current research being done on type 1 diabetes

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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.

Latest Research and Reviews

Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes

• Fucheng Guo
• Xiaoling Zhang

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

• Casper S. Poulsen
• Mette K. Andersen

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.

• Jamie L. Felton
• Maria J. Redondo
• Paul W. Franks

Dynamic associations between glucose and ecological momentary cognition in Type 1 Diabetes

• Z. W. Hawks
• L. T. Germine

Generative deep learning for the development of a type 1 diabetes simulator

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.

• Omer Mujahid
• Ivan Contreras

High dose cholecalciferol supplementation causing morning blood pressure reduction in patients with type 1 diabetes mellitus and cardiovascular autonomic neuropathy

• João Felício
• Lorena Moraes
• Karem Felício

News and Comment

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

• Noel G. Morgan

Slowly progressive insulin-dependent diabetes mellitus in type 1 diabetes endotype 2

• Tetsuro Kobayashi
• Takashi Kadowaki

METTL3 restrains autoimmunity in β-cells

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.

• Balasubramanian Krishnamurthy
• Helen E. Thomas

Type 1 diabetes mellitus: a brave new world

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.

• Pieter-Jan Martens
• Chantal Mathieu

β-cells protected from T1DM by early senescence programme

• Olivia Tysoe

Antivirals in the treatment of new-onset T1DM

• Claire Greenhill

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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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Clinical Trials

Type 1 diabetes.

Displaying 71 studies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The purpose of this study is to demonstrate the performance of the Guardian™ Sensor (3) with an advanced algorithm in subjects age 2 - 80 years, for the span of 170 hours (7 days).

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

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

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

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

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

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

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

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

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

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

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

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

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A Cure for Type 1 Diabetes? For One Man, It Seems to Have Worked.

A new treatment using stem cells that produce insulin has surprised experts and given them hope for the 1.5 million Americans living with the disease.

By Gina Kolata

Brian Shelton’s life was ruled by Type 1 diabetes.

When his blood sugar plummeted, he would lose consciousness without warning. He crashed his motorcycle into a wall. He passed out in a customer’s yard while delivering mail. Following that episode, his supervisor told him to retire, after a quarter century in the Postal Service. He was 57.

His ex-wife, Cindy Shelton, took him into her home in Elyria, Ohio. “I was afraid to leave him alone all day,” she said.

Early this year, she spotted a call for people with Type 1 diabetes to participate in a clinical trial by Vertex Pharmaceuticals. The company was testing a treatment developed over decades by a scientist who vowed to find a cure after his baby son and then his teenage daughter got the devastating disease.

Mr. Shelton was the first patient. On June 29, he got an infusion of cells, grown from stem cells but just like the insulin-producing pancreas cells his body lacked.

Now his body automatically controls its insulin and blood sugar levels.

Mr. Shelton, now 64, may be the first person cured of the disease with a new treatment that has experts daring to hope that help may be coming for many of the 1.5 million Americans suffering from Type 1 diabetes.

“It’s a whole new life,” Mr. Shelton said. “It’s like a miracle.”

Diabetes experts were astonished but urged caution. The study is continuing and will take five years, involving 17 people with severe cases of Type 1 diabetes. It is not intended as a treatment for the more common Type 2 diabetes.

“We’ve been looking for something like this to happen literally for decades,” said Dr. Irl Hirsch, a diabetes expert at the University of Washington who was not involved in the research. He wants to see the result, not yet published in a peer-reviewed journal, replicated in many more people. He also wants to know if there will be unanticipated adverse effects and if the cells will last for a lifetime or if the treatment would have to be repeated.

But, he said, “bottom line, it is an amazing result.”

Dr. Peter Butler, a diabetes expert at U.C.L.A. who also was not involved with the research, agreed while offering the same caveats.

“It is a remarkable result,” Dr. Butler said. “To be able to reverse diabetes by giving them back the cells they are missing is comparable to the miracle when insulin was first available 100 years ago.”

And it all started with the 30-year quest of a Harvard University biologist, Doug Melton.

‘A Terrible, Terrible Disease’

Dr. Melton had never thought much about diabetes until 1991 when his 6-month-old baby boy, Sam, began shaking, vomiting and panting.

“He was so sick, and the pediatrician didn’t know what it was,” Dr. Melton said. He and his wife Gail O’Keefe rushed their baby to Boston Children’s Hospital. Sam’s urine was brimming with sugar — a sign of diabetes.

The disease, which occurs when the body’s immune system destroys the insulin-secreting islet cells of the pancreas, often starts around age 13 or 14. Unlike the more common and milder Type 2 diabetes, Type 1 is quickly lethal unless patients get injections of insulin. No one spontaneously gets better.

“It’s a terrible, terrible disease,” said Dr. Butler at U.C.L.A.

Patients are at risk of going blind — diabetes is the leading cause of blindness in this country. It is also the leading cause of kidney failure. People with Type 1 diabetes are at risk of having their legs amputated and of death in the night because their blood sugar plummets during sleep. Diabetes greatly increases their likelihood of having a heart attack or stroke. It weakens the immune system — one of Dr. Butler’s fully vaccinated diabetes patients recently died from Covid-19.

Added to the burden of the disease is the high cost of insulin, whose price has risen each year.

The only cure that has ever worked is a pancreas transplant or a transplant of the insulin-producing cell clusters of the pancreas, known as islet cells, from an organ donor’s pancreas. But a shortage of organs makes such an approach an impossibility for the vast majority with the disease.

“Even if we were in utopia, we would never have enough pancreases,” said Dr. Ali Naji, a transplant surgeon at the University of Pennsylvania who pioneered islet cell transplants and is now a principal investigator for the trial that treated Mr. Shelton.

For Dr. Melton and Ms. O’Keefe, caring for an infant with the disease was terrifying. Ms. O’Keefe had to prick Sam’s fingers and feet to check his blood sugar four times a day. Then she had to inject him with insulin. For a baby that young, insulin was not even sold in the proper dose. His parents had to dilute it.

“Gail said to me, ‘If I’m doing this you have to figure out this damn disease,’” Dr. Melton recalled. In time, their daughter Emma, four years older than Sam, would develop the disease too, when she was 14.

Dr. Melton had been studying frog development but abandoned that work, determined to find a cure for diabetes. He turned to embryonic stem cells, which have the potential to become any cell in the body. His goal was to turn them into islet cells to treat patients.

One problem was the source of the cells — they came from unused fertilized eggs from a fertility clinic. But in August 2001, President George W. Bush barred using federal money for research with human embryos. Dr. Melton had to sever his stem cell lab from everything else at Harvard. He got private funding from the Howard Hughes Medical Institute, Harvard and philanthropists to set up a completely separate lab with an accountant who kept all its expenses separate, down to the light bulbs.

Over the 20 years it took the lab of 15 or so people to successfully convert stem cells into islet cells, Dr. Melton estimates the project cost about $50 million.

The challenge was to figure out what sequence of chemical messages would turn stem cells into insulin-secreting islet cells. The work involved unraveling normal pancreatic development, figuring out how islets are made in the pancreas and conducting endless experiments to steer embryonic stem cells to becoming islets. It was slow going.

After years when nothing worked, a small team of researchers, including Felicia Pagliuca, a postdoctoral researcher, was in the lab one night in 2014, doing one more experiment.

“We weren’t very optimistic,” she said. They had put a dye into the liquid where the stem cells were growing. The liquid would turn blue if the cells made insulin.

Her husband had already called asking when was she coming home. Then she saw a faint blue tinge that got darker and darker. She and the others were ecstatic. For the first time, they had made functioning pancreatic islet cells from embryonic stem cells.

The lab celebrated with a little party and a cake. Then they had bright blue wool caps made for themselves with five circles colored red, yellow, green, blue and purple to represent the stages the stem cells had to pass through to become functioning islet cells. They’d always hoped for purple but had until then kept getting stuck at green.

The next step for Dr. Melton, knowing he’d need more resources to make a drug that could get to market, was starting a company.

Moments of Truth

His company Semma was founded in 2014, a mix of Sam and Emma’s names.

One challenge was to figure out how to grow islet cells in large quantities with a method others could repeat. That took five years.

The company, led by Bastiano Sanna, a cell and gene therapy expert, tested its cells in mice and rats, showing they functioned well and cured diabetes in rodents.

At that point, the next step — a clinical trial in patients — needed a large, well financed and experienced company with hundreds of employees. Everything had to be done to the exacting standards of the Food and Drug Administration — thousands of pages of documents prepared, and clinical trials planned.

Chance intervened. In April 2019, at a meeting at Massachusetts General Hospital, Dr. Melton ran into a former colleague, Dr. David Altshuler, who had been a professor of genetics and medicine at Harvard and the deputy director of the Broad Institute. Over lunch, Dr. Altshuler, who had become the chief scientific officer at Vertex Pharmaceuticals, asked Dr. Melton what was new.

Dr. Melton took out a small glass vial with a bright purple pellet at the bottom.

“These are islet cells that we made at Semma,” he told Dr. Altshuler.

Vertex focuses on human diseases whose biology is understood. “I think there might be an opportunity,” Dr. Altshuler told him.

Meetings followed and eight weeks later, Vertex acquired Semma for $950 million. With the acquisition, Dr. Sanna became an executive vice president at Vertex.

The company will not announce a price for its diabetes treatment until it is approved. But it is likely to be expensive. Like other companies, Vertex has enraged patients with high prices for drugs that are difficult and expensive to make.

Vertex’s challenge was to make sure the production process worked every time and that the cells would be safe if injected into patients. Employees working under scrupulously sterile conditions monitored vessels of solutions containing nutrients and biochemical signals where stem cells were turning into islet cells.

Less than two years after Semma was acquired, the F.D.A. allowed Vertex to begin a clinical trial with Mr. Shelton as its initial patient.

Like patients who get pancreas transplants, Mr. Shelton has to take drugs that suppress his immune system. He says they cause him no side effects, and he finds them far less onerous or risky than constantly monitoring his blood sugar and taking insulin. He will have to continue taking them to prevent his body from rejecting the infused cells.

But Dr. John Buse, a diabetes expert at the University of North Carolina who has no connection to Vertex, said the immunosuppression gives him pause. “We need to carefully evaluate the trade-off between the burdens of diabetes and the potential complications from immunosuppressive medications.”

Mr. Shelton’s treatment, known as an early phase safety trial, called for careful follow-up and required starting with half the dose that would be used later in the trial, noted Dr. James Markmann, Mr. Shelton’s surgeon at Mass General who is working with Vertex on the trial. No one expected the cells to function so well, he said.

“The result is so striking,” Dr. Markmann said, “It’s a real leap forward for the field.”

Last month, Vertex was ready to reveal the results to Dr. Melton. He did not expect much.

“I was prepared to give them a pep talk,” he said.

Dr. Melton, normally a calm man, was jittery during what felt like a moment of truth. He had spent decades and all of his passion on this project. By the end of the Vertex team’s presentation, a huge smile broke out on his face; the data were for real.

He left Vertex and went home for dinner with Sam, Emma and Ms. O’Keefe. When they sat down to eat, Dr. Melton told them the results.

“Let’s just say there were a lot of tears and hugs.”

For Mr. Shelton the moment of truth came a few days after the procedure, when he left the hospital. He measured his blood sugar. It was perfect. He and Ms. Shelton had a meal. His blood sugar remained in the normal range.

Mr. Shelton wept when he saw the measurement.

“The only thing I can say is ‘thank you.’”

Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including “Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny, and The Science That Saved Them.” More about Gina Kolata

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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Clinical Research in Type 1 Diabetes

Determinants, etiology, progression, prevention, and treatment of Type 1 Diabetes in children and adults.

The Clinical Research in Type 1 Diabetes program includes studies across the lifespan that address the etiology, pathogenesis, prevention and treatment (medical- and self-management) of type 1 diabetes in youth and adults. The program also supports research on hypoglycemia in T1D, including clinical studies and basic research using healthy individuals to understand the physiologic mechanisms of hypoglycemia. The program includes investigator-initiated clinical or behavioral studies, large, multi-center clinical trials that are conducted under cooperative agreements or contracts, and secondary analyses of ongoing clinical trials in diabetes and endocrinology.

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• Guillermo A. Arreaza-Rubín, M.D. Diabetes and endocrine disease bioengineering and glucose sensing
• Miranda Broadney, M.D., M.P.H. Pediatrics, Pediatric Endocrinology, Clinical Management of Diabetes Mellitus, Insulin Resistance, Pediatric Obesity
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Siblings with unique genetic change help scientists progress drug search for type 1 diabetes

Two siblings who have the only known mutations in a key gene anywhere in the world have helped scientists gain new insights that could help progress the search for new treatments in type 1 diabetes.

Type 1 diabetes (also known as autoimmune diabetes) is a devastating and life-long disease, in which the patient's immune cells wrongly destroy the insulin producing beta cells in the pancreas. People living with autoimmune diabetes need to test their blood sugar and inject insulin throughout their lives to control their blood sugars and prevent complications.

Autoimmune diabetes with clinical onset in very early childhood is rare and can result from a variety of genetic variants. However, there are many cases of early onset diabetes without known genetic explanation. In addition, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors -- which target the same pathway that the mutation was found in -- are prone to developing autoimmune diabetes. The reason why only this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood. Like type 1 diabetes, genetic or immunotherapy-associated autoimmune diabetes requires life-long insulin replacement therapy -- there is currently no cure.

The new research, published in the Journal of Experimental Medicine , began when researchers studied two siblings who were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. The University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before they are nine months old. For most of these babies, this service provides a genetic diagnosis and in around half of these babies, it allows for a change in treatment.

When researchers tested the two siblings in the study, no mutation in any of the known causes was identified. The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. Through this sequencing, they found a mutation in the gene encoding PD-L1 in the siblings and realised it could be responsible for their very-early-onset autoimmune diabetes.

Study authorDr Matthew Johnson, from the University of Exeter, UK, said: "PD-L1 has been particularly well studied in animal models because of its crucial function in sending a stop signal to the immune system and its relevance to cancer immunotherapy. But, to our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1. We searched the globe, looking at all the large-scale datasets that we know of, and we haven't been able to find another family. These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans."

The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed exclusively on immune cells. When the two proteins bind together it provides a stop signal to the immune system, preventing collateral damage to the bodies tissues and organs.

Researchers from the Rockefeller Institute in New York and King's College London joined forces with Exeter to study the siblings, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health. After contacting the family's clinician in Morocco, the Exeter team visited the siblings where they were living to collect samples and return them to King's College London, within the crucial ten-hour window for analysis while the immune cells were still alive. The London and New York teams then performed extensive analysis on the siblings' cells.

Study co-author Dr Masato Ogishi, from the Rockefeller University in New York, said: "We first showed that the mutation completely disabled the function of PD-L1 protein. We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes. As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings. To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study. Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of human immune system. We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy."

Study co-author Professor Timothy Tree, from King's College London, said: "Through studying this one set of siblings -- unique in the world to our knowledge -- we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for 'everyday' immune function. This leads us to the grand question; 'what is the role of PD-L1 in our pancreas making it critical for preventing our immune cells destroying our beta cells?' We know that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to work out the "communication" between different cell types that is critical for preventing autoimmune diabetes.

"This finding increases our knowledge of how autoimmune forms of diabetes such as type 1 diabetes develop. It opens up a new potential target for treatments that could prevent diabetes in the future. Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a type 1 diabetes treatment -- our findings will help accelerate the search for new and better drugs."

Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: "Pioneering treatments that alter the behaviour of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the USA, and are awaiting approval here in the UK.

"By zeroing in on the precise role of an important player in the type 1 diabetes immune attack, this exciting discovery could pave the way for treatments that are more effective, more targeted and more transformational for people with or at risk of type 1 diabetes."

Helmsley Program Officer Ben Williams said: "New drugs often fail in development because scientific discoveries made in animal models don't translate into humans. As such, drug developers strongly prefer to pursue new drugs where human genetic evidence supports the drug's target. This study provides such compelling evidence that PD-L1 is a high-priority target to treat T1D, and should be pursued with the ambition of eventually reducing the burden of this difficult to manage disease."

The paper is entitled 'Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency' and is published in the Journal of Experimental Medicine. The research was supported by the National Institute of Health and Care Research (NIHR) Exeter Biomedical Research Centre and The NIHR Exeter Clinical Research Facility.

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Materials provided by University of Exeter . Original written by Louise Vennells. Note: Content may be edited for style and length.

Journal Reference :

• Matthew B. Johnson et al. Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency . JEM , 2024 DOI: 10.1084/jem.20231704

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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.

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Research Gaps Around Type 1 Diabetes

A large body of research on Type 2 diabetes has helped to develop guidance, informing how patients are diagnosed, treated, and manage their lifestyle. In contrast, Type 1 diabetes, often mistakenly associated only with childhood, has received less attention.

In this Q&A, adapted from the  April 17 episode of Public Health On Call , Stephanie Desmon speaks to Johns Hopkins epidemiologists  Elizabeth Selvin , PhD '04, MPH, and  Michael Fang , PhD, professor and assistant professor, respectively, in the Department of Epidemiology, about recent findings that challenge common beliefs about type 1 diabetes. Their conversation touches on the misconception that it’s solely a childhood condition, the rise of adult-onset cases linked to obesity, and the necessity for tailored approaches to diagnosis and care. They also discuss insulin prices and why further research is needed on medications like Ozempic in treating Type 1 diabetes.

I want to hear about some of your research that challenges what we have long understood about Type 1 diabetes, which is no longer called childhood diabetes. 

MF: Type 1 diabetes was called juvenile diabetes for the longest time, and it was thought to be a disease that had a childhood onset. When diabetes occurred in adulthood it would be type 2 diabetes. But it turns out that approximately half of the cases of Type 1 diabetes may occur during adulthood right past the age of 20 or past the age of 30.

The limitations of these initial studies are that they've been in small clinics or one health system. So, it's unclear whether it's just that particular clinic or whether it applies to the general population more broadly. 

We were fortunate because the CDC has collected new data that explores Type 1 diabetes in the U.S. Some of the questions they included in their national data were, “Do you have diabetes? If you do, do you have Type 1 or Type 2? And, at what age were you diagnosed?”

With these pieces of information, we were able to characterize how the age of diagnosis of Type 1 diabetes differs in the entire U.S. population.

Are Type 1 and Type 2 diabetes different diseases?

ES:  They are very different diseases and have a very different burden. My whole career I have been a Type 2 diabetes epidemiologist, and I’ve been very excited to expand work with Type 1 diabetes.

There are about 1.5 million adults with Type 1 diabetes in the U.S., compared to 21 million adults with Type 2 diabetes. In terms of the total cases of diabetes, only 5 to 10 percent have Type 1 diabetes. Even in our largest epidemiologic cohorts, only a small percentage of people have Type 1 diabetes. So, we just don't have the same national data, the same epidemiologic evidence for Type 1 diabetes that we have for Type 2. The focus of our research has been trying to understand and characterize the general epidemiology and the population burden of Type 1 diabetes.

What is it about Type 1 that makes it so hard to diagnose?

MF: The presentation of symptoms varies by age of diagnosis. When it occurs in children, it tends to have a very acute presentation and the diagnosis is easier to make. When it happens in adulthood, the symptoms are often milder and it’s often misconstrued as Type 2 diabetes. 

Some studies have suggested that when Type 1 diabetes occurs in adulthood, about 40% of those cases are misdiagnosed initially as Type 2 cases. Understanding how often people get diagnosed later in life is important to correctly diagnose and treat patients. 

Can you talk about the different treatments?

MF:  Patients with Type 1 diabetes are going to require insulin. Type 2 diabetes patients can require insulin, but that often occurs later in the disease, as oral medications become less and less effective.

ES: Because of the epidemic of overweight and obese in the general population, we’re seeing a lot of people with Type 1 diabetes who are overweight and have obesity. This can contribute to issues around misdiagnosis because people with Type 1 diabetes will have signs and will present similarly to Type 2 diabetes. They'll have insulin resistance potentially as a result of weight gain metabolic syndrome. Some people call it double diabetes—I don't like that term—but it’s this idea that if you have Type 1 diabetes, you can also have characteristics of Type 2 diabetes as well.

I understand that Type 1 used to be considered a thin person's disease, but that’s not the case anymore.  MF:  In a separate paper, we also explored the issue of overweight and obesity in persons with Type 1 diabetes. We found that approximately 62% of adults with Type 1 diabetes were either overweight or obese, which is comparable to the general U.S. population.

But an important disclaimer is that weight management in this population [with Type 1 diabetes] is very different. They can't just decide to go on a diet, start jogging, or engage in rigorous exercise. It can be a very, very dangerous thing to do.

Everybody's talking about Ozempic and Mounjaro—the GLP-1 drugs—for diabetes or people who are overweight to lose weight and to solve their diabetes. Where does that fit in with this population?

ES: These medications are used to treat Type 2 diabetes in the setting of obesity. Ozempic and Mounjaro are incretin hormones. They mediate satiation, reduce appetite, slow gastric emptying, and lower energy intake. They're really powerful drugs that may be helpful in Type 1 diabetes, but they're  not approved for the management of obesity and Type 1 diabetes. At the moment, there aren't data to help guide their use in people with Type 1 diabetes, but I suspect they're going to be increasingly used in people with Type 1 diabetes.

MF:   The other piece of managing weight—and it's thought to be foundational for Type 1 or Type 2—is dieting and exercising. However, there isn’t good guidance on how to do this in persons with Type 1 diabetes, whereas there are large and rigorous trials in Type 2 patients. We’re really just starting to figure out how to safely and effectively manage weight with lifestyle changes for Type 1 diabetics, and I think that's an important area of research that should continue moving forward.

ES: Weight management in Type 1 diabetes is complicated by insulin use and the risk of hypoglycemia, or your glucose going too low, which can be an acute complication of exercise. In people with Type 2 diabetes, we have a strong evidence base for what works. We know modest weight loss can help prevent the progression and development of Type 2 diabetes, as well as weight gain. In Type 1, we just don't have that evidence base.

Is there a concern about misdiagnosis and mistreatment? Is it possible to think a patient has Type 2 but they actually have Type 1? 

MF: I think so. Insulin is the overriding concern. In the obesity paper, we looked at the percentage of people who said their doctors recommended engaging in more exercise and dieting. We found that people with Type 1 diabetes were less likely to receive the same guidance from their doctor. I think providers may be hesitant to say, “Look, just go engage in an active lifestyle.”

This is why it's important to have those studies and have that guidance so that patients and providers can be comfortable in improving lifestyle management.

Where is this research going next?

ES:  What's clear from these studies is that the burden of overweight and obesity is substantial in people with Type 1 diabetes and it's not adequately managed. Going forward, I think we're going to need clinical trials, clear clinical guidelines, and patient education that addresses how best to tackle obesity in the setting of Type 1 diabetes.

It must be confusing for people with Type 1 diabetes who are   hearing about people losing all this weight on these drugs, but they go to their doctor who says, “Yeah, but that's not for you.”

ES: I hope it's being handled more sensitively. These drugs are being used by all sorts of people for whom they are not indicated, and I'm sure that people with Type 1 diabetes are accessing these drugs. I think the question is, are there real safety issues? We need thoughtful discussion about this and some real evidence to make sure that we're doing more good than harm.

MF:  Dr. Selvin’s group has published a paper, estimating that about 15% of people with Type 1 diabetes are on a GLP-1. But we don't have great data on what potentially can happen to individuals.

The other big part of diabetes that we hear a lot about is insulin and its price. Can you talk about your research on this topic?

MF:  There was a survey that asked, “Has there been a point during the year when you were not using insulin because you couldn’t afford it?” About 20% of adults under the age of 65 said that at some point during the year, they couldn't afford their insulin and that they did engage in what sometimes is called “cost-saving rationing” [of insulin].

Medicare is now covering cheaper insulin for those over 65, but there are a lot of people for whom affordability is an issue. Can you talk more about that? 

MF:  The fight is not over. Just because there are national and state policies, and now manufacturers have been implementing price caps, doesn't necessarily mean that the people who need insulin the most are now able to afford it. 

A recent study in the  Annals of Internal Medicine looked at states that adopted or implemented out-of-pocket cost caps for insulin versus those that didn't and how that affected insulin use over time. They found that people were paying less for insulin, but the use of insulin didn't change over time. The $35 cap is an improvement, but we need to do more.

ES: There are still a lot of formulations of insulin that are very expensive. $35 a month is not cheap for someone who is on insulin for the rest of their lives.

• Overweight and Obesity in People With Type 1 Diabetes Nearly Same as General Population
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Type 1 Research Highlights

While the Association’s priority is to improve the lives of all people affected by diabetes, type 1 diabetes is a critical focus of the organization. In fact, in 2016, 37 percent of our research budget was dedicated to projects relevant to type 1 diabetes. Read more about the critical research made possible by the American Diabetes Association.

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A Possible Trigger for Type 1 Diabetes

In order to prevent or reverse the development of type 1 diabetes, it is essential to understand why and how the immune system attacks the body’s own cells. Association-funded Researcher Thomas Delong, PhD, found a possible answer to these questions.

Enhancing Survival of Beta Cells for Successful Transplantation

Islet transplantation has long offered hope as a curative measure for type 1 diabetes. However, more than 80% of transplanted islets die within one week after transplantation. Research efforts are working to improve their survival and the promise of stem cells to reverse diabetes.

Explore: Type 1 Research Highlights

Investments in type 1 diabetes research

The CDC estimates that nearly 1.6 million Americans have it, including about 187,000 children and adolescents. The American Diabetes Association funds a productive research portfolio that offers significant progress and hope for improved outcomes for people with type 1 diabetes.

Identifying type 1 diabetes before beta cell loss

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Beta cell replacement

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Enhancing survival of beta cells for successful transplantation

Islet transplantation has long offered hope as a curative measure for type 1 diabetes. However, more than 80% of transplanted islets die within one week after transplantation. Research efforts are working to improve their survival and the promise of stem cells to reverse diabetes.


New insight into how diabetes leads to blindness

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Current and future therapies for type 1 diabetes

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• Published: 17 February 2021
• Volume 64 , pages 1037–1048, ( 2021 )

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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.

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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 , 3 , 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. 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 , 125 , 126 , 127 , 128 , 129 , 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 , 11 , 12 , 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 , 24 , 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 , 3 , 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. 1 ). Below we review selected current and in-development interventions meeting these three criteria (Table 1 ).

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 , 28 , 29 , 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. 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 , 37 , 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 , 45 , 46 , 47 , 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. 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 , 74 , 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 , 79 , 80 , 81 , 82 , 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 , 86 , 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 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 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 , 109 , 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 , 114 , 115 , 116 , 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 , 121 , 122 , 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 , 136 , 137 , 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 , 140 , 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.

Abbreviations

Anti-thymocyte globulin

Granulocyte colony stimulating factor

Glucagon-like peptide-1

Receptor agonist

Sodium-glucose cotransporter

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von Scholten, B.J., Kreiner, F.F., Gough, S.C.L. et al. Current and future therapies for type 1 diabetes. Diabetologia 64 , 1037–1048 (2021). https://doi.org/10.1007/s00125-021-05398-3

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Affiliations.

• 1 Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China.
• 2 Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China. [email protected].
• PMID: 32641151
• PMCID: PMC7346484
• DOI: 10.1186/s13287-020-01793-6

Type 1 diabetes mellitus (T1DM) is the most common chronic autoimmune disease in young patients and is characterized by the loss of pancreatic β cells; as a result, the body becomes insulin deficient and hyperglycemic. Administration or injection of exogenous insulin cannot mimic the endogenous insulin secreted by a healthy pancreas. Pancreas and islet transplantation have emerged as promising treatments for reconstructing the normal regulation of blood glucose in T1DM patients. However, a critical shortage of pancreases and islets derived from human organ donors, complications associated with transplantations, high cost, and limited procedural availability remain bottlenecks in the widespread application of these strategies. Attempts have been directed to accommodate the increasing population of patients with T1DM. Stem cell therapy holds great potential for curing patients with T1DM. With the advent of research on stem cell therapy for various diseases, breakthroughs in stem cell-based therapy for T1DM have been reported. However, many unsolved issues need to be addressed before stem cell therapy will be clinically feasible for diabetic patients. In this review, we discuss the current research advances in strategies to obtain insulin-producing cells (IPCs) from different precursor cells and in stem cell-based therapies for diabetes.

Keywords: Insulin-producing cells; Pancreatic islets; Stem cells; Transplantation; Type 1 diabetes mellitus.

Publication types

• Research Support, Non-U.S. Gov't
• Cell Differentiation
• Diabetes Mellitus, Type 1* / therapy
• Insulin-Secreting Cells*
• Islets of Langerhans Transplantation*
• Stem Cell Transplantation

• Open access
• Published: 08 July 2020

Current progress in stem cell therapy for type 1 diabetes mellitus

• Shuai Chen 1 ,
• Kechen Du 1 &
• Chunlin Zou   ORCID: orcid.org/0000-0002-3308-5544 1  

Stem Cell Research & Therapy volume  11 , Article number:  275 ( 2020 ) Cite this article

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Type 1 diabetes mellitus (T1DM) is the most common chronic autoimmune disease in young patients and is characterized by the loss of pancreatic β cells; as a result, the body becomes insulin deficient and hyperglycemic. Administration or injection of exogenous insulin cannot mimic the endogenous insulin secreted by a healthy pancreas. Pancreas and islet transplantation have emerged as promising treatments for reconstructing the normal regulation of blood glucose in T1DM patients. However, a critical shortage of pancreases and islets derived from human organ donors, complications associated with transplantations, high cost, and limited procedural availability remain bottlenecks in the widespread application of these strategies. Attempts have been directed to accommodate the increasing population of patients with T1DM. Stem cell therapy holds great potential for curing patients with T1DM. With the advent of research on stem cell therapy for various diseases, breakthroughs in stem cell-based therapy for T1DM have been reported. However, many unsolved issues need to be addressed before stem cell therapy will be clinically feasible for diabetic patients. In this review, we discuss the current research advances in strategies to obtain insulin-producing cells (IPCs) from different precursor cells and in stem cell-based therapies for diabetes.

Introduction

Diabetes mellitus (DM) is a group of chronic metabolic disorders characterized by hyperglycemia due to insufficient secretion of insulin or insulin resistance. DM is mainly divided into four categories: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes, and monogenic diabetes. Patients with T1DM need daily insulin injections because of the absolute insufficiency of endogenous insulin caused by autoimmune destruction of pancreatic β cells. Thus, type 1 diabetes is also known as insulin-dependent DM. Patients with type 2 diabetes may need exogenous insulin injections when oral medications cannot properly control the blood glucose levels. Diabetes without proper treatment can cause many complications. Acute complications include hypoglycemia, diabetic ketoacidosis, or hyperosmolar nonketotic coma (HHNC). Long-term complications include cardiovascular disease, diabetic nephropathy, and diabetic retinopathy [ 1 ]. Although hyperglycemia can be ameliorated by drugs or exogenous insulin administration, these treatments cannot provide physiological regulation of blood glucose. Therefore, the ideal treatment for diabetes should restore both insulin production and insulin secretion regulation by glucose in patients (Fig.  1 ).

Attempts to cure T1DM. The discovery of insulin has enhanced the life span of T1DM patients, and successes in islet/pancreas transplantation have provided direct evidence for the feasibility of reestablishing β cells in vivo to treat T1DM. However, the restriction of a pancreas shortage has driven scientists to generate IPCs, and even whole pancreas, in vitro from hESCs, iPSCs, and adult stem cells. Studies focusing on the immune mechanism of T/B cell destruction in T1DM have made breakthroughs. Gene therapy has shown great promise as a potential therapeutic to treat T1DM, although its safety still needs to be confirmed in humans

Clinical pancreas or islet transplantation has been considered a feasible treatment option for T1DM patients with poor glycemic control. Dr. Richard Lillehei performed the first pancreas transplantation in 1966 [ 2 ]. Up until 2015, more than 50,000 patients (> 29,000 in the USA and > 19,000 elsewhere) worldwide had received pancreas transplantations according to the International Pancreas Transplant Registry (IPTR) [ 3 ]. Islet cell transplantation was first performed in 1974. However, efforts toward routine islet cell transplantation as a means for reversing type 1 diabetes have been hampered by limited islet availability and immune rejection. In 2000, Shapiro et al. reported that seven consecutive patients with type 1 diabetes attained sustained insulin independence after treatment with glucocorticoid-free immunosuppression combined with the infusion of adequate islet mass. Moreover, tight glycemic control and correction of glycated hemoglobin levels were observed in all seven patients. This treatment became known as the Edmonton protocol [ 4 ]. Over the past two decades, continuous improvements in islet isolation and immunosuppression have increased the efficiency of pancreatic islet transplant, and approximately 60% of patients with T1DM have achieved insulin independence 5 years after islet transplantation [ 3 , 5 , 6 , 7 , 8 ].

However, the worldwide shortage of pancreas donors in clinical islet transplantation remains a major challenge. Intensive studies have been conducted for the generation of IPCs or islet organoids in vitro since human pluripotent stem cells (hPSCs) have been anticipated for application in regenerative medicine. The sources for the generation of IPCs or islet organoids in vitro mainly include hPSCs (human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs)), adult stem cells, and differentiated cells from mature tissues that can be transdifferentiated into IPCs. Current strategies for generating IPCs are mainly based on approaches that mimic normal pancreas development. The obtained IPCs are supposed to express specific biological markers of normal β cells that identify a terminal differentiation status, such as MAFA (a basic leucine zipper transcription factor expressed in mature β cells and absent in pancreatic progenitors and other cell types), NEUROD1 (downstream factor of NGN3 expressed in most pancreatic endocrine cells, including β cells), and PDX1/NKX 6.1 (restricted coexpression in β cells), as well as key functional features of adult β cells, including glucose-stimulated insulin secretion (GSIS) and C-peptide secretion [ 9 , 10 , 11 , 12 , 13 , 14 ]. In addition, after implantation into DM patients or immunodeficient diabetic animals, these in vitro-generated IPCs or islet organoids should respond to changing blood glucose and produce sufficient insulin and finally reverse hyperglycemia.

In the last two decades, many protocols have been successfully designed for the generation of IPCs or islet organoids in vitro. In this review, we summarized the research progress in the generation of IPCs and islet organoids from hPSCs and adult stem cells and the new technological advances in stem cell-based therapy for T1DM.

Generating IPCs from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)

ESCs are pluripotent cells isolated from the inner cell mass of a blastocyst, the early mammalian embryo that implants into the uterus. ESCs show the characteristics of infinite proliferative capacity and self-renewal and are able to differentiate into multiple types of adult cells in vitro [ 15 ]. iPSCs, which are reprogrammed from somatic cells, hold a similar capacity to proliferate and differentiate like ESCs. Hence, hPSCs provide a promising platform to produce in vitro insulin-secreting cells. Ethical issues in the applications of ESCs are still controversial due to their origins. In contrast, iPSCs are derived from adult somatic cells that have been reprogrammed back into an embryonic-like pluripotent state using Yamanaka factors [ 16 , 17 ]. During the last two decades, numerous methods to generate IPCs from hPSCs have been reported [ 9 , 10 , 11 , 12 , 18 , 19 , 20 , 21 , 22 ].

Ordinarily, the schemes for the generation of functional IPCs from hPSCs were based on imitating the in vivo development of the embryonic pancreas (Fig.  2 ). The pivotal stages of embryonic pancreas development include the development of the definitive endoderm (DE), primitive gut tube (PGT), pancreatic progenitor (PP), endocrine progenitor (EP), and hormone-expressing endocrine cells. By adding diverse cytokines (e.g., epidermal growth factor, bFGF) and signaling modulators (e.g., bone morphogenetic proteins, γ-secretase inhibitors) to each stage to activate or inhibit specific signaling pathways (e.g., Notch, Wnt) involved in the generation of adult β cells, the hPSC cell fate is manipulated into the β cell phenotype [ 18 , 20 , 23 ].

Generation of insulin-producing β cells from hPSCs. Schematic illustration of the differentiation protocol for generating insulin-producing β cells from hPSCs by mimicking the in vivo development of the embryonic pancreas. The key molecules of all key developmental stages of pancreatic islet β cells are illustrated

D’Amour et al. set up the first stepwise protocol to produce endocrine hormone-expressing cells that were able to synthesize and release multiple hormones from hESCs. However, at the final stage, the average percentage of insulin-positive cells in differentiated hES cell cultures was only 7.3%. Furthermore, these polyhormonal cells failed to respond to a high-glucose stimulus [ 18 ]. It is known that the fetal pancreas also possesses these characteristics, and previous studies demonstrated that fetal human pancreatic tissues could develop functionally after transplantation into animals [ 24 , 25 , 26 , 27 ]. Thus, the authors chose to determine whether these immature β cells derived from hESCs could mature into functional β cells under an in vivo environment. They generated pancreatic endoderm cells (similar to fetal 6- to 9-week pancreatic tissue) using an optimized protocol and then transplanted them into immunodeficient mice. The pancreatic endoderm cells successfully differentiated and matured into β-like cells in response to both fasting-induced hypoglycemia and glucose challenge and maintained normal glucose homeostasis for 3 months [ 28 ].

Similarly, the generation of IPCs from iPSCs is based on consecutive regulation of specific signaling pathways involved in pancreas development. Tateishi et al. first demonstrated that skin fibroblast-derived iPSCs were capable of producing islet-like clusters (ILCs) in vitro by mimicking the in vivo development of the pancreas. However, under high glucose stimulation (40 mM), the amount of C-peptide secreted by iPSC-derived ILCs and ESC-derived ILCs was only 0.3 ng/μg DNA and 0.15 ng/μg DNA, respectively [ 29 ].

Although the above studies have confirmed that hESCs and hiPSCs have the potential to differentiate into IPCs, this differentiation is done only cautiously owing to the low differentiation efficiency of protocols and the polyhormonal features of these β-like cells.

One of the breakthroughs comes from Rezania et al. in 2014, and the authors reported a more detailed protocol and generated mature and functional IPCs from hPSCs that were comparable to human β cells. The differentiation protocol was divided into 7 sequential stages, including definitive endoderm (stage 1), primitive gut hub (stage 2), posterior foregut (stage 3), pancreatic endoderm (stage 4), pancreatic endocrine precursors (stage 5), immature β cells (stage 6), and maturing β cells (stage 7). The obtained cells expressed key markers of mature β cells, such as MAFA, PDX1/NKX6.1, and INS, and showed functional similarities to human islets after transplantation in vivo. These β-like cells rapidly reversed hyperglycemia in STZ-diabetic mice by secreting C-peptide and insulin [ 20 ]. Nevertheless, the S7 (stage 7) cells were not equivalent to mature human β cells. S7 cells exhibited a very small and blunt response to high glucose stimulation, which differs from that of mature islet β cells. Moreover, a scalable suspension-based culture system developed by Paliuca et al. showed the possibility of generating large-scale stem cell-derived β cells (SC-β) [ 9 ]. Expression of NGN3 marks the initiation of endocrine differentiation. Previous studies have confirmed that inhibition of the Notch signaling pathway using γ secretase inhibitors or BMP inhibitors is essential for the induction of NGN3, followed by the addition of fibroblast growth factor 10 and keratinocyte growth factor (KGF), resulting in the robust generation of PDX1 + pancreatic progenitors and an increase in insulin expression in hPSC-derived progeny [ 9 , 20 ]. However, Russ et al. demonstrated that the use of BMP inhibitors promoted the precocious induction of endocrine differentiation in PDX1 + pancreatic progenitors and that omitting addition at pancreatic specification could successfully reduce the formation of polyhormonal cells. Subsequent exposure to retinoic acid and epidermal growth factors (EGF)/KGF cocktail efficiently induced the formation of PDX1 + /NKX6.1 + progenitor cells that differentiated into IPCs in vitro [ 10 ]. Recently, Yabe et al. reported that the addition of the selective glycogen synthase-kinase-3 β (GSK-3β) inhibitor (a substitute for Wnt3a; regarded as a key molecule for definitive endodermal induction from hPSCs) during definitive endodermal induction significantly decreased the death rate of endodermal cells [ 12 , 18 , 30 ]; further, spheroid formation of postendocrine progenitor cells rather than monolayer formation was crucial for generating IPCs from hiPSCs, which may be explained by the unique architecture of adult islets.

Among the above studies, the obtained cell population contains an average of 45% β cells, and the phenotypes of the remaining cells were unclarified. Identification of cell types that formed during differentiation is particularly important to improve the differentiated proportion of β cells. In a recent study, single-cell RNA sequencing in hPSCs undergoing in vitro β cell differentiation mapped a comprehensive description of cell production during stem-to-β cell differentiation [ 31 ]. Four distinct cell populations were isolated and identified from stem cell-derived islets, including SC-β cells, α-like polyhormonal cells, nonendocrine cells, and stem cell-derived enterochromaffin (SC-EC) cells. An in vitro study confirmed that α-like polyhormonal cells were transient toward SC-α cells and that nonendocrine cells were capable of generating exocrine cells (pancreatic acinar, mesenchymal and ductal cells). Additionally, CD49a was characterized as a surface marker of SC-β cells but not of adult islet β cells. Furthermore, SC-β cells could be purified up to 80% from SC islets using a scalable reaggregation method and magnetic sorting.

As patient-derived hiPSCs have been shown to provide tremendous advantages for studying the pathogenesis and pathophysiology of disease in vitro, studies on producing iPSCs from diabetic patients have generated great interest. Patient-specific iPSCs can overcome current obstacles in stem cell therapy, such as immune rejection and immune mismatch, and provide a platform to establish a personalized disease model to investigate pathogenic mechanisms and seek therapeutic methods for the disease. Maehr et al. successfully generated hiPSCs from skin fibroblasts of patients with T1DM (T1DM-specific iPSCs, DiPSCs). These DiPSCs resembled ESCs in the global gene expression profile and were capable of differentiating into pancreatic cell lineages, paving the path of generating T1DM SC-β cells and making autologous stem cell-derived pancreatic progeny transplantation for T1DM possible [ 32 ]. In 2015, Millman et al. confirmed that SC-β cells derived from DiPSCs functionally resembled adult islet β cells both in vivo and in vitro. GSIS tests showed that under high glucose stimulation (20 mM incubation for 30 min), T1DM and nondiabetic (ND) SC-β cells secreted 2.0 ± 0.4 and 1.9 ± 0.3 mIU of human insulin per 10 3 cells, respectively, and both of these cells functioned similarly to adult primary islets in a previous study. After transplantation into ND immunodeficient mice, the engraft function was evaluated by serum human insulin before and 30 min after an injection of glucose. At the early time point (2 weeks after transplantation), most engrafts responded to glucose and released more insulin after glucose injection, and the ratio of insulin secretion after glucose stimulation averaged 1.4 and 1.5 for T1DM and ND SC-β cells, respectively. The effects of these engrafts on insulin secretion were observed for several months. Of note, compared to the early time point, after 12–16 weeks, the human insulin content increased approximately 1.5 times after glucose stimulation [ 33 ]. It should be acknowledged that diversities exist among T1DM patients, and a larger number of specific stem cell lines from T1DM need to be developed for future clinical use. Although DiPSCs are an alternative source for cell replacement therapy for diabetes, some T1DM-specific stem cell lines have shown low efficiency in generating PDX1 + pancreatic progenitors [ 34 ]. Evaluated by flow cytometry, the number of IPCs derived from ND iPSCs (25–50.5%) was comparable to that of the β cells found in human primary islets, whereas the number of IPCs differentiated from T1DM iPSC lines was much lower (15.9%) [ 35 , 36 ]. Upon a strict differentiation protocol, pancreatic progenitors derived from T1DM iPSCs showed lower expression of PDX1 than ND iPSCs at a specific differentiation stage. Epigenetic changes resulting from dysmetabolism in T1DM might be responsible for the poor yield of β cells from T1DM iPSCs. Transient demethylation treatment of DE cells rescued the expression of PDX1 by inhibiting methyl group deposition on the cytosine residues of DNA and led to the differentiation of DE cells into IPCs [ 36 ]. The effect of demethylation on IPC differentiation has been shown to promote pancreatic progenitor induction rather than DE induction [ 37 ].

Generating pancreatic progenitors from ESCs and iPSCs

Pancreatic progenitors that coexpress specific markers indispensable for inducing a β-cell fate are a crucial cell state of differentiating hPSCs into β cells in vitro. Pancreatic and duodenal homeobox 1 (PDX1) transcription factor and NK6 homeobox transcription factor-related locus 1 (NKX6.1) have been considered to be the regulatory factors of differentiating DE into pancreatic progenitors [ 38 ]. Notably, high coexpression of PDX1 and NKX6.1 in pancreatic progenitors is essential for the efficient generation of mature and functional β cells [ 39 , 40 ].

Of note, the efficiency and safety of pancreatic progenitors that coexpress PDX1 and NKX6.1 for T1DM treatment are currently being evaluated in clinical trials by ViaCyte Company. Thus, elevating the production of hPSC-derived β cells, optimizing the in vitro differentiation protocols in multiple aspects, and generating a high population of PDX1 + /NKX6.1 + pancreatic progenitors are needed to accelerate the clinical trial. Multiple studies have been carried out to determine the appropriate cocktail of cytokines to mimic in vivo development [ 41 , 42 , 43 ]. Recently, Nostro et al. demonstrated that the combination of EGF and nicotinamide induced a higher production of NKX6.1 + pancreatic progenitors in adherent culture [ 44 ]. Importantly, the authors focused on the temporal window of foregut differentiation into the pancreatic endoderm and confirmed that the size of the NKX6.1 + population decreased with extended duration. Although previous studies have shown that the maintenance of cellular aggregation during the differentiation process could significantly elevate the efficiency of pancreatic progenitors [ 10 , 45 , 46 ], the impact of culture condition changes that affect the physical environment of cells on pancreatic progenitor differentiation is still less studied. Memon et al. showed that the generation of PDX1 + /NKX6.1 + pancreatic progenitors could be dramatically induced after dissociating and replating pancreatic endodermal cells at half density in monolayer culture [ 47 ]. Intriguingly, a novel NKX6.1 + /PDX1 − cell population that holds the potential to generate functional β cells was discovered, and the cell type was confirmed to be a new type of pancreatic progenitor cell by the same team [ 48 ].

Another important issue that needs to be resolved before hPSC-derived pancreatic progenitors can be used in the clinic is how the recipient’s in vivo environment affects the maturation and differentiation of these undifferentiated cells. Although many studies have highlighted the importance of the in vivo environment in promoting islet cell differentiation, the system mechanism regulating the response of the transplanted cells to the in vivo environment has not been well studied [ 9 , 20 , 21 ]. Most recently, Legøy et al. confirmed that short-term exposure of encapsulated pancreatic progenitors to an in vivo environment was beneficial for cell fate determination, as revealed by increased islet proteome characteristics [ 49 ]. These effects could be partially mediated by the levels of hepatocyte nuclear factor 1-α (HNF1A) and hepatocyte nuclear factor 4-α (HNF4A) in recipients.

Generating islet organoids/islets from ESCs and iPSCs

The pancreatic islet of Langerhans is comprised of α, β, δ, ε, and pancreatic polypeptide cells [ 46 , 50 ]. Many studies have highlighted the importance of reciprocal coordination and complementary interactions of different types of islet cells for glucose hemostasis [ 51 , 52 , 53 , 54 ]. Thus, it may be beneficial for producing whole islets or islet organoids rather than differentiating cells into a specific type.

Organoids are defined as 3D cultures maintained in vitro that can be generated from adult tissues or hPSCs and recapitulate the in vivo morphologies, cellular architecture and organ-specific functionality of the original tissue. Kim et al. developed islet-like organoids from hPSCs that showed a glucose response in vitro and in vivo [ 55 ]. Endocrine cells (ECs) were generated from hPSCs using a multistep protocol and expressed pancreatic hormones. Notably, dissociated ECs spontaneously formed islet-like spheroids, referred to as endocrine cell clusters (ECCs), under optimal 3D culture conditions in 24 h. The diameter of the ECCs was approximately 50–150 μm and contained 5 × 10 4 cells. ECCs consisted of several types of islet endocrine cells, apart from α cells, indicating that ECCs derived from hPSCs are partially similar to human adult islets. After high glucose stimulation (27.5 mM) for 1 h, ECCs showed increases in both insulin and C-peptide secretion, from 1.01 ± 0.22% up to 2.6 ± 0.21% and from 159.6 ± 20.01 pmol/L up to 336.3 ± 29.21 pmol/L, respectively. Additionally, ECCs exhibited intracellular Ca 2+ oscillation under a high glucose stimulus. Furthermore, a major breakthrough was that after ECCs were implanted into STZ-induced diabetic mice, normoglycemia was rapidly achieved within 3 days. In previous studies, transplanted hPSC-derived ECs took a long period (over 40 days) to normalize the glucose level in diabetic mice [ 9 , 10 , 20 , 28 ]. Therefore, this study suggested that it was promising to generate functional islet-like organoids from hPSCs and provided an alternative cell source for treating diabetes. Soon after that, based on a biomimetic 3D scaffold, islet organoids were successfully generated from hESCs [ 56 ]. The organoids contained all types of pancreatic cells (α, β, δ, and pancreatic polypeptide cells), specific markers of mature β cells as well as insulin secretory granules, which were characterized by a round electron-dense crystalline core surrounded by a distinctive large, clear halo. Insulin granules have been reported as an indication of mature β cells and a key participant in glucose homeostasis [ 36 , 57 ]. Generally, insulin granules in adult β cells were differentiated according to the shape and density of the core. Through transmission electron microscopy, insulin granules generally possess a characteristic “halo,” which is a product of glutaraldehyde fixation that does not exist in other endocrine granules. Many studies have reported remarkable insulin granules during the differentiation of hPSCs into IPCs [ 9 , 20 ]. Glucose loading experiments demonstrated that islet organoids exhibited a sharp increase in insulin secretion under high glucose conditions. Under the same glucose stimulation conditions (exposure from 5.5 mM to 25 mM), the 3D-induced cells had an insulin content that increased by seven-fold, whereas the 2D-induced cells had an insulin content that increased by 3.7-fold. These results suggested that 3D-induced IPCs are more sensitive to glucose stimulation due to their elevated maturity.

Fundamental studies of islet development during embryogenesis will promote optimization of protocols for differentiating hPSCs into 3D islet clusters or islet organoids. The traditional model of islet development is based on epithelial-mesenchymal transition (EMT) during the differentiation of pancreatic progenitors. However, this hypothesis was recently challenged by a study in which the dynamic changes in transcripts involved in islet formation were mapped [ 46 ]. Sharon et al. reported that along with EP differentiation, they maintained intact cell-to-cell adhesion and formed bud-like islet precursors (defined as peninsula-like structures) rather than undergoing EMT. Further in vitro generation of SC-β cells showed that the maintenance of cell adhesion could efficiently induce hESCs into peninsula-like structures. Importantly, these peninsula-like clusters could generate INS + and GCG + monohormonal cells after transplantation into SCID mice. This study provides a new framework for understanding islet embryogenesis and offers novel ideas to optimize the current protocols for the differentiation of SC-β cells.

Generating interspecific pancreatic chimeras from pancreatic stem cells (PSCs)

Interspecific chimeras, defined as organisms with cells originating from at least two different species, are able to produce organs completely consisting of donor-origin cells. Thus, human-animal chimeras have great potential for providing immune-compatible patient-specific human organs for transplantation.

In 2010, Kobayashi et al. successfully generated a functional rat pancreas in PDX1 −/− (pancreatogenesis knockout) mice via interspecies blastocyst complementation [ 58 ]. The rat iPSC-derived pancreas (rat M pancreas) in PDX1 −/− mice showed both exocrine and endocrine characteristics and expressed several pancreatic enzymes and hormones. In addition, outcomes from glucose tolerance testing (GTT) in adulthood indicated that endogenous insulin secretion was increased under high blood glucose, and glucose homeostasis was preserved. Recently, the same group reported the reverse experiment; mouse PSCs were injected into PDX1 −/− rat blastocysts to generate a pancreas (mouse R pancreas) the size of a rat pancreas with pancreatic cells primarily originating from mouse PSCs [ 59 ]. Most importantly, the isolated islets from the mouse R pancreas were subsequently injected into STZ-induced diabetic mice, and functional glucose-induced insulin secretion was successfully established in recipients for over 1 year. These data strongly supported the hypothesis that donor PSC-derived organs could be generated in a xenogeneic environment and provided the theoretical possibility of applying donor PSC-derived islets generated by animal-human interspecific blastocyst complementation in clinical trials. It is worth noting that rat M pancreases were the size of a rat pancreas, rather than the size of a mouse pancreas or an intermediate size, whereas mouse R pancreases were the size of a mouse pancreas. Thus, to adapt interspecific blastocyst complementation for patients, it seems necessary to generate organs in animals that are closer to humans in both size and evolutionary distance, such as sheep, pigs, and nonhuman primates (NHPs). Exogenic pancreases have been generated in vivo in transgenic cloned pigs by blastocyst complementation [ 60 ]. In this study, donor morula blastomeres derived from female cloned embryos were injected into the morula of male pancreatogenesis-disabled fetuses, and morphologically and functionally normal donor-derived pancreases were formed in adult chimeric pigs. Furthermore, PDX1 −/− sheep generated using CRISPR/Cas9 have been reported and can potentially serve as a host for interspecies organ generation [ 61 ]. However, blastocyst complementation has failed to generate chimeras in NHPs [ 62 ].

Differentiation of adult stem cells into IPCs

The search for adult pancreatic stem cells.

The adult pancreas consists of two unique parts: the exocrine pancreas and the endocrine pancreas, with unique morphology and function, respectively. The pancreas arises from two separate primordia along the dorsal and ventral surfaces of the posterior foregut. Lineage-tracing studies have demonstrated that all of the mature pancreatic cells were developed from PDX1 + /PTF1A + progenitor cells [ 63 , 64 ]. However, if there are detectable pancreatic stem cells in adult animal and human pancreases, how these cells participate in the regeneration of β cells is still under debate. The hypothesis was initially supported by histological observation of neogenesis occurring in adult rodent pancreatic ducts after pancreatic duct ligation (PDL) [ 65 ]. However, genetic lineage-tracing studies indicated that there was no contribution to endocrine regeneration during the adult life or after injury, and the major mechanism was enhanced replication by only preexisting β cells [ 63 , 66 , 67 ]. In 2007, supporting evidence comes from a study by Xu et al., in which NGN3 + (the earliest islet cell-specific transcription factor) endocrine precursors appeared in the ductal lining after PDL in mice and gave rise to all types of islet cells, including glucose-responsive β cells [ 68 ]. Additionally, increased proliferation and ectopic NGN3 + pancreatic progenitors were reported in experiments of α-to-β-cell reprogramming [ 69 , 70 ]. In conclusion, whether adult pancreatic stem cells exist in adulthood is unclear. Recent events in single-cell RNA sequencing are promising for mapping dynamic gene expression changes during the adult lifespan or after injury in animal and human pancreases, for constructing differentiation trajectories of pancreas/islet cells and for illustrating the mechanisms involved in β cell regeneration.

Pancreatic duct-derived stem cells

Theoretically, pancreatic duct epithelial cells possess a promising capacity for β cell generation because both originate from the same embryonic precursor [ 46 , 71 ]. Budding of β cells or new islets generated from ductal epithelium occurs during pancreatic regeneration in adults and has been reported [ 72 , 73 ]. Since then, studies have been designed to reprogram pancreatic ductal cells into β cells. Ramiya et al. isolated pancreatic ductal epithelial cells from prediabetic adult nonobese diabetic (NOD) mice, cultured them in vitro, and ensued the formation of ILCs that contained α, β, and δ cells. Subsequently, the blood glucose level of diabetic NOD mice was decreased from 400 to 180–220 mg/dl in 7 days [ 74 ]. Moreover, Bonner-Weir et al. demonstrated that the pancreatic ductal epithelium could expand and further differentiate into functional islet tissues in a Matrigel-based 3D culture system in vitro [ 75 ]. Further studies demonstrated that CK19 + nonendocrine pancreatic epithelial cells (NEPECs) can be differentiated into β cells in vitro [ 76 ].

Over the past two decades, attempts have been directed toward optimizing the protocols for generating IPCs from pancreas duct-derived stem cells. Since CA19-9 and CD133 were identified as specific membrane proteins of pancreas duct-derived stem cells, it became easier to purify these cells from the adult human pancreas [ 77 , 78 ]. It has been demonstrated that diverse growth factors (e.g., bFGF, EGF, and KGF) benefit the proliferation and differentiation of human pancreatic duct-derived stem cells [ 74 , 79 ]. Generally, epithelial cells show limited mitotic activity in vitro. Corritore et al. developed a differentiation protocol in which isolated human pancreatic duct cells from the pancreas were forced to undergo EMT to achieve a phenotypic change and allow them to extensively proliferate. After proliferation of these cells in vitro, pancreatic duct-derived cells differentiated into IPCs with a large array of specific marker expression and insulin secretion [ 78 ]. More recently, Zhang et al. reported that diabetic mice continuously administered gastrin and EGFs had accelerated transdifferentiation of SOX9 + duct cells into IPCs and consequently maintained blood glucose homeostasis [ 80 ].

Nestin-positive mesenchymal stem cells from islets

Nestin is an intermediate filament protein that is specifically expressed in neuronal and muscle precursor cells [ 81 , 82 ]. Recent studies have indicated that nestin-positive (nestin + ) cells resided in pancreatic islets and could differentiate into IPCs and islet-like cell clusters (Fig.  3 ), and now, nestin has been accepted as a critical pancreatic progenitor marker [ 83 , 84 ]. Zulewski et al. first demonstrated the existence of a distinct cell population within islets isolated from the human pancreas that express nestin, termed nestin-positive islet-derived progenitor cells (NIPs). These NIPs displayed features of stem cells and were able to generate cells with either pancreatic exocrine or endocrine phenotypes in vitro. Most importantly, the terminally differentiated cells were capable of secreting pancreatic hormones, such as insulin and glucagon [ 85 ]. Another study performed by the same group reported that NIPs also showed characteristics of bone marrow side population (SP) stem cells due to their coexpression of the ATP-binding cassette transporter ABCG2, which has been previously demonstrated to be a major component of the SP phenotype [ 85 , 86 , 87 ]. This was further supported by a study showing that NIPs isolated from a human fetal pancreas expressed ABCG2 and nestin [ 88 ]. Moreover, CD44, CD90, and CD147, which represent the phenotypes of bone marrow-derived mesenchymal stem cells, were also detected on NIPs. These data strongly indicated that NIPs have a high potential to become an alternative cell source for producing IPCs and islets in vitro. Huang et al. isolated and cultured NIPs from a human fetal pancreas. In this study, NIPs formed islet-like cell clusters (ICCs) in confluent cultures. Moreover, differentiation of ICCs from NIPs results in increased pancreatic islet-specific gene expression, along with a concomitant downregulation of ABCG2 and nestin. Additionally, the transplantation of ICCs reversed hyperglycemia in diabetic NOD-SCID mice [ 89 ].

Generation of IPCs from adult stem cells. Adult pancreatic stem cells may be a potential source of IPCs. Functional IPCs have been generated from pancreatic ductal cells and NIPs isolated from adult islets. During embryogenesis, the liver and pancreas arise from common endoderm progenitors. Liver cells can transdifferentiate into IPCs by ectopic expression of pancreatic transcription factors. Additionally, a high pluripotent cell population termed HLSCs can also produce IPCs in vitro. Bone marrow-derived stem cells show the capacity to generate insulin cell clusters

The studies mentioned above about NIPs are based on rodent models. Nonhuman primate models often serve as an important bridge from laboratory research to clinical application; thus, generating pancreatic stem cells/progenitor cells from NHPs has led to great interest. Our previous study indicated that pancreatic progenitor cells existed in the adult pancreases of type 1 diabetic monkeys as well as in the pancreases of normal monkeys. The isolated pancreatic progenitor cells were able to proliferate in vitro and form ICCs in differentiation media. Furthermore, glucose-induced insulin and C-peptide secretion from the ICCs suggested that the ICCs functionally resembled primary islets [ 90 ]. In view of pathogenetic differences between STZ-induced diabetic monkeys and patients with T1DM, it still needs to be clarified whether NIPs also reside in T1DM patients.

Differentiation of bone marrow-derived stem cells (BMDSCs)

Several studies have reported that BMDSCs have the ability to differentiate into IPCs. Tang et al. reported that BMDSCs could spontaneously differentiate and form ICCs when continuously cultured with high glucose concentrations. The ICCs expressed multiple pancreatic lineage genes, including INS, GLUT2, glucose kinase, islet amyloid polypeptide, nestin, PDX-1, and PAX6, with β cell development. Moreover, ICCs could respond to glucose stimulation and release insulin and C-peptide in vitro, and following implantation into diabetic mice, hyperglycemia was reversed [ 91 ]. Since then, numerous studies have demonstrated the generation of IPCs from human and rat bone marrow stem cells (Fig. 3 ). However, the efficacy of BMDSC differentiation is low and highly variable with the current protocols. In particular, the quantity of insulin secreted by these cells was far from that secreted by adult β cells. Gabr and colleagues tested the efficiency of three differentiation protocols using immunolabeling, and the proportion of generated IPCs was modest (≈ 3%) in all protocols [ 92 ]. The expression of pancreatic-associated genes in generated IPCs was quite low compared to the expression in human islets. Optimizing differentiation protocols to upregulate the expression of specific genes by determining optimal molecules and culture conditions is crucial. Extracellular matrix proteins play a vital role in cell differentiation and proliferation. Laminin, one of the pancreatic extracellular matrices, has been confirmed to enhance the expression of insulin and promote the formation of ICCs from BMDSCs, whereas collagen type IV affects the expression of NEUROD1 and GCG [ 93 ]. Generally, differentiation of BMDSCs into IPCs is performed on nonadherent polymer surfaces and hydrogels. A recent study reported that 3D culture of BMDSCs on agar (a hydrogel-forming polysaccharide widely used in biomedical research) for 7 days followed by 2D culture of formed cellular clusters in high glucose media could enhance the production of IPCs from BMDSCs [ 94 ]. IPCs expressed INS genes at a 2215.3 ± 120.8-fold higher level than BMDSCs, whereas this fold change in previous studies was 1.2–2000-fold.

Differentiation of liver cells

The liver and pancreas originate from appendages of the upper primitive foregut endoderm. Later, separation of the liver and pancreas during organogenesis left both tissues with multipotent cells capable of generating both hepatic and pancreatic cell lineages. The common embryonic origin of the liver and pancreas raises the intriguing speculation that it may be possible to convert liver cells to pancreatic ECs (Fig. 3 ). Several studies have demonstrated that adult or fetal liver cells and biliary epithelial cells are capable of reprogramming into IPCs by inducing the expression of endocrine pancreatic-specific transcription factors [ 95 , 96 , 97 , 98 ]. The in vivo data showed that these hepatic cell-derived IPCs could ameliorate hyperglycemia upon implantation into diabetic mice. However, the efficiency of liver-to-pancreas reprogramming is still low, and the obtained IPCs are likely immature β-like cells. In addition, Herrera et al. isolated and characterized a population of human liver stem cells (HLSCs). HLSCs express both mesenchymal stromal cells (MSCs) and immature hepatocyte markers. In addition, HLSCs expressing nestin and vimentin are capable of differentiating into multiple cell lineages, including epithelial, endothelial, osteogenic, and islet-like structure (ILS) cells [ 99 ]. Later, Navarro-Tableros et al. confirmed that HLS-ILS cells expressed β cell transcription factors, such as NKX6.1, NKX6.3, and MAFA, and could respond to glucose loading by releasing C-peptide. Hyperglycemia was rapidly reversed in diabetic SCID mice after implantation [ 100 ]. These data suggest that HLSCs could be a novel potential resource for stem cell-based therapy for diabetes.

Encapsulation technique for stem cell therapy for T1DM

The encapsulation technique is based on a matrix that prevents immune cells, cytokines, and antibodies from reacting to grafts while allowing nutrient, oxygen, and signaling molecule diffusion. An appropriate encapsulation device is especially crucial for T1DM to prevent an autoimmune reaction against transplanted hPSC-derived pancreatic progeny, including allogenic grafts. Criteria to evaluate an encapsulation device should take many variables into consideration, including the biocompatibility, stability and permselectivity of the membrane, interaction with the bloodstream, availability of nutrients and oxygen, among others [ 101 , 102 , 103 ]. Studies have been performed to detect optimal materials to improve these properties and have mainly been developed for pancreatic islet transplantation.

Alginate, a scaffolding polysaccharide produced by brown seaweeds, has been widely employed by virtue of its biocompatibility [ 102 , 104 , 105 ]. Alginates are linear unbranched polymers containing β-(1 → 4)-linked d -mannuronic acid (M) and α-(1 → 4)-linked l -guluronic acid (G) residues and possess eminent gel-forming properties in the presence of polyvalent cations, such as Ca 2+ and Ba 2+ [ 103 , 106 , 107 , 108 ]. Earlier studies have confirmed that compared to nonencapsulated islets, encapsulated islets have significantly improved survival, long-term biocompatibility and function with the use of purified alginate [ 109 , 110 , 111 , 112 ]. Additionally, specific modifications to alginates trigger great interest, as they could circumvent the local immune response after transplantation of an allo- or xenograft. The incorporation of the chemokine CXCL2 with alginate microcapsules prevented allo- or xenoislet transplantation from immune reactions by establishing sustained local immune isolation [ 113 ]. Most recently, the same team confirmed that these modifications on alginates could also efficiently prolong the survival and function of hPSC-derived β cells and achieve long-term immunoprotection in immunocompetent mice with T1DM without systemic immunosuppression [ 114 ]. Of note, CXCL2 enhanced the GSIS activity of β cells, thus making it a crucial biomaterial to study for stem cell-based therapy for T1DM.

ViaCyte, leading the first and only islet cell replacement therapies derived from stem cells for diabetes, is testing for the safety and efficacy of its encapsulation devices PEC-Encap and PEC-Direct in clinical trials. The PEC-Encap is designed to fully contain hPSC-derived pancreatic progenitors in a semipermeable pouch so that vital nutrients and proteins can travel between the cells inside the device and the blood vessels, which grow along the outside of the device. In the case of PEC-Encap, the implanted cells were completely segregated from the recipients’ immune system. Another device called PEC-Direct allowed blood vessels to enter the device and directly interact with the implanted cells. Thus, immune suppression therapy was necessary for patients who received PEC-Direct, which made it suitable only for people with high-risk type 1 diabetes.

Immune modulation in stem cell therapy for T1DM

Human ESC/iPS-derived β cells have been proposed as a potential β cell replacement source for the treatment of T1DM. However, both the alloimmune and autoimmune responses remain a major problem for the wide application of cell replacement therapies for T1DM. Although massive efforts have been made in the progress of encapsulation technology, the engraftment of transplanted hPSC-derived pancreatic progenitors or β cells still faces challenges. The engraftments will certainly be destroyed by the recipient’s immune system if the encapsulation system is eliminated. Certain modulations of these encapsulated cells to circumvent autoimmune attack seem promising. Human leukocyte antigen (HLA) mismatching is the major molecular mechanism of immune rejection in allo- or xenografts [ 115 ]. Studies have proven that elimination of HLA-A genes by zinc-finger nucleases in hematopoietic stem cells could increase donor compatibility [ 116 , 117 ]. Likewise, knocking out the β2-microglobulin (B2M) gene, which abolishes all HLA class I molecules, or deleting HLA-A and HLA-B biallelically, retained one allele of HLA-C to allow the hPSC grafts to avoid T and NK cell attack [ 118 ]. Other protocols for immunosuppressive effects have been reported, such as targeted overexpression of PDL1-CTLA4Ig in β cells, which efficiently prevented the development of T1DM and allo-islet rejection, in turn promoting the survival of β cell mass [ 119 ]. Therefore, immune modulation strategies for hPSCs could be promising to overcome challenges associated with engraft rejection.

Clinical trials in stem cell therapy for T1DM

In the last few years, controlled clinical trials have been carried out to estimate the efficiency and safety of stem cell therapy for T1DM. It has been demonstrated that MSCs can ameliorate or reverse the manifestation of diabetes in animal models of T1DM. In 2014, Carlsson et al. confirmed that MSC treatment could preserve β cell functions in new-onset T1DM patients. Twenty adult patients (aged 18–40 years) with newly diagnosed (< 3 weeks) T1DM were enrolled and randomized to MSC treatment or to the control group and followed by a 1-year follow-up examination [ 120 ]. At the end of the clinical trial, mixed-meal tolerance tests (MMTTs) revealed that both C-peptide peak values and C-peptide significantly decreased in the treatment group. Of note, MSC treatment side effects were not observed during the follow-up examination. During January 2009 and December 2010, 42 patients aged 18–40 years with a history of T1DM for ≥ 2 years and ≤ 16 years were randomized into either the stem cell transplantation (umbilical cord MSCs in combination with autologous bone marrow mononuclear cells) or standard insulin care treatment groups [ 121 ]. A 1-year follow-up examination indicated that the C-peptide increased from 6.6 to 13.6 pmol/mL/180 min in treated patients, whereas it decreased from 8.4 to 7.7 pmol/mL/180 min in control groups; insulin increased from 1477.8 to 2205.5 mmol/mL/180 min in treated patients; and it decreased from 1517.7 to 1431.7 mmol/mL/180 min in control patients. Additionally, HbA 1c and fasting glycemia decreased in the treated groups and increased in the control subjects. Daily insulin requirements in the treated groups also decreased compared to those of the control groups. During the follow-up period, severe hypoglycemic events reported by patients were significantly decreased. Limitations of these studies could be a small sample size and the short follow-up period. Moreover, the treated patients did not achieve complete insulin independence. Even so, these results help to improve clinical trial outcomes in future large-scale trials.

Conclusions and perspectives

Stem cell-based therapy has been considered a promising potential therapeutic method for diabetes treatment, especially for T1DM. As mentioned in this review, major advances in research on the derivation of IPCs from hPSCs have improved our chance of reestablishing glucose-responsive insulin secretion in patients with T1DM. However, the clinical trial results of stem cell therapies for T1DM are still dissatisfactory [ 122 ], and many questions and technical hurdles still need to be solved. The major problems include the following four aspects: (1) how to generate more mature functional β-like cells in vitro from hPSCs; (2) how to improve the differentiation efficiency of IPCs from hPSCs; (3) how to protect implanted IPCs from autoimmune attack; (4) how to generate sufficient numbers of desired cell types for clinical transplantation; and (5) how to establish thorough insulin independence. Despite these obstacles, the application of stem cell-based therapy for T1DM represents the most advanced approach for curing type 1 diabetes.

Availability of data and materials

Not applicable.

Abbreviations

• Type 1 diabetes mellitus
• Insulin-producing cells

Diabetes mellitus

Type 2 diabetes mellitus

Hyperosmolar nonketotic coma

International Pancreas Transplant Registry

Human pluripotent stem cells

Human embryonic stem cells

Human induced pluripotent stem cells

MAF bZIP transcription factor A

Neuronal differentiation 1

Pancreatic and duodenal homeobox 1

NK6 homeobox transcription factor-related locus 1

Glucose-stimulated insulin secretion

Embryonic stem cells

Induced pluripotent stem cells

Definitive endoderm

Primitive gut tube

Pancreatic progenitor

Endocrine progenitor

Basic fibroblast growth factor

Islet-like clusters

Streptozocin

Stem cell-derived β cells

Neurogenin 3

Bone morphogenetic protein

Keratinocyte growth factor

Epidermal growth factors

Glycogen synthase-kinase-3 β

Stem cell-derived enterochromaffin

T1DM-specific iPSCs

Nondiabetic

Hepatocyte nuclear factor 1-α

Hepatocyte nuclear factor 4-α

Endocrine cells

Endocrine cell clusters

Epithelial-mesenchymal transition

Severe combined immunodeficiency

Pancreatic stem cells

Glucose tolerance testing

Nonhuman primates

Pancreas associated transcription factor 1a

Pancreatic duct ligation

Nonobese diabetic

Nonendocrine pancreatic epithelial cells

SRY-box transcription factor 9

Nestin-positive islet-derived progenitor cells

Side population

ATP binding cassette subfamily G member 2

Bone marrow-derived stem cells

Glucose transporter 2

Paired box 6

Human liver stem cells

Mesenchymal stromal cells

Islet-like structure

NK6 homeobox transcription factor-related locus 3

C-X-C motif chemokine ligand 2

Human leukocyte antigen

Major histocompatibility complex, class I, A

Major histocompatibility complex, class I, B

Major histocompatibility complex, class I, C

β2-microglobulin

Natural killer cell

Programmed cell death 1 ligand 1-cytotoxic T-lymphocyte antigen-4

Mixed-meal tolerance tests

Octamer-binding transcription factor-4

Nanog homeobox

SRY-box transcription factor 2

SRY-box transcription factor 17

Forkhead box A2

Hepatocyte nuclear factor 1-β

Hepatocyte nuclear factor 6

Somatostatin

Vascular endothelial growth factor

Hepatocyte growth factor

Insulin-like growth factor

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Acknowledgements

We gratefully acknowledge the funding support from the National Key Research and Development Program of China (2016YFC1305703), the National Natural Science Foundation of China (81670750, 81971191, and 61627807), Guangxi Natural Science Foundation (2014GXNSFDA118030), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.

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Shuai Chen, Kechen Du & Chunlin Zou

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Chen, S., Du, K. & Zou, C. Current progress in stem cell therapy for type 1 diabetes mellitus. Stem Cell Res Ther 11 , 275 (2020). https://doi.org/10.1186/s13287-020-01793-6

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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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• Diseases & Conditions
• Type 1 diabetes

Diagnostic tests include:

• Glycated hemoglobin (A1C) test. This blood test shows your average blood sugar level for the past 2 to 3 months. It measures the amount of blood sugar attached to the oxygen-carrying protein in red blood cells (hemoglobin). The higher the blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5% or higher on two separate tests means you have diabetes.

If the A1C test isn't available, or if you have certain conditions that can make the A1C test inaccurate — such as pregnancy or an uncommon form of hemoglobin (hemoglobin variant) — your provider may use these tests:

• Random blood sugar test. A blood sample will be taken at a random time and may be confirmed by additional tests. Blood sugar values are expressed in milligrams per deciliter (mg/dL) or millimoles per liter (mmol/L). No matter when you last ate, a random blood sugar level of 200 mg/dL (11.1 mmol/L) or higher suggests diabetes.
• Fasting blood sugar test. A blood sample will be taken after you don't eat (fast) overnight. A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is healthy. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.

If you're diagnosed with diabetes, your provider may also run blood tests. These will check for autoantibodies that are common in type 1 diabetes. The tests help your provider decide between type 1 and type 2 diabetes when the diagnosis isn't certain. The presence of ketones — byproducts from the breakdown of fat — in your urine also suggests type 1 diabetes, rather than type 2.

After the diagnosis

You'll regularly visit your provider to talk about managing your diabetes. During these visits, the provider will check your A1C levels. Your target A1C goal may vary depending on your age and various other factors. The American Diabetes Association generally recommends that A1C levels be below 7%, or an average glucose level of about 154 mg/dL (8.5 mmol/L).

A1C testing shows how well the diabetes treatment plan is working better than daily blood sugar tests. A high A1C level may mean you need to change the insulin amount, meal plan or both.

Your provider will also take blood and urine samples. They will use these samples to check cholesterol levels, as well as thyroid, liver and kidney function. Your provider will also take your blood pressure and check the sites where you test your blood sugar and deliver insulin.

More Information

• Blood pressure test

Treatment for type 1 diabetes includes:

• Taking insulin
• Counting carbohydrates, fats and protein
• Monitoring blood sugar often
• Eating healthy foods
• Exercising regularly and keeping a healthy weight

The goal is to keep the blood sugar level as close to normal as possible to delay or prevent complications. Generally, the goal is to keep the daytime blood sugar levels before meals between 80 and 130 mg/dL (4.44 to 7.2 mmol/L). After-meal numbers should be no higher than 180 mg/dL (10 mmol/L) two hours after eating.

Insulin and other medications

Anyone who has type 1 diabetes needs insulin therapy throughout their life.

There are many types of insulin, including:

• Short-acting insulin. Sometimes called regular insulin, this type starts working around 30 minutes after injection. It reaches peak effect at 90 to 120 minutes and lasts about 4 to 6 hours. Examples are Humulin R, Novolin R and Afrezza.
• Rapid-acting insulin. This type of insulin starts working within 15 minutes. It reaches peak effect at 60 minutes and lasts about 4 hours. This type is often used 15 to 20 minutes before meals. Examples are glulisine (Apidra), lispro (Humalog, Admelog and Lyumjev) and aspart (Novolog and FiAsp).
• Intermediate-acting insulin. Also called NPH insulin, this type of insulin starts working in about 1 to 3 hours. It reaches peak effect at 6 to 8 hours and lasts 12 to 24 hours. Examples are insulin NPH (Novolin N, Humulin N).
• Long- and ultra-long-acting insulin. This type of insulin may provide coverage for as long as 14 to 40 hours. Examples are glargine (Lantus, Toujeo Solostar, Basaglar), detemir (Levemir) and degludec (Tresiba).

You'll probably need several daily injections that include a combination of a long-acting insulin and a rapid-acting insulin. These injections act more like the body's normal use of insulin than do older insulin regimens that only required one or two shots a day. A combination of three or more insulin injections a day has been shown to improve blood sugar levels.

• Insulin pump

An insulin pump is a device about the size of a cellphone that's worn on the outside of your body. A tube connects the reservoir of insulin to a catheter that's inserted under the skin of your abdomen. Insulin pumps are programmed to dispense specific amounts of insulin automatically and when you eat.

Insulin delivery options

Insulin can't be taken by mouth to lower blood sugar because stomach enzymes will break down the insulin, preventing it from working. You'll need to either get shots (injections) or use an insulin pump.

Injections. You can use a fine needle and syringe or an insulin pen to inject insulin under the skin. Insulin pens look like ink pens and are available in disposable or refillable varieties.

If you choose shots (injections), you'll probably need a mixture of insulin types to use during the day and night.

An insulin pump. This is a small device worn on the outside of your body that you program to deliver specific amounts of insulin throughout the day and when you eat. A tube connects a reservoir of insulin to a catheter that's inserted under the skin of your abdomen.

There's also a tubeless pump option that involves wearing a pod containing the insulin on your body combined with a tiny catheter that's inserted under your skin.

Blood sugar monitoring

Depending on the type of insulin therapy you select or need, you may have to check and record your blood sugar level at least four times a day.

The American Diabetes Association recommends testing blood sugar levels before meals and snacks, before bed, before exercising or driving, and whenever you think you have low blood sugar. Careful monitoring is the only way to make sure that your blood sugar level remains within your target range. More frequent monitoring can lower A1C levels.

Even if you take insulin and eat on a strict schedule, blood sugar levels can change. You'll learn how your blood sugar level changes in response to food, activity, illness, medications, stress, hormonal changes and alcohol.

Continuous glucose monitoring

Continuous glucose monitoring (CGM) monitors blood sugar levels. It may be especially helpful for preventing low blood sugar. These devices have been shown to lower A1C .

Continuous glucose monitors attach to the body using a fine needle just under the skin. They check blood glucose levels every few minutes.

Closed loop system

A closed loop system is a device implanted in the body that links a continuous glucose monitor to an insulin pump. The monitor checks blood sugar levels regularly. The device automatically delivers the right amount of insulin when the monitor shows that it's needed.

The Food and Drug Administration has approved several hybrid closed loop systems for type 1 diabetes. They are called "hybrid" because these systems require some input from the user. For example, you may have to tell the device how many carbohydrates are eaten, or confirm blood sugar levels from time to time.

A closed loop system that doesn't need any user input isn't available yet. But more of these systems currently are in clinical trials.

Other medications

Other medications also may be prescribed for people with type 1 diabetes, such as:

• High blood pressure medications. Your provider may prescribe angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) to help keep your kidneys healthy. These medications are recommended for people with diabetes who have blood pressures above 140/90 millimeters of mercury (mm Hg).
• Aspirin. Your provider may recommend you take baby or regular aspirin daily to protect your heart. Your provider may feel that you have an increased risk of a cardiovascular event. Your provider will discuss the risk of bleeding if you take aspirin.

Cholesterol-lowering drugs. Cholesterol guidelines are stricter for people with diabetes because of their higher risk of heart disease.

The American Diabetes Association recommends that low-density lipoprotein (LDL, or "bad") cholesterol be below 100 mg/dL (2.6 mmol/L). High-density lipoprotein (HDL, or "good") cholesterol is recommended to be over 50 mg/dL (1.3 mmol/L) in women and over 40 mg/dL (1 mmol/L) in men. Triglycerides, another type of blood fat, should be less than 150 mg/dL (1.7 mmol/L).

Healthy eating and monitoring carbohydrates

There's no such thing as a diabetes diet. However, it's important to center your diet on nutritious, low-fat, high-fiber foods such as:

• Whole grains

Your registered dietitian will recommend that you eat fewer animal products and refined carbohydrates, such as white bread and sweets. This healthy-eating plan is recommended even for people without diabetes.

You'll need to learn how to count the amount of carbohydrates in the foods you eat. By doing so, you can give yourself enough insulin. This will allow your body to properly use those carbohydrates. A registered dietitian can help you create a meal plan that fits your needs.

Physical activity

Everyone needs regular aerobic exercise, including people who have type 1 diabetes. First, get your provider's OK to exercise. Then choose activities you enjoy, such as walking or swimming, and do them every day when you can. Try for at least 150 minutes of moderate aerobic exercise a week, with no more than two days without any exercise.

Remember that physical activity lowers blood sugar. If you begin a new activity, check your blood sugar level more often than usual until you know how that activity affects your blood sugar levels. You might need to adjust your meal plan or insulin doses because of the increased activity.

Activities of concern

Certain life activities may be of concern for people who have type 1 diabetes.

• Driving. Low blood sugar can occur at any time. It's a good idea to check your blood sugar anytime you're getting behind the wheel. If it's below 70 mg/dL (3.9 mmol/L), have a snack with 15 grams of carbohydrates. Retest again in 15 minutes to make sure it has risen to a safe level before you start driving.
• Working. Type 1 diabetes can pose some challenges in the workplace. For example, if you work in a job that involves driving or operating heavy machinery, low blood sugar could pose a serious risk to you and those around you. You may need to work with your provider and your employer to ensure that certain adjustments are made. You may need additional breaks for blood sugar testing and fast access to food and drink. There are federal and state laws that require employers to provide these adjustments for people with diabetes.

Being pregnant. The risk of complications during pregnancy is higher for people with type 1 diabetes. Experts recommend that you see your provider before you get pregnant. A1C readings should be less than 6.5% before you try to get pregnant.

The risk of diseases present at birth (congenital diseases) is higher for people with type 1 diabetes. The risk is higher when diabetes is poorly controlled during the first 6 to 8 weeks of pregnancy. Careful management of your diabetes during pregnancy can lower your risk of complications.

• Being older or having other conditions. For those who are weak or sick or have difficulty thinking clearly, tight control of blood sugar may not be practical. It could also increase the risk of low blood sugar. For many people with type 1 diabetes, a less strict A1C goal of less than 8% may be appropriate.

Potential future treatments

• Pancreas transplant. With a successful pancreas transplant, you would no longer need insulin. But pancreas transplants aren't always successful — and the procedure poses serious risks. Because these risks can be more dangerous than the diabetes itself, pancreas transplants are generally used for those with very difficult-to-manage diabetes. They can also be used for people who also need a kidney transplant.
• Islet cell transplantation. Researchers are experimenting with islet cell transplantation. This provides new insulin-producing cells from a donor pancreas. This experimental procedure had some problems in the past. But new techniques and better drugs to prevent islet cell rejection may improve its chances of becoming a successful treatment.

Signs of trouble

Despite your best efforts, sometimes problems will happen. Certain short-term complications of type 1 diabetes, such as low blood sugar, require care immediately.

Low blood sugar (hypoglycemia)

Diabetic hypoglycemia occurs when someone with diabetes doesn't have enough sugar (glucose) in the blood. Ask your provider what's considered a low blood sugar level for you. Blood sugar levels can drop for many reasons, such as skipping a meal, eating fewer carbohydrates than called for in your meal plan, getting more physical activity than normal or injecting too much insulin.

Learn the symptoms of hypoglycemia. Test your blood sugar if you think your levels are low. When in doubt, always test your blood sugar. Early symptoms of low blood sugar include:

• Looking pale (pallor)
• Dizziness or lightheadedness
• Hunger or nausea
• An irregular or fast heartbeat
• Difficulty concentrating
• Feeling weak and having no energy (fatigue)
• Irritability or anxiety
• Tingling or numbness of the lips, tongue or cheek

Nighttime hypoglycemia may cause you to wake with sweat-soaked pajamas or a headache. Nighttime hypoglycemia sometimes might cause an unusually high blood sugar reading first thing in the morning.

If diabetic hypoglycemia isn't treated, symptoms of hypoglycemia worsen and can include:

• Confusion, unusual behavior or both, such as the inability to complete routine tasks
• Loss of coordination
• Difficulty speaking or slurred speech
• Blurry or tunnel vision
• Inability to eat or drink
• Muscle weakness

Severe hypoglycemia may cause:

• Convulsions or seizures
• Unconsciousness
• Death, rarely

You can raise your blood sugar quickly by eating or drinking a simple sugar source, such as glucose tablets, hard candy or fruit juice. Tell family and friends what symptoms to look for and what to do if you're not able to treat the condition yourself.

If a blood glucose meter isn't readily available, treat for low blood sugar anyway if you have symptoms of hypoglycemia, and then test as soon as possible.

Inform people you trust about hypoglycemia. If others know what symptoms to look for, they might be able to alert you to early symptoms. It's important that family members and close friends know where you keep glucagon and how to give it so that a potentially serious situation can be easier to safely manage. Glucagon is a hormone that stimulates the release of sugar into the blood.

Here's some emergency information to give to others. If you're with someone who is not responding (loses consciousness) or can't swallow due to low blood sugar:

• Don't inject insulin, as this will cause blood sugar levels to drop even further
• Don't give fluids or food, because these could cause choking
• Give glucagon by injection or a nasal spray
• Call 911 or emergency services in your area for immediate treatment if glucagon isn't on hand, you don't know how to use it or the person isn't responding

Hypoglycemia unawareness

Some people may lose the ability to sense that their blood sugar levels are getting low. This is called hypoglycemia unawareness. The body no longer reacts to a low blood sugar level with symptoms such as lightheadedness or headaches. The more you experience low blood sugar, the more likely you are to develop hypoglycemia unawareness.

If you can avoid having a hypoglycemic episode for several weeks, you may start to become more aware of coming lows. Sometimes increasing the blood sugar target (for example, from 80 to 120 mg/DL to 100 to 140 mg/DL) at least for a short time can also help improve low blood sugar awareness.

High blood sugar (hyperglycemia)

Blood sugar can rise for many reasons. For example, it can rise due to eating too much, eating the wrong types of foods, not taking enough insulin or fighting an illness.

• Frequent urination
• Increased thirst
• Blurred vision
• Irritability

If you think you have hyperglycemia, check your blood sugar. If it is higher than your target range, you'll likely need to administer a "correction." A correction is an additional dose of insulin given to bring your blood sugar back to normal. High blood sugar levels don't come down as quickly as they go up. Ask your provider how long to wait until you recheck. If you use an insulin pump, random high blood sugar readings may mean you need to change the place where you put the pump on your body.

If you have a blood sugar reading above 240 mg/dL (13.3 mmol/L), test for ketones using a urine test stick. Don't exercise if your blood sugar level is above 240 mg/dL or if ketones are present. If only a trace or small amounts of ketones are present, drink extra noncalorie fluids to flush out the ketones.

If your blood sugar is persistently above 300 mg/dL (16.7 mmol/L), or if your urine ketones stays high in spite of taking correction doses of insulin, call your provider or seek emergency care.

Increased ketones in your urine (diabetic ketoacidosis)

If your cells are starved for energy, the body may begin to break down fat. This produces toxic acids known as ketones. Diabetic ketoacidosis is a life-threatening emergency.

Symptoms of this serious condition include:

• Abdominal pain
• A sweet, fruity smell on your breath
• Shortness of breath

If you suspect ketoacidosis, check the urine for excess ketones with an over-the-counter ketones test kit. If you have large amounts of ketones in the urine, call your provider right away or seek emergency care. Also, call your provider if you have vomited more than once and you have ketones in the urine.

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Lifestyle and home remedies

Careful management of type 1 diabetes can lower your risk of serious — even life-threatening — complications. Consider these tips:

• Make a commitment to manage your diabetes. Take your medications as recommended. Learn all you can about type 1 diabetes. Make healthy eating and physical activity part of your daily routine. Establish a relationship with a diabetes educator. Ask your health care team for help.
• Identify yourself. Wear a tag or bracelet that says you are living with diabetes. Keep a glucagon kit nearby in case of a low blood sugar emergency. Make sure your friends and loved ones know how to use the kit.
• Schedule a yearly physical exam and regular eye exams. Your regular diabetes checkups aren't meant to replace yearly physicals or routine eye exams. During the physical, your provider will look for any diabetes-related complications. Your provider will also look for other medical problems. Your eye care specialist will check for signs of eye complications, such as retina damage, cataracts and glaucoma.

Keep your vaccinations up to date. High blood sugar can weaken the immune system. Get a flu shot every year. Your provider will likely recommend the pneumonia vaccine, too. They may also recommend getting the COVID-19 vaccine.

The Centers for Disease Control and Prevention (CDC) recommends hepatitis B vaccination if you haven't had it before and you're an adult between the ages of 19 and 59 years with type 1 or type 2 diabetes. The CDC recommends vaccination as soon as possible after diagnosis with type 1 or type 2 diabetes. If you are age 60 or older and have diabetes and haven't received the vaccine, talk to your provider about whether it's right for you.

• Pay attention to your feet. Wash your feet daily in lukewarm water. Dry them gently, especially between the toes. Moisturize your feet with lotion. Check your feet every day for blisters, cuts, sores, redness or swelling. Consult your provider if you have a sore or other foot problem that doesn't heal.
• Keep your blood pressure and cholesterol under control. Eating healthy foods and exercising regularly can help control high blood pressure and cholesterol. Medication also may be needed.
• If you smoke or use other forms of tobacco, ask your provider to help you quit. Smoking increases your risk of diabetes complications. These include heart attack, stroke, nerve damage and kidney disease. Talk to your provider about ways to stop smoking or to stop using other types of tobacco.
• If you drink alcohol, do so responsibly. Alcohol can cause either high or low blood sugar. It depends on how much you drink and if you eat at the same time. If you choose to drink, do so only in moderation and always with a meal. Check your blood sugar levels before going to sleep.
• Take stress seriously. The hormones the body produces when you're under long-term stress may prevent insulin from working properly. This can stress and frustrate you even more. Take a step back and set some limits. Prioritize your tasks. Learn ways to relax. Get plenty of sleep.

Coping and support

Diabetes can affect emotions both directly and indirectly. Poorly controlled blood sugar can directly affect emotions by causing behavior changes, such as irritability. There may be times when you resent your diabetes.

People living with diabetes have an increased risk of depression and diabetes-related distress. Many diabetes specialists regularly include a social worker or psychologist as part of their diabetes care team.

You may find that it helps to talk to other people with type 1 diabetes. Online and in-person support groups are available. Group members often know about the latest treatments. They may also share their own experiences or helpful information. For example, they may share where to find carbohydrate counts for your favorite takeout restaurant.

If you're interested in a support group, your provider may be able to recommend one in your area. Or you can visit the websites of the American Diabetes Association (ADA) or the Juvenile Diabetes Research Foundation (JDRF). These sites may list support group information and local activities for people with type 1 diabetes. You can also reach the ADA at 800-DIABETES ( 800-342-2383 ) or JDRF at 800-533-CURE ( 800-533-2873 ).

Preparing for your appointment

If you think that you or your child might have type 1 diabetes, see your provider immediately. A simple blood test can show if you need more evaluation and treatment.

After diagnosis, you'll need close medical follow-up until your blood sugar level is stable. A provider who specializes in hormonal disorders (endocrinologist) usually works with other specialists on diabetes care. Your health care team will likely include:

• Certified diabetes educator
• Registered dietitian
• Social worker or mental health professional
• Health care provider who specializes in eye care (ophthalmologist)
• Health care provider who specializes in foot health (podiatrist)

Once you've learned how to manage type 1 diabetes, your provider likely will recommend checkups every few months. A thorough yearly exam and regular foot and eye exams also are important. This is especially true if you're having a hard time managing your diabetes, if you have high blood pressure or kidney disease, or if you're pregnant.

These tips can help you prepare for your appointments. They can also let you know what to expect from your provider.

What you can do

• Write down any questions you have. Once you begin insulin treatment, the first symptoms of diabetes should go away. However, you may have new issues that you need to address. These include having low blood sugar that happens often or finding ways to control high blood sugar after eating certain foods.
• Write down key personal information, including any major sources of stress or recent changes in your life. Many factors can affect your diabetes control, including stress.
• Make a list of all the medications, vitamins and supplements you're taking.
• For your regular checkups, bring the records of your glucose values or your meter to your appointments.
• Write down questions to ask your provider.

Preparing a list of questions can help you make the most of your time with your provider and the rest of your health care team. Things you want to discuss with your provider, registered dietitian or diabetes educator include:

• When and how often you should monitor your blood glucose
• Insulin therapy — types of insulin used, timing of dosing, amount of dose
• Insulin administration — shots versus a pump
• Low blood sugar — how to recognize and treat
• High blood sugar — how to recognize and treat
• Ketones — testing and treatment
• Nutrition — types of food and their effect on blood sugar
• Carbohydrate counting
• Exercise — adjusting insulin and food intake for activity
• Medical management — how often to visit your provider and other diabetes care team members
• Sick day management

What to expect from your doctor

Your provider is likely to ask you many questions, including:

• How comfortable are you managing your diabetes?
• How frequent are your low blood sugar episodes?
• Do you know when your blood sugar is getting low?
• What's a typical day's diet like?
• Are you exercising? If so, how often?
• On average, how much insulin are you using daily?

What you can do in the meantime

If you're having trouble managing your blood sugar or you have questions, contact your health care team in between appointments.

• Summary of revisions: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-Srev.
• Papadakis MA, et al., eds. Diabetes mellitus. In: Current Medical Diagnosis & Treatment 2022. 61st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 4, 2022.
• What is diabetes? National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes. Accessed May 4, 2022.
• Levitsky LL, et al. Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Diabetes mellitus (DM). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed May 4, 2022.
• AskMayoExpert. Type 1 diabetes mellitus. Mayo Clinic; 2021.
• Robertson RP. Pancreas and islet transplantation in diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Levitsky LL, et al. Management of type 1 diabetes mellitus in children during illness, procedures, school, or travel. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Hyperglycemia (high blood glucose). American Diabetes Association. https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hyperglycemia. Accessed May 4, 2022.
• Diabetes and DKA (ketoacidosis). American Diabetes Association. https://www.diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed May 4, 2022.
• Insulin resistance & prediabetes. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance. Accessed May 4, 2022.
• Blood sugar and insulin at work. American Diabetes Association. https://www.diabetes.org/tools-support/diabetes-prevention/high-blood-sugar. Accessed May 4, 2022.
• Inzucchi SE, et al. Glycemic control and vascular complications in type 1 diabetes. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Diabetes and oral health. American Diabetes Association. https://www.diabetes.org/diabetes/keeping-your-mouth-healthy. Accessed May 4, 2022.
• Drug treatment of diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/drug-treatment-of-diabetes-mellitus. Accessed May 4, 2022.
• Weinstock DK, et al. Management of blood glucose in adults with type 1 diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 7, 2022.
• FDA proves first automated insulin delivery device for type 1 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-automated-insulin-delivery-device-type-1-diabetes. Accessed May 4, 2022.
• Boughton CK, et al. Advances in artificial pancreas systems. Science Translational Medicine. 2019; doi:10.1126/scitranslmed.aaw4949.
• Hypoglycemia (low blood sugar). American Diabetes Association. https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hypoglycemia. Accessed May 4, 2022.
• Diabetes in the workplace and the ADA. U.S. Equal Opportunity Employment Commission. https://www.eeoc.gov/laws/guidance/diabetes-workplace-and-ada. Accessed May 4, 2022.
• Cardiovascular disease and risk management: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S010.
• Diabetes technology. Standards of Medical Care in Diabetes — 2022. 2022; doi:10.2337/dc22-S007.
• FDA authorizes a second artificial pancreas system. JDRF. https://www.jdrf.org/blog/2019/12/13/jdrf-reports-fda-authorizes-second-artificial-pancreas-system/. Accessed May 4, 2022.
• Classification and diagnosis of diabetes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S002.
• Retinopathy, neuropathy, and foot care: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.
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• Centers for Disease Control and Prevention. Use of hepatitis B vaccination for adults with diabetes mellitus: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report. 2011;60:1709.
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• Older adults: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S013.
• FDA approves first-of-its-kind automated insulin delivery and monitoring system for use in young pediatric patients. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-automated-insulin-delivery-and-monitoring-system-use-young-pediatric#:~:text=Today, the U.S. Food and,by individuals aged 2 to. Accessed May 8, 2022.
• What you need to know: Getting a COVID-19 vaccine. American Diabetes Association. https://www.diabetes.org/coronavirus-covid-19/vaccination-guide. Accessed June 1, 2022.
• What is type 1 diabetes? A Mayo Clinic expert explains

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NIH Research To Prevent Type 1 Diabetes: George Eisenbarth's Legacy

W e remember George Eisenbarth for his many contributions to the scientific understanding of the pathogenesis of type 1 diabetes (T1D). In this article we frame our discussion of Dr. Eisenbarth's legacy, citing quotations from a noted scientific philosopher of the modern era, David Hume:

The sweetest and most inoffensive path of life leads through the avenues of science and learning; and whoever can either remove any obstructions in this way, or open up any new prospect, ought so far to be esteemed a benefactor to mankind. — David Hume, 1748

George Eisenbarth certainly followed the “sweet and inoffensive path of life through science,” and those with the good fortune to join him along the way were enriched and sincerely grateful for his guidance and good company. Eisenbarth was also known for “removing obstructions and opening up new prospects.” In part, the impact of his contributions can be measured by the citation of his work by others, the scientific product of the many people he trained, and his service to the community through National Institutes of Health (NIH) peer review.

According to the bibliographic search service SCOPUS, George Eisenbarth was listed as an author on 548 published articles from 1998 to 2012. His articles were cited by 15,493 other articles (excluding self-reference) during this period of time. Excluding reviews, chapters and books, Eisenbarth coauthored 406 original published reports from 1973 through 2012. One of his most frequently cited articles is “Type 1 diabetes: a chronic autoimmune disease,” published in the New England Journal of Medicine in 1986. 1 This article characterizes the pathogenesis of T1D as a progression from genetic susceptibility through environmental triggers and gradual β-cell destruction. This model has withstood the test of time and continues to guide the field toward its goal of preventing the disease.

Other frequently cited and notable articles from Eisenbarth include “The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes,” 2 “Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies,” 3 and “Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.” 4 These articles are part of the rationale for insulin administration for desensitization to prevent T1D. This idea was first investigated in the Diabetes Prevention Trial Type 1 (DPT-1). This study showed possible efficacy in the oral insulin subgroup with the highest insulin antibody titers, 5 which TrialNet is attempting to verify in its current oral insulin trial. In addition, Eisenbarth's early article from his days as an NIH fellow, authored with Nobelist Marshall Nirenberg, “Monoclonal antibody to a plasma membrane antigen of neurons,” 6 remains one of the most highly cited articles from Nirenberg's neurobiology period. This article is still cited by neurobiologists every year, demonstrating the durability of even one of Eisenbarth's earliest contributions.

Eisenbarth was continuously funded by the NIH since 1979, including a prestigious MERIT award in 1992 from the National Institute of Diabetes, Digestive, & Kidney Diseases (NIDDK). This funding history represents a major achievement for any investigator and is a reflection of his research productivity, his ability to identify important problems for investigation, his knack for effective communication, and his capacity to embrace constructive disagreement. Eisenbarth welcomed scientific discussion gladly and eagerly, even when it challenged his own most strongly favored hypotheses.

Indulge your passion for science, says she, but let your science be human, and such as may have a direct reference to action and society. —David Hume, 1748

Eisenbarth's scientific interests followed Hume's prescription in being focused on that which has the potential to alleviate human suffering. He chose important problems that necessitated solution and did not shy away from technically difficult challenges. Eisenbarth played a key role in efforts to standardize antibody measurements internationally so that results can be compared across studies and measurements can reliably be performed in multiple labs. The scientific rigor and attention to practical considerations Eisenbarth brought to measurement of antibody levels have been critical for many NIH consortia, such as The Environmental Determinants of Diabetes in the Young (TEDDY), the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), and the Immune Tolerance Network (ITN). It is also his work that the T1D research community relies on to stage people's disease risk through both genetic tests and antibody measurements. This is essential to clinical trials for prevention performed by T1D TrialNet. Eisenbarth recognized that once methods are established to prevent T1D, cost-effective and reliable risk screening technology will be needed to identify people at risk. NIDDK is funding research to develop simpler and cheaper tests through a Small Business Innovation Research award to a company that Eisenbarth attracted to the field of T1D research. This work continues to emerge, striving to simplify and remove the significant obstacle of expensive and technically difficult autoantibody measurement through technological innovation. Eisenbarth recognized that without cost-effective and reliable risk screening technology in hand, the field will not be ready to identify people at risk and to intervene to prevent the disease, even if effective strategies are identified.

Eisenbarth was a consultant to the Congressionally established Diabetes Research Working Group that produced Conquering Diabetes: A Strategic Plan for the 21st Century . 7 , 8 A decade later he was a member of the Type 1 Diabetes and Autoimmunity Working Group that contributed to development of the current Diabetes Strategic Plan issued in 2011. These activities are critically important for informing the public as well as Congress about the importance of diabetes research and the burden of T1D on the population.

Eisenbarth was a dedicated peer reviewer. He participated in 41 NIH review meetings spanning two decades. He was also an engaged and active consortium member, serving on many committees within TrialNet, TEDDY, and other large clinical research networks. Eisenbarth provided leadership in laboratory monitoring activities and the practical aspects of clinical trial operations in addition to his conceptual scientific leadership mentioned previously.

Eisenbarth's work has had global impact, which is in no small part due to his active training of the next generation of scientists. Eisenbarth's 40 trainees are located at institutions around the world ( Fig. 1 ). IN-SPIRE, 5 a text analysis tool, was used to evaluate up to 100 published abstracts from each of 37 of George Eisenbarth's trainees (a total of over 1,000 abstracts), and the results are graphically represented in Figure 2 . This analysis shows the depth and breadth of diabetes research as a result of Eisenbarth's exemplary mentorship.

Publications from Eisenbarth trainees were downloaded from SCOPUS, and the authors' locations are displayed as a word cloud using the free program Word it Out ( http://worditout.com/ ).

The text mining and graphical display program IN-SPIRE 5 (version 5.4.0) was used to analyze up to 100 of the most recent published abstracts from each of 37 Eisenbarth trainees (a total of 1,037 abstracts). Results are displayed as Themeview with the peak height corresponding to topic frequency in the dataset.

George Eisenbarth's outstanding scientific achievements, and his service to the community of T1D researchers, have brought us a good way closer to preventing the disease. We can expect to continue to enjoy being reminded of George Eisenbarth as we progress along the pathway toward new therapies to treat and prevent T1D. His living legacy consists of the many scientists he mentored and the colleagues he inspired as the epitome of a creative, compassionate, and caring physician and scientist.

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.

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