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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.

• DeVries JH ,
• Hess-Fischl A ,
• Gregory GA ,
• Robinson TIG ,
• Linklater SE ,
• International Diabetes Federation Diabetes Atlas Type 1 Diabetes in Adults Special Interest Group
• Harding JL ,
• Wander PL ,
• Dabelea D ,
• Mayer-Davis EJ ,
• SEARCH for Diabetes in Youth Study
• Lawrence JM ,
• SEARCH for Diabetes in Youth Study Group
• Fazeli Farsani S ,
• Souverein PC ,
• van der Vorst MM ,
• Sutherland J ,
• Rokszin G ,
• Stahl-Pehe A ,
• Kamrath C ,
• Atkinson MA ,
• Bingley PJ ,
• Bonifacio E ,
• Leslie RD ,
• Evans-Molina C ,
• Freund-Brown J ,
• Thomas NJ ,
• Zimmet PZ ,
• Rowley MJ ,
• Knowles W ,
• Fourlanos S ,
• Greenbaum CJ ,
• ElSayed NA ,
• American Diabetes Association
• Miller RG ,
• Secrest AM ,
• Sharma RK ,
• Songer TJ ,
• McDonald T ,
• Greenfield JR
• Tridgell DM ,
• Spiekerman C ,
• Greenbaum CJ
• Glessner J ,
• Foster NC ,
• Miller KM ,
• Becker DJ ,
• Khawandanah J
• Pedrosa MR ,
• Franco DR ,
• Gieremek HW ,
• Nathan DM ,
• Diabetes Control and Complications Trial Research Group
• Klonoff DC ,
• Parkes JL ,
• Kovatchev BP ,
• Raghinaru D ,
• iDCL Trial Research Group
• Riddlesworth T ,
• DIAMOND Study Group
• Leelarathna L ,
• Neupane S ,
• FLASH-UK Trial Study Group
• Polonsky W ,
• Hirsch IB ,
• Pratley RE ,
• Kanapka LG ,
• Rickels MR ,
• Wireless Innovation for Seniors With Diabetes Mellitus (WISDM) Study Group
• Tauschmann M ,
• APCam11 Consortium
• Russell SJ ,
• Damiano ER ,
• Bionic Pancreas Research Group
• Bailey TS ,
• Group Information ,
• Bergenstal RM ,
• Dellva MA ,
• Mathieu C ,
• Herold KC ,
• Type 1 Diabetes TrialNet Study Group
• Libman IM ,
• DiMeglio LA ,
• T1D Exchange Clinic Network Metformin RCT Study Group
• Petrie JR ,
• Chaturvedi N ,
• REMOVAL Study Group
• Dandona P ,
• Phillip M ,
• DEPICT-1 Investigators
• Rosenstock J ,
• Marquard J ,
• Laffel LM ,
• Hemmingsson JU ,
• ADJUNCT ONE Investigators
• Pieber TR ,
• ADJUNCT TWO Investigators
• Reynolds J ,
• Battelino T ,
• Liljenquist D ,
• Becker RH ,
• Bergmann K ,
• Lehmann A ,
• Cheng AYY ,
• Stender-Petersen K ,
• Hövelmann U ,
• Carlson AL ,
• Komatsu M ,
• Coutant DE ,
• Stamati A ,
• Karagiannis T ,
• Christoforidis A
• Heinemann L ,
• Baughman R ,
• Akturk HK ,
• Snell-Bergeon JK ,
• Prabhu JN ,
• Seyed Ahmadi S ,
• Westman K ,
• Pivodic A ,
• Hermann JM ,
• Freiberg C ,
• DPV Initiative
• Dicembrini I ,
• Cosentino C ,
• Mannucci E ,
• Abelseth J ,
• Karageorgiou V ,
• Papaioannou TG ,
• Weisman A ,
• Cardinez M ,
• Kramer CK ,
• Asarani NAM ,
• Reynolds AN ,
• Elbalshy M ,
• Jennings P ,
• Burnside MJ ,
• Williman JA ,
• Fridell JA ,
• Stratta RJ ,
• Gruessner AC
• Robertson RP
• Shapiro AM ,
• Pepper AR ,
• Shapiro AMJ
• Walker JT ,
• Saunders DC ,
• Brissova M ,
• Gitelman SE ,
• Bluestone JA
• Hagopian W ,
• Ferry RJ Jr . ,
• Protégé Trial Investigators
• von Scholten BJ ,
• Kreiner FF ,
• Gough SCL ,
• von Herrath M
• Type 1 Diabetes TrialNet Abatacept Study Group
• Hardie DG ,
• Dejgaard TF ,
• Christiansen E ,
• ADJUNCT ONE and ADJUNCT TWO Investigators
• Yunasan E ,
• Peters AL ,
• Palanca A ,
• van Nes F ,
• Ampudia Blasco FJ ,
• Dobbins RL ,
• Greenway FL ,
• Zambrowicz BP ,
• Brodovicz K ,
• Soleymanlou N ,
• Wissinger E ,
• Juhaeri J ,
• Mayer-Davis EJ
• Dhatariya KK ,
• Glaser NS ,
• Umpierrez GE
• Ramphul K ,
• Umpierrez G ,
• Korytkowski M
• Weinstock RS ,
• T1D Exchange Clinic Network
• Eshkoli T ,
• Brandstaetter E ,
• Jotkowitz A
• Dhatariya KK
• Joint British Diabetes Societies for Inpatient Care
• Kilpatrick ES ,
• Butler AE ,
• Ostlundh L ,
• Koufakis T ,
• Agiostratidou G ,
• International Hypoglycaemia Study Group
• van de Ven KC ,
• Heerschap A ,
• van der Graaf M ,
• de Galan BE
• Alsifri S ,
• Aronson R ,
• HAT Investigator Group
• Pettus JH ,
• Shepherd L ,
• Van Houten HK ,
• Ziegenfuss JY ,
• Wermers RA ,
• Schernthaner G ,
• Anderson J ,
• Saunders AL ,
• Snell-Bergeon J ,
• Forlenza GP ,
• Bispham J ,
• Gabbay RA ,
• Pontiroli AE ,
• Tagliabue E
• T1D Exchange Intranasal Glucagon Investigators
• Freckmann G ,
• Ehrmann D ,
• El Laboudi A ,
• Spanudakis E ,
• Anantharaja S ,
• Peleckis AJ ,
• Dalton-Bakes C ,
• van Beers CA ,
• Kleijer SJ ,
• CGM Intervention in Teens and Young Adults with T1D (CITY) Study Group ,
• Piras de Oliveira C ,
• Ribeiro A ,
• Chigutsa F ,
• Malecki MT ,
• Hopkins D ,
• Lawrence I ,
• Mansell P ,
• Stanton-Fay SH ,
• Hamilton K ,
• Chadwick PM ,
• DAFNEplus study group
• Goldsmith K ,
• Yudkin JS ,
• Buntinx F ,
• Mapatano MA ,
• De Clerck M ,
• Truyers C ,
• Chambers D ,
• O’Cathain A
• Klatman EL ,
• Auzanneau M ,
• Tanenbaum ML ,
• Iturralde E ,
• Lipman TH ,
• Bhutta ZA ,
• Pfiester E ,
• Thieffry A ,
• Ballhausen H ,
• Gajewska KA ,
• O’Donnell S
• Wareham NJ ,
• Joosse HJ ,
• Raposo JF ,
• de Courten M
• Hemmingsen B ,
• Abouhassan T ,
• Albanese-O’Neill A ,
• Jacobsen L ,
• Haller MJ ,
• Castorino K ,
• Lovblom LE ,
• Cardinez N ,
• Nguyen KT ,
• Andersen G ,
• Meiffren G ,
• Famulla S ,
• Castellanos LE ,
• Balliro CA ,
• Sherwood JS ,
• Tsoukas MA ,
• Bernier-Twardy S ,
• Martinson LA ,
• Carlsson PO ,
• Schwarcz E ,
• Korsgren O ,
• Oliveira MC ,
• Stracieri AB ,
• Buzzetti R ,
• Mauricio D ,
• McGibbon A ,
• Ingersoll K ,
• Tugwell B ,
• Diabetes Canada Clinical Practice Guidelines Expert Committee
• Fleming GA ,
• McCall AL ,
• Gianchandani R ,

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

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

Harvard Correspondent

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

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

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

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

GAZETTE: Would you walk us through the approach?

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

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

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

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

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

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

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

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

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

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

GAZETTE: What’s next?

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

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

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Apr. 27, 2023

Study unlocks potential breakthrough in type 1 diabetes treatment, rice u. scientists optimize biomaterials screening, identify ‘winning’ formulations.

For the over 8 million people around the globe living with Type 1 diabetes , getting a host immune system to tolerate the presence of implanted insulin-secreting cells could be life-changing.

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

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

According to the study in Nature Biomedical Engineering , using one of the alginate formulations to encapsulate human insulin-secreting islet cells provided long-term blood sugar level control in diabetic mice. Catheters coated with two other high-performing materials did not clog up. “This work was motivated by a major unmet need,” said Veiseh, a Rice assistant professor of bioengineering and Cancer Prevention and Research Institute of Texas scholar. “In Type 1 diabetes patients, the body’s immune system attacks the insulin-producing cells of the pancreas. As those cells are killed off, the patient loses the ability to regulate their blood glucose.”

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

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

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

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

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

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

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

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

Trials are underway for stem cell-derived islet cell use in diabetic patients. However, current islet treatments require immunosuppression, making it a taxing way to treat Type 1 diabetes. “Currently, in order to use implanted islet cells in diabetic patients, you have to suppress the entire immune system, just as if you were trying to do an organ transplant,” Veiseh said. “That comes with a lot of complications for the patient.

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

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

“We wanted to test a library of these materials, with the selection pressure of having cells inside the beads that makes it harder for the material to not get noticed by the immune system,” Veiseh said. “There’s a lot of interest from all the islet cell manufacturers to be able to get rid of immunosuppression and instead use these alginate hydrogel matrices to protect the implanted cells.” The new high-throughput “barcoding” approach can be deployed to screen for other medical applications using fewer live test subjects.

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

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

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

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

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

“I am pleased to work with Omid to enable the development of improved biomaterials using my team's expertise in DNA sequencing,” added Zhang, who was a co-investigator on the grant. “These improved biomaterials can enable durable implanted cell therapies to function as living drug factories, and can have a positively disruptive impact on patients with a variety of chronic diseases.” The National Institutes of Health (R01 DK120459), JDRF (3-SRA-2021-1023-S-B), the National Science Foundation (CBET1626418), the Rice University Academy Fellowship and Rice’s Shared Equipment Authority supported the research.

Screening hydrogels for antifibrotic properties by implanting cellularly barcoded alginates in mice and a non-human primate | Nature Biomedical Engineering | DOI: 10.1038/s41551-023-01016-2 Authors: Sudip Mukherjee, Boram Kim, Lauren Cheng, Michael David Doerfert, Jiaming Li, Andrea Hernandez, Lily Liang, Maria Ruocco, Peter Rios, Sofia Ghani, Irax Joshi, Douglas Isa, Trisha Ray, Tanguy Terlier, Cody Fell, Ping Song, Roberto Miranda, Jose Oberholzer, David Yu Zhang and Omid Veiseh https://www.nature.com/articles/s41551-023-01016-2

https://news-network.rice.edu/news/files/2023/03/230310_Veiseh-Lab_LG.jpg CAPTION: Omid Veiseh is a Rice assistant professor of bioengineering and Cancer Prevention and Research Institute of Texas scholar. (Photo by Gustavo Raskoksy/Rice University) https://news-network.rice.edu/news/files/2023/03/230310_Boram_Kim_LG.jpg CAPTION: Boram Kim is a Rice graduate student and co-lead author on the study. (Photo by Gustavo Raskosky/Rice University) https://news-network.rice.edu/news/files/2023/03/230310_Veiseh_Kim_LG.jpg CAPTION: Omid Veiseh and Boram Kim. Kim is holding a medical-grade catheter similar to ones used in the study experiments. (Photo by Gustavo Raskosky/Rice University) https://news-network.rice.edu/news/files/2023/03/230310_Veiseh-Lab_capsules1.jpg CAPTION: Different biomaterial formulations look the same, making it impossible to identify high-performing ones in the absence of some telltale trait. To overcome these constraints, Rice researchers tagged each alginate formulation with a unique “barcode” that allowed them to identify the ones that performed best. The multicolored beads illustrate the barcoded biomaterial capsules. (Photo by Gustavo Raskosky/Rice University) https://news-network.rice.edu/news/files/2023/03/230310_Veiseh-Lab_capsules2.jpg CAPTION: The new high-throughput “barcoding” approach can be deployed to screen for other medical applications using fewer live test subjects. (Photo by Gustavo Raskosky/Rice University) https://news-network.rice.edu/news/files/2023/03/José_Oberholzer_LG.jpeg CAPTION: Dr. José Oberholzer is a researcher and transplant surgeon at the University of Virginia. (Photo courtesy of José Oberholzer) https://news-network.rice.edu/news/files/2023/03/Lauren_Cheng_LG.jpg CAPTION: Lauren Cheng is a Rice alum and co-lead author on the study. (Photo courtesy of Lauren Cheng) https://news-network.rice.edu/news/files/2023/03/Sudip_Mukherjee_LG.jpg CAPTION: Sudip Mukherjee, a former Rice postdoctoral associate, is an assistant professor in the School of Biomedical Engineering at the Indian Institute of Technology Varanasi and co-lead author on the study. (Photo courtesy of Sudip Mukherjee)

Fats help tag medical implants as friend or foe: https://news.rice.edu/news/2023/fats-help-tag-medical-implants-friend-or-foe Upgraded tumor model optimizes search for cancer therapies: https://news.rice.edu/news/2023/upgraded-tumor-model-optimizes-search-cancer-therapies HIV ‘drug factory’ implant promises once-a-year therapy: https://news.rice.edu/news/2022/hiv-drug-factory-implant-promises-once-year-therapy Rice lab’s ‘drug factory’ implants cleared for human trials: https://news.rice.edu/news/2022/rice-labs-drug-factory-implants-cleared-human-trials

Department of Bioengineering: https://bioengineering.rice.edu/ Veiseh lab: https://veisehlab.rice.edu/team Cancer Prevention and Research Institute of Texas (CPRIT): https://www.cprit.state.tx.us/

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 4,552 undergraduates and 3,998 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 1 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

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.

• Immune System
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Story Source:

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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Scientists close in on a pain-free method for controlling type 1 diabetes

by Vittoria D'Alessio, Horizon: The EU Research & Innovation Magazine

Lee Calladine pricks his skin with a needle up to eight times a day to give himself an injection of insulin—the hormone that keeps his type 1 diabetes in check. Without insulin, his blood-sugar levels would become dangerously high and eventually fatal.

Calladine, aged 54, has been diabetic for 25 years and the insulin top-up routine is so familiar to him that he's long past feeling squeamish about piercing his skin . Still, the practice is burdensome.

"I have to rotate where I do my injections," said Calladine, who lives in the UK city of Portsmouth and works as an event coordinator for the Diabetes Research & Wellness Foundation. "If you inject the same place too often, you damage the tissue and get a lump. And if you then inject into that lump, the insulin won't get absorbed."

While a cure for type 1 diabetes is the holy grail , another game changer for Calladine and millions of other people like him around the world would be the ability to deliver insulin without needles or syringes.

That's where Professor David Fernandez Rivas, a bioengineer at the University of Twente in the Netherlands, believes he can help.

Fernandez Rivas leads a research project to develop a method to deposit liquids into skin and other soft materials using compression rather than needles.

The technique is known as BuBble Gun, which is also the name given to the five-year project that will run until the end of 2024. Fernandez Rivas invented the BuBble Gun with his research team, which is now refining the technology in the hopes of turning it into a reality.

Speedy squeeze

While electronic pumps that release insulin into the body throughout the day do exist, they are imperfect and still require a cannula needle to be inserted at the connection point.

With BuBble Gun, a laser beam is directed at the fluid medicine in a glass cartridge, heating it until it boils and creates a bubble. This bubble grows until it squeezes the liquid at high velocity —30 to 100 meters a second—out of its tube and, in the case of a medicine, into the skin.

Rather than piercing the skin, the way a needle would, the drug is pushed between skin cells. This limits damage both to the skin and to the cells beneath it.

"The liquid effectively becomes the needle," said Fernandez Rivas, who moved to the Netherlands from Cuba in 2007 with a first degree in nuclear engineering and has been working in bioengineering and green technology ever since.

This approach could be a relief not just for 9 million people worldwide including Calladine who have type 1 diabetes but also for millions of others who have unrelated conditions that also require regular injections.

Other potential beneficiaries are the 25% of people who are scared of needles and who can, as a result, avoid certain medical interventions including vaccination.

"Removing pain and fear from the injection process will have a big impact on a lot of people with needle phobia," said Fernandez Rivas.

Tissue challenges

Most injections penetrate the body until they reach muscle. These are regarded as the simplest injections to administer and the dose gradually diffuses out of the muscle into the body's blood-circulation system.

Many drugs, however, can do the job just as well—or perhaps better—when delivered into the more superficial layers of skin.

Fernandez Rivas is confident that many vaccines, for instance, would work just as well when delivered between the layers of the skin . Currently, they tend to be injected into muscle.

This means BuBble Gun has potential uses beyond insulin delivery.

A key technical challenge tackled by the research team relates to skin depth, which varies depending on age, gender, ethnicity and lifestyle. Smoking, for instance, makes the skin thinner.

As a result, the "gun" pressure needs to be adjusted to take these differences into consideration.

"You need the jet of fluid to penetrate the skin to just the right depth without splashback or seeping into nearby tissue or material, which would alter the dose unpredictably," said Fernandez Rivas.

The researchers are still working on precisely controlling the drug jet as it enters soft tissue.

Since 2018 , they've been conducting laboratory experiments on materials that simulate skin as well as on real skin tissue. Tests on human tissue have been in progress since 2022.

If all goes well, trials on healthy human volunteers will start later this year.

Planned prototype

The BuBle Gun team has created a startup company called FlowBeams . Through this, the researchers hope that a prototype of the gun will be ready to showcase to potential industry partners before 2025.

Fernandez Rivas foresees a time eventually when diabetes patients will be able to use a modified version that incorporates the microjet technology into a skin patch.

The patch would include a sensor that both tests blood-sugar levels on a continual basis and pushes insulin into the body as the need arises.

"Imagine how this would transform the life of an anxious parent who wakes up multiple times in the night to check their child with diabetes isn't having a blood-sugar swing in their sleep," Fernandez Rivas said.

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Current and future therapies for type 1 diabetes

Bernt johan von scholten.

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

Frederik F. Kreiner

Stephen c. l. gough, matthias von herrath.

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

Associated Data

Graphical abstract.

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

Supplementary Information

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

Introduction

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

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

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

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

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

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

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

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

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

Immune-focused therapies

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

Cell-directed interventions

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

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

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

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

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

Cytokine-directed interventions

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

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

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

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

Antigen vaccination

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

Non-immunomodulatory adjunctives

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

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

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

Sodium-glucose cotransporter inhibitors

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

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

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

Future perspectives

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

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

Immune interventions

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

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

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

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

Management of cardiometabolic complications

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

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

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

Combination therapies

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

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

Stem cell replacement therapy

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

Closing thoughts

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

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Large study sheds new light on the complex type 1 diabetes genetics landscape and potential drug targets

In new research, scientists analyzed genetic contributors to type 1 diabetes by studying over 61,000 participants (with and without the disease), including individuals from diverse ancestries. This approach led to the identification of 36 new gene regions associated with type 1 diabetes, some of which are also associated with other autoimmune diseases. Additionally, the scientists did “fine mapping” studies to pinpoint the specific disease-causing variants in genetic regions previously associated with type 1 diabetes, toward elucidating the role these variants may play in the disease process. In another set of experiments, they used their genetic association results with data about other autoimmune diseases to identify 12 genes that could potentially be drug targets for type 1 diabetes. Drugs targeting these genes (by affecting the proteins the genes encode) have been studied in clinical trials for other autoimmune diseases, suggesting they could be repurposed for type 1 diabetes. Some of the targets are already being studied in type 1 diabetes clinical trials of various therapies, but others could potentially be explored in future trials to prevent type 1 diabetes.

This large research study with a diverse population has provided important knowledge about the complex type 1 diabetes genetics landscape, revealing new genetic regions associated with the disease, shedding light on how some genetic variants may influence disease, and identifying potential drug targets. Understanding what genes play a role in type 1 diabetes, and what role they play, paves the way to identify new targets to prevent or treat this autoimmune disease.

Robertson CC, Inshaw JRJ, Onengut-Gumuscu S,…Rich SS. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes . Nat Genet 53: 962-971, 2021.

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• Published: 06 December 2023

Diabetes mellitus in 2023

Type 1 diabetes mellitus: a brave new world

• Pieter-Jan Martens 1 &
• Chantal Mathieu   ORCID: orcid.org/0000-0002-4055-5233 1  

Nature Reviews Endocrinology volume  20 ,  pages 71–72 ( 2024 ) Cite this article

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• Pre-diabetes
• Type 1 diabetes

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.

Key advances

Automated insulin delivery improves glycaemic control and pregnancy outcomes in pregnancy complicated by maternal type 1 diabetes mellitus (T1DM) compared to standard of care 2 .

Once-weekly basal insulin is non-inferior compared to its once-daily counterpart, in terms of HbA 1c (ref. 5 ).

Whole-blood gene expression signatures can help in stratifying the heterogeneity of T1DM 6 .

In patients with T1DM, detection of disease earlier in its course rather than later yields a more favourable clinical outcome at symptom onset 8 .

Teplizumab not only preserves β-cell function at stage 2 T1DM 7 , but also at stage 3 (symptom-onset) T1DM 10 .

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Phillip, M. et al. Consensus recommendations for the use of automated insulin delivery technologies in clinical practice. Endocr. Rev. 44 , 254–280 (2023).

Article   PubMed   Google Scholar  

Lee, T. T. M. et al. Automated insulin delivery in women with pregnancy complicated by type 1 diabetes. N. Engl. J. Med. 389 , 1566–1578 (2023).

Article   CAS   PubMed   Google Scholar  

Ekberg, N. R., Hartvig, N. V., Kaas, A., Møller, J. B. & Adolfsson, P. Smart pen exposes missed basal insulin injections and reveals the impact on glycemic control in adults with type 1 diabetes. J. Diabetes Sci. Technol. https://doi.org/10.1177/19322968221104142 (2022).

Kazda, C. M. et al. Novel once-weekly basal insulin Fc achieved similar glycemic control with a safety profile comparable to insulin degludec in patients with type 1 diabetes. Diabetes Care 46 , 1052–1059 (2023).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Russell-Jones, D. et al. Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial. Lancet 402 , 1636–1647 (2023).

Suomi, T. et al. Gene expression signature predicts rate of type 1 diabetes progression. EBioMedicine 92 , 104625 (2023).

Herold, K. C. et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 381 , 603–613 (2019).

Hummel, S. et al. Children diagnosed with presymptomatic type 1 diabetes through public health screening have milder diabetes at clinical manifestation. Diabetologia 66 , 1633–1642 (2023).

Sims, E. K. et al. Screening for type 1 diabetes in the general population: a status report and perspective. Diabetes 71 , 610–623 (2022).

Ramos, E. L. et al. Teplizumab and β-cell function in newly diagnosed type 1 diabetes. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2308743 (2023).

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Pieter-Jan Martens & Chantal Mathieu

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C.M. serves or has served on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd, Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz and Vertex. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for C.M. from Medtronic, Imcyse, Novo Nordisk, Sanofi and ActoBio Therapeutics; C.M. serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca and Novartis. Financial compensation for these activities has been received by KU Leuven. C.M. is president of EASD. All external support of EASD is to be found on http://www.easd.org/ . P.M. has no competing interests.

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Martens, PJ., Mathieu, C. Type 1 diabetes mellitus: a brave new world. Nat Rev Endocrinol 20 , 71–72 (2024). https://doi.org/10.1038/s41574-023-00936-y

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Type 1 Diabetes Research

Through the JDRF – Beyond Type 1 Alliance , Beyond Type 1 has partnered with JDRF—the world’s biggest nonprofit funder of type 1 diabetes research —to educate our community on the important role research plays in the lives of everyone affected by type 1 diabetes (T1D). It was diabetes research that led to the discovery of insulin in 1921. It was research that led to the creation of the first insulin pump in 1963, and research that led to the modern analog insulins used by many living with T1D today. Without research, we wouldn’t have continuous glucose monitors (CGMs), hybrid closed loop systems, or treatment for the complications that arise from living with diabetes. And it is research that will some day lead to the cure for type 1 diabetes.

Cure Research: The most promising cures for Type 1 diabetes will need to address two challenges: the loss of insulin-producing beta cells, and the immune system’s attack on those beta cells.

Vertex VX-880 Clinical Results Lead To Insulin-Independence

Explaining the Research: What Will It Take to Cure Diabetes?

Vertex Acquires ViaCyte, Combining Resources Toward a T1D Cure

Beta Cell Replacement Therapy: A Pathway to a Cure for Type 1 Diabetes?

New Documentary: ‘The Human Trial’ is a Quest to Cure Type 1 Diabetes

Beta Cell Therapies

Immunotherapies

Improving lives: a future cure is not enough for people living with t1d today. research also focuses on improving lives through glucose control and treating complications..

Glucose Control Therapies

Complications Treatment Research

Learn more about t1d research and the importance of trial participation.

Research Trials

Research News

Research Funding

To learn more about all the great T1D research being funded by JDRF,  visit their research and impact page here.

WRITTEN BY BT1 Editorial Team, POSTED 02/13/21, UPDATED 01/03/23

The isolated caregiver—a mom’s story -, losing will hauver -, life with type 1—a photo essay -, how diabetes impacts your mental health -, signs of type 1 diabetes -.

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GLP-1 drug may mitigate Parkinson’s progression

Posted April 17, 2024 by University of Washington Diabetes Research Center

A small study published in The New England Journal of Medicine suggests that a GLP-1 receptor agonist similar to the diabetes medication Ozempic and obesity drug Wegovy may lead to modest slowing of Parkinson’s disease symptoms. Parkinson’s expert Michael Okun called the findings “a really encouraging step forward," and Hyun Joo Cho of the National Institute of Neurological Disorders and Stroke said the study is important but further research is needed.

 Full Story: The New York Times  

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Kendall EK , Olaker VR , Kaelber DC , Xu R , Davis PB. Association of SARS-CoV-2 Infection With New-Onset Type 1 Diabetes Among Pediatric Patients From 2020 to 2021. JAMA Netw Open. 2022;5(9):e2233014. doi:10.1001/jamanetworkopen.2022.33014

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Association of SARS-CoV-2 Infection With New-Onset Type 1 Diabetes Among Pediatric Patients From 2020 to 2021

• 1 Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, Ohio
• 2 The Center for Clinical Informatics Research and Education, The MetroHealth System, Cleveland, Ohio
• 3 Center for Community Health Integration, Case Western Reserve University School of Medicine, Cleveland, Ohio

Incidence of new-onset type 1 diabetes (T1D) increased during the COVID-19 pandemic, 1 and this increase has been associated with SARS-CoV-2 infection. 2 The US Centers for Disease Control and Prevention reported that pediatric patients with COVID-19 were more likely to be diagnosed with diabetes after infection, although types 1 and 2 were not separated. 3 Therefore, whether COVID-19 was associated with new-onset T1D among youths remains unclear. This cohort study assessed whether there was an increase in new diagnoses of T1D among pediatric patients after COVID-19.

Data were obtained using TriNetX Analytics Platform, a web-based database of deidentified electronic health records of more than 90 million patients, from the Global Collaborative Network, which includes 74 large health care organizations across 50 US states and 14 countries with diverse representation of geographic regions, self-reported race, age, income, and insurance types. 4 The MetroHealth System institutional review board deemed the study exempt because it was determined to be non–human participant research. The study followed the STROBE reporting guideline.

The study population comprised pediatric patients in 2 cohorts: (1) patients aged 18 years or younger with SARS-CoV-2 infection between March 2020 and December 2021 and (2) patients aged 18 years or younger without SARS-CoV-2 infection but with non–SARS-CoV-2 respiratory infection during the same period. SARS-CoV-2 infection was defined as described in prior studies. 5 These cohorts were subdivided into groups aged 0 to 9 years and 10 to 18 years.

Cohorts were propensity score matched (1:1 using nearest-neighbor greedy matching) for demographics and family history of diabetes ( Table ). Risk of new diagnosis of T1D within 1, 3, and 6 months after infection were compared between matched cohorts using hazard ratios (HRs) and 95% CIs. Statistical analyses were conducted in the TriNetX Analytics Platform. Further details and analyses from the TriNetX database are given in the eMethods in the Supplement .

The Table shows population characteristics before and after matching. The study population included 1 091 494 pediatric patients: 314 917 with COVID-19 and 776 577 with non–COVID-19 respiratory infections. The matched cohort included 571 256 pediatric patients: 285 628 with COVID-19 and 285 628 with non–COVID-19 respiratory infections. By 6 months after COVID-19, 123 patients (0.043%) had received a new diagnosis of T1D, but only 72 (0.025%) were diagnosed with T1D within 6 months after non–COVID-19 respiratory infection. At 1, 3, and 6 months after infection, risk of diagnosis of T1D was greater among those infected with SARS-CoV-2 compared with those with non–COVID-19 respiratory infection (1 month: HR, 1.96 [95%CI, 1.26-3.06]; 3 months: HR, 2.10 [95% CI, 1.48-3.00]; 6 months: HR, 1.83 [95% CI, 1.36-2.44]) and in subgroups of patients aged 0 to 9 years, a group unlikely to develop type 2 diabetes, and 10 to 18 years ( Figure ). Similar increased risks were observed among children infected with SARS-CoV-2 compared with other control cohorts at 6 months (fractures: HR, 2.09 [95% CI, 1.41- 3.10]; well child visits: HR, 2.10 [95% CI, 1.61- 2.73]).

In this study, new T1D diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems). Respiratory infections have previously been associated with onset of T1D, 6 but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths. Study limitations include potential biases owing to the observational and retrospective design of the electronic health record analysis, including the possibility of misclassification of diabetes as type 1 vs type 2, and the possibility that additional unidentified factors accounted for the association. Results should be confirmed in other populations. The increased risk of new-onset T1D after COVID-19 adds an important consideration for risk-benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations.

Accepted for Publication: August 6, 2022.

Published: September 23, 2022. doi:10.1001/jamanetworkopen.2022.33014

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Kendall EK et al. JAMA Network Open .

Corresponding Author: Rong Xu, PhD, Sears Tower T303, Center for Artificial Intelligence in Drug Discovery ( [email protected] ); Pamela B. Davis, MD, PhD, Sears Tower T402, Center for Community Health Integration ( [email protected] ), Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106.

Author Contributions : Ms Kendall and Ms Olaker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kendall, Xu, Davis.

Acquisition, analysis, or interpretation of data: Kendall, Olaker, Kaelber, Xu.

Drafting of the manuscript: Kendall, Olaker.

Critical revision of the manuscript for important intellectual content: Kendall, Kaelber, Xu, Davis.

Statistical analysis: Kendall, Olaker, Xu.

Obtained funding: Xu.

Administrative, technical, or material support: All authors.

Supervision: Kaelber, Xu, Davis.

Conflict of Interest Disclosures: Dr Kaelber reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Funding/Support : This study was supported by grants AG057557 (Dr Xu), AG061388 (Dr Xu), AG062272 (Dr Xu), and AG076649 (Drs Xu and Davis) from the National Institute on Aging; grant R01AA029831 (Drs Xu and Davis) from the National Institute on Alcohol Abuse and Alcoholism; grant UG1DA049435 from the National Institute on Drug Abuse, and grant 1UL1TR002548-01 from the Clinical and Translational Science Collaborative of Cleveland.

Role of the Funder/Sponsor : The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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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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