to restore natural insulin production so that the body can stabilize blood sugar levels on its own.

Get more answers to your questions about type 1 diabetes, type 2 diabetes and gestational diabetes symptoms and treatments. (In Spanish: ¿Que es La Diabetes?).

Educate teachers, school personnel and other child care providers about taking care of your child with type 1 diabetes.

Get news about research toward a cure, diabetes management tips, information for parents of children with type 1 diabetes and more. Sign up and become a DRI Insider today!

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Type 1 diabetes: What you need to know

People with type 1 diabetes must take insulin every day. One way to do this is with an insulin pen injection.

More than 37 million Americans have diabetes , which causes high blood sugar. Normally, your body produces insulin, a hormone that helps regulate levels of blood glucose, also called blood sugar. With diabetes, your body either can’t produce enough insulin or can’t properly use the insulin it does produce. For people with type 1 diabetes , the immune system destroys cells in the pancreas that make insulin. This causes sugar to build up in the blood. Over time, high blood sugar can damage your nerves, heart , eyes, kidneys, gums and teeth, and other organs.

While type 2 is the most common type of diabetes, 5% of people in the United States with diabetes have type 1. This disease is usually diagnosed in children and young adults, but it can appear at any age. Having a parent or sibling with this disease may increase your chance of developing it.

We don’t know for sure what causes type 1 diabetes, but experts think it may be caused by genes and environmental factors that might trigger the disease. Recent research shows we can also delay the onset of type 1 diabetes and even detect early stages, before clinical symptoms appear.

What are the symptoms?

Symptoms of type 1 diabetes are serious and usually start over a few days to weeks. They may include:

• Being very thirsty
• Peeing often
• Feeling very hungry or tired
• Losing weight without trying
• Having dry, itchy skin
• Losing feeling in your feet or feeling tingling in your feet
• Having blurry eyesight

Type 1 diabetes also affects blood flow around a wound, which can make it harder for your skin to heal from injuries. Chronic diabetic wounds that don’t heal within a few weeks or months may lead to limb amputations, disability, and even death.

Sometimes symptoms of type 1 diabetes are signs of a life-threatening condition called diabetic ketoacidosis (DKA). If you or your child have symptoms of DKA, contact your health care professional immediately or go to the nearest emergency room. These symptoms include:

• Breath that smells sweet or like fruit
• Dry or flushed skin
• Nausea or vomiting
• Stomach pain
• Trouble breathing
• Trouble paying attention or feeling confused

  People with type 1 diabetes need to check their blood sugar daily to make decisions about food, physical activity, and medicines.

How is it diagnosed?

A blood test can show whether you have diabetes. But these tests cannot tell the type of diabetes you have. To tell if your diabetes is type 1, your health care provider may test your blood for certain autoantibodies. Autoantibodies attack your healthy tissues and cells by mistake. Because type 1 diabetes can run in families, your health care provider may also want to test your family members for autoantibodies.

How is it treated?

People with type 1 diabetes must take insulin every day. There are multiple types of insulin , and each works for different lengths of time. Your health care provider can determine what type of insulin you need and whether you need to use more than one type.

You can take insulin in different ways, including injections or an insulin pump. Injections are needed several times during the day, while a pump gives you small, steady doses throughout the day.

People with type 1 diabetes also need to check their blood sugar daily to make decisions about food, physical activity, and medicines. Research shows that people with type 1 diabetes may benefit from a continuous glucose monitor—a device that automatically checks blood sugar levels throughout the day and night—or an artificial pancreas . An artificial pancreas combines a continuous glucose monitor, an insulin pump, and a software program to automatically check your blood sugar levels. It also delivers insulin to your body when you need it.

The continuous glucose monitor sends information through a software program called a "control algorithm." The control algorithm could be installed on a computer, cell phone, or other device. The algorithm tells the insulin pump how much insulin to deliver.

For people ages 8 and older with autoantibodies and an early stage of type 1 diabetes, an injectable medication called teplizumab may slow the progress of the disease.

No matter what treatments you use to manage type 1 diabetes, it’s important to eat a healthy diet, avoid smoking, and get regular physical activity. Some people also follow a special meal plan to manage their blood sugar.

Talk with your health care provider about creating a treatment plan that works for you. Don’t change it without first talking to your provider. Also, talk to them about whether diabetes medicines will give you side effects or interact with other medicines you take.

By following a treatment plan and making positive lifestyle changes, people with type 1 diabetes can lead full, healthy lives.

April 23, 2024

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