latest research for type 1 diabetes

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Type 1 diabetes articles from across Nature Portfolio

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

Latest Research and Reviews

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

• Casper S. Poulsen
• Mette K. Andersen

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

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

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

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

• Z. W. Hawks
• L. T. Germine

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

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

• Omer Mujahid
• Ivan Contreras

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

• João Felício
• Lorena Moraes
• Karem Felício

Does minimed 780G TM insulin pump system affect energy and nutrient intake?: long-term follow-up study

• Yasemin Atik-Altinok
• Yelda Mansuroglu
• Damla Goksen

News and Comment

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

• Noel G. Morgan

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

• Tetsuro Kobayashi
• Takashi Kadowaki

METTL3 restrains autoimmunity in β-cells

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

• Balasubramanian Krishnamurthy
• Helen E. Thomas

Type 1 diabetes mellitus: a brave new world

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

• Pieter-Jan Martens
• Chantal Mathieu

β-cells protected from T1DM by early senescence programme

• Olivia Tysoe

Antivirals in the treatment of new-onset T1DM

• Claire Greenhill

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New advances in type 1 diabetes

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

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

Introduction

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

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

Sources and selection criteria

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

Epidemiology

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

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

Autoantibody characteristics associated with increased risk of type 1 diabetes 10

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

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

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

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

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

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

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

Advances in monitoring

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

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

Summary of trials for each topic covered

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

Standardized continuous glucose monitoring metrics for adults with diabetes 52

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

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

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

Advances in treatments

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

Pharmacokinetics of commonly used insulin preparations

Ultra-long acting basal insulins

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

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

Ultra-rapid acting prandial insulins

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

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

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

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

Pulmonary inhaled insulin

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

Insulin delivery systems

Approved automated insulin delivery systems.

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

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

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

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

Comparison of commercially available hybrid closed loop systems 75

Unapproved systems

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

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

β cell replacement therapies

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

Pancreas transplantation

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

Islet transplantation

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

Disease modifying treatments for β cell preservation

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

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

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

Non-immunomodulatory adjunctive therapies

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

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

Glucagon-like peptide receptor agonists

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

Sodium-glucose cotransporter inhibitors

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

Updates in acute complications of type 1 diabetes

Diabetic ketoacidosis.

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

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

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

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

Hypoglycemia

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

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

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

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

Management in under-resourced settings

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

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

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

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

Emerging technologies and treatments

Monitoring systems.

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

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

Insulin and delivery systems

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

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

Immunotherapy for type 1 diabetes

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

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

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

Guidelines in type 1 diabetes

Conclusions

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

Glossary of abbreviations

ADA—American Diabetes Association

AID—automated insulin delivery

BGM—blood glucose monitoring

CGM—continuous glucose monitoring

CKM—continuous ketone monitoring

DCCT—Diabetes Control and Complications Trial

DIY—do-it-yourself

FDA—Food and Drug Administration

GADA—glutamic acid decarboxylase antibody

GLP-1—glucagon-like peptide 1

GRS—genetic risk scoring

HbA1c—glycated hemoglobin

HCL—hybrid closed loop

LADA—latent autoimmune diabetes of adults

LMIC—low and middle income country

PAKT—pancreas after kidney transplant

RCT—randomized controlled trial

SGLT-2—sodium-glucose cotransporter 2

SPKT—simultaneous pancreas-kidney transplant

Questions for future research

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

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

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

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

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

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

How patients were involved in the creation of this manuscript

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

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

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

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

Provenance and peer review: Commissioned; externally peer reviewed.

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“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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New and Emerging Technologies in Type 1 Diabetes

There has been a rapid advancement in the pace of development of new diabetes technologies and therapies for the management of type 1 diabetes over the past decade. The Diabetes Control and Complications Trial conclusively established that tight glycemic control with intensive insulin therapy decreases the rates of diabetes complications in proportion to glycemic control, and diabetes technologies have accordingly been developed to help patients reach these goals. In this review, the authors discuss new diabetes therapeutics and technologies, including new insulin analogues, insulin pumps, continuous glucose monitoring systems, and automated insulin delivery systems.”

• • Innovative and novel technologies for the management of type 1 diabetes hold promise for improving glycemia, decreasing burden of disease management, and improving long-term outcomes.
• • Improvements in the accuracy of real-time continuous glucose monitoring (CGM) have allowed for the development of automated insulin delivery systems that can adjust insulin delivery based on CGM glucose input.
• • The development of new drugs, such as ultrarapid-acting insulins that better mimic physiologic insulin secretion, may lead to improved postprandial glycemia. The advent of stable glucagon formulations may allow for development of dual-hormone closed-loop systems that could further improve glycemic regulation.

New technologies in type 1 diabetes

Intensive insulin therapy for the management of type 1 diabetes (T1D) was established as the standard of care based on the results of the Diabetes Control and Complication Trial (DCCT), which conclusively demonstrated the benefits of tight glycemic control. 1 However, those who received intensive insulin management were at increased risk for severe hypoglycemia, which can be acutely life threatening and can result in seizures, coma, or death. Based on DCCT and other data, the American Diabetes Association (ADA) recommends glycosylated hemoglobin (HbA1c) less than 7% in adults, and recently also in many children and adolescents, in order to decrease the risk of both macrovascular and microvascular complications. 2 To achieve these recommended glycemic targets, patients must monitor blood glucose multiple times a day, closely estimate carbohydrate intake to calculate appropriate meal coverage, and administer multiple doses of insulin, which can have varying effects based on several physiologic factors such as physical activity, illness, or stress. This program results in a significant burden of disease management. Recently published data from the T1D Exchange, which includes more than 22,000 children and adults in the United States, show that less than a quarter of patients with T1D are meeting HbA1c goals. 3 Diabetes technologies are being developed to help decrease disease burden and improve glycemic outcomes. In this article, the authors highlight diabetes technology and therapies including new insulin analogues, continuous glucose monitoring systems (CGM), continuous subcutaneous insulin infusion (insulin pump therapy), as well as automated insulin delivery (AID) systems that integrate CGM and insulin pump technology with mathematical algorithms that automatically adjust insulin delivery ( Box 1 ).

Box 1

Key definitions, glucose monitoring.

Self-monitoring of blood glucose (SMBG) with finger-stick glucose (FSG) concentrations has become a key component of diabetes care. The ability to obtain a blood glucose measurement and adjust therapy accordingly is a mainstay of treatment to reach glucose targets and prevent hypoglycemia. Glucometer accuracy has increased throughout the years, but not all meters available on the market today meet standards set forth by the Food and Drug Administration (FDA) and International Organization for Standardization. 4 Identifying glucose trends and patterns based on SMBG to make insulin adjustments had been the standard of care set forth by the DCCT, and increased frequency of SMBG is associated with improved glycemic control. 5 Some newer glucometers are Bluetooth enabled and can pair with smartphone applications for patients to better track and identify patterns. 6 However, FSG has limitations in that they provide only an instantaneous snapshot in time of current glucose and do not provide information on glucose trends or direction of change.

CGM and FGM devices measure interstitial glucose and estimate plasma glucose every 5 to 15 minutes, depending on the system. Real-time CGM systems (Dexcom G6, Senseonics Eversense, Medtronic Guardian) actively transmit glucose information to a dedicated receiver, insulin pump, smartphone/watch, and to a cloud network if desired and can provide real-time information to the user regarding (1) rate of glucose change, (2) hyperglycemia and hypoglycemia based on individualized thresholds, and (3) impending hypoglycemia alarms based on glucose trends. The glucose measurements can also be shared by patients with others, such as family members, in real-time for an added degree of security. In the only currently available FGM system (Abbott Freestyle Libre), data are stored within the sensor and can be obtained by scanning the device with dedicated receiver or smartphone. Of note, the next-generation Freestyle Libre 2 CGM recently approved by the FDA is capable of “pushing” optional real-time threshold alerts to a receiver or smartphone. Both CGM and FGM devices can be used in blinded mode to record glucose data on the device for later analysis of glycemic patterns to assist health care professionals in making therapeutic decisions.

Externally worn CGM (Dexcom G6, Medtronic Guardian) and FGM (Abbott Freestyle Libre) devices measure interstitial glucose via a transcutaneous sensor, a filament placed in the subcutaneous tissue connected to an overlying transmitter. More recently a CGM with an implantable sensor system with an externally worn transmitter, the Senseonics Eversense, has been approved for 3 or 6 months of use before replacement in the United States and Europe, respectively. Some devices require regular calibration, with FSG input required at least twice daily (Medtronic Guardian and Senseonics Eversense), or are factory calibrated with no additional measurements required (Dexcom G6 and Abbott Freestyle Libre).

Data from CGM and FGM devices can be downloaded by clinicians and provide a standardized ambulatory glucose profile with information regarding percentage of time spent in hypo- and hyperglycemic ranges, time in target range, and glucose variability. Mean glucose as determined by CGM can be used to calculate the glucose management indicator, which provides an estimate of HbA1c 7 to help determine if patients are achieving target glucose goals. 8 In fact, because the relationship between HbA1c and average glucose can be modified by the mean red blood cell lifespan, mean CGM glucose may be a better predictor of long-term complications than HbA1c when the measured HbA1c and GMI are not in agreement. 7 Recently the ADA has published consensus guidelines regarding the recommended percentage of time in target range as well as hyper- and hypoglycemic targets for patients with T1D. 9 Time in target range of 70 to 180 mg/dL (TIR) has been shown to correlate with mean glucose and HbA1c. TIR of 70% correlates to an HbA1c of approximately 7%. TIR has been suggested as a new treatment standard based on the argument that TIR is easier for people with diabetes to understand and is more actionable on a day-to-day basis. 2 , 10 Targets for time below range (TBR) and time above range (TAR) have also been established ( Table 1 ).

Table 1

Continuous glucose monitoring recommendations for patients with type 1 diabetes to achieve HbA1c 7% a

CGM accuracy has improved significantly since its inception, and many CGM devices have obtained approval for nonadjunctive use (Dexcom G6, Senseonics Eversense, Freestyle Libre), meaning that CGM data can be used as a replacement for FSG when making insulin-dosing decisions. 11 Studies have shown that CGM use is associated with improved HbA1c and a reduction in hypoglycemia. 12 , 13 More recently, the FDA has created an interoperable integrated continuous glucose monitoring system standard, which allows an approved CGM device to be used as part of an integrated system with other compatible medical devices and electronic interfaces, including insulin delivery systems. Approved systems (currently, the Dexcom G6 and the Freestyle Libre 2) meet accuracy and reliability standards set forth by the FDA, securely transmit glucose data to other devices, and may be used interchangeably with AID devices for the purpose of managing glycemia.

One of the major challenges to managing glycemia in patients with diabetes is the inability of currently available insulin formulations to mimic the kinetics and action of endogenous insulin secretion. 14 In individuals without diabetes, incretin-stimulated insulin release and a rapid hepatic exposure to insulin in response to a meal occur and lead to decreased hepatic glucose production. 15 This physiology is no longer intact in patients with T1D. Exogenous insulin administered in the subcutaneous tissue takes time to be absorbed in the systemic circulation. This delayed systemic delivery of exogenous insulin is a major physiologic difference with the immediate entry of endogenous insulin into the hepatic circulation for rapid effects. 16

Since the discovery of insulin in 1921, insulin therapy has greatly advanced from porcine and bovine insulin derivatives to the development of rapid-acting, and then ultrarapid-acting, insulin analogues. Older insulins such as Neutral Protamine Hagedorn and regular human insulin have a slow action of onset and long duration, which require patients to have rigid food consumption timing and routines to match the kinetics of insulin action. Rapid-acting insulin analogues (aspart, lispro, and glulisine) have a faster onset of action and quicker time to peak insulin action, which help better match postprandial glucose excursion. These rapid-acting insulins permit greater flexibility for patients: doses can be adjusted based on the timing and quantity of carbohydrates consumed rather. However, rapid-acting insulin analogues still require injection 10 to 15 minutes before meal intake for optimal action. 14

New ultrarapid-acting insulins have even faster on-off kinetics than rapid-acting insulin. 17 , 18 , 19 , 20 , 21 Faster aspart (also known as Fiasp) is currently FDA approved for adults and children with diabetes and uses nicotinamide as an excipient and l -arginine to increase stability. Ultrarapid lispro (URLi), which has recently completed a phase 3 trial, uses treprostinil to promote vasodilation and citrate as an excipient. 21 BioChaperone lispro, which uses BC222, an oligosaccharide modified with natural molecules and citrate as an excipient, is currently in development. Postprandial glucose were found to be lower with use of faster aspart in both pump and MDI delivery. 19 , 22 Overall rates of blood glucose–confirmed hypoglycemia and severe hypoglycemia have been reported to be similar between aspart and faster aspart. 19 Faster aspart is labeled for use to be administered up to 20 minutes after meal, which can provide further flexibility to patients. A trial of URLi in patients with T1D showed decreased postprandial glycemic excursions at 1 and 2 hours compared with lispro. 21 A short-term, cross-over trial comparing BioChaperone Lispro with insulin lispro has also shown decreases in early postprandial hyperglycemia. 20 In a head-to-head study, BioChaperone Lispro had slightly faster on-off kinetics than insulin lispro and may more closely mimic normal postprandial insulin secretion. 17 Inhaled insulin (Afrezza) is FDA approved and has much more rapid kinetics than injectable insulin delivered subcutaneously. Limitations in clinical use include lack of dose equivalency with injectable insulin and possible respiratory side effects including lung function decreases that are reversible on discontinuation. 23

Insulin delivery modalities

Multiple daily injection.

Insulin has been traditionally administered via MDI therapy via insulin syringe or insulin pen. Smart pen technology pairs the insulin pen with a smartphone to allow patients to more easily calculate and track insulin administration. The InPen (Companion Medical) is currently the only FDA-approved smart pen device, although others are in development. The InPen connects with a smartphone app via Bluetooth allowing patients to track insulin dosing history, calculate insulin doses, keep track of “insulin on board” (an estimate of rapid-acting insulin still in effect) and adjust calculated dosing accordingly, and set dosing reminders. 24 In addition, the phone application can also receive CGM data directly and in real time. Patients can export data collected from the application and share it with their health care team. Smart pen technology may have extra utility in certain patient populations or clinical scenarios, such as those who have difficulty remembering insulin dosing (eg, pediatric patients or those with cognitive or memory impairment) or those with limited health numeracy. 25 Accurate tracking of insulin dose administration is also of use to treatment teams to aid in insulin regimen adjustments. Further research is needed to determine clinical benefits of this technology, and other companies (including major insulin manufacturers) have announced plans to release smart pens in the future.

Insulin Pumps

Insulin pumps deliver a continuous infusion of insulin via a cannula placed in the subcutaneous tissue, sometimes referred to as continuous subcutaneous insulin infusion (CSII). Most of the pumps available use an infusion set with tubing to deliver insulin (in the United States, pumps from Tandem and Medtronic), but some systems known as patch pumps attach directly to the skin without the need for tubing (in the United States, the Insulet Omnipod system). Insulin pumps have programmable basal and bolus settings that can vary based on the time of the day. Insulin pumps track insulin usage and contain bolus calculators to assist in the calculation of meal-time insulin coverage and glucose correction. The pump also keeps track of “insulin on board” and adjusts calculated doses accordingly. The abilities to use different basal rates at different times of the day, to make temporary basal rate adjustments in response to glucose trend or activity level, and to deliver meal-time bolus insulin over extended periods of time based on user input are all unique to insulin pumps.

Patients can achieve target HbA1c goals with either MDI or insulin pump therapy, and extensive research has sought to determine if glycemic control with pump therapy is superior to that of MDI management. A systematic review and meta-analysis showed that both MDI and pump therapy resulted in comparable levels of glycemic control and incidence of severe hypoglycemia in children and adolescents with T1D and that pump therapy may have favorable effects on glycemic control in adults with T1D. 26 Insulin pump therapy is also associated with improved quality of life in both pediatric and adult populations. 27 , 28 By allowing varied basal rates, insulin pumps permit more flexible and physiologic insulin delivery that can be changed based on time of day and other factors such as exercise, as well as varied delivery of meal-time insulin bolus (eg, dual-wave or square-wave delivery set by the user) based on the type of food consumed. In addition, pump therapy eliminates the need for multiple daily injections of insulin, instead requiring only infusion set be changed every 2 to 3 days. Uptake of CSII has increased over the past decade, and currently nearly half of all patients with T1D in the United States manage their diabetes with pump therapy. 3

Automated Insulin Delivery

AID systems (also known as closed-loop, artificial pancreas, or bionic pancreas systems) use real-time glucose measurements fed into a control algorithm that automatically adjusts the rate of subcutaneous insulin delivery via an insulin pump ( Table 2 ). The earliest approved AID systems used threshold suspend, in which insulin delivery way automatically suspended when blood glucose level dropped less than a certain threshold. 29 Predictive glucose suspend improves on this feature by suspending insulin delivery when a hypoglycemic event is predicted in the future. Predictive low glucose suspend functionality decreases the percentage of time spent in hypoglycemic ranges in both the daytime and overnight. 30 By suspending insulin before a hypoglycemic event, this feature also reduces the duration of hypoglycemic events when they do occur.

Table 2

Current Food and Drug Administration–approved automated insulin delivery systems

Later generation AID systems entail more complex algorithms to not only suspend insulin delivery based on hypoglycemia but continuously adjust insulin delivery in response to glycemic trends. The most advanced AID systems that are commercially available today are referred to as hybrid closed-loop systems. Patient input is still required to count carbohydrates and administer correction boluses, but the system will additionally modulate insulin delivery in the background, and in some systems deliver partial correction boluses, based on glycemic trends. Other systems that have been studied but are not yet available use qualitative meal announcements to estimate carbohydrate content, describing meals as “typical,” “more than typical,” “less than typical,” or “a small bite,” rather than requiring quantitative carbohydrate counting. 31

Currently available FDA-approved hybrid closed-loop systems include the Medtronic 670G and Tandem t:slim X2 with Control IQ. The first hybrid closed-loop system available in United States, the Medtronic 670G, was approved in 2017 for adult and pediatric patients as young as age 7 years. The approval relied on a nonrandomized study without a control arm. 32 The system can be used as a traditional pump or in “auto mode,” in which the pump automatically adjusts basal insulin rates up to every 5 minutes by increasing, decreasing, or suspending delivery of insulin based on CGM trends. Patients are still required to count carbohydrates and enter them into the system, and meal boluses are calculated based on a programmed carbohydrate ratio. As a safety feature, the system may exit auto mode and revert to preprogrammed delivery if insulin delivery approaches maximum or minimum insulin delivery thresholds, if POC and CGM readings are discrepant, or if CGM signal is lost. In a real-world, prospective observational study of 92 youth who started this system, 30% discontinued use of the auto mode within the first 6 months. Another real-world cohort study of 79 pediatric and adult patients reported that 33% discontinued auto mode use within 12 months. 33 , 34 Reasons cited included the number of alarms, challenges with requiring calibrations, and dissatisfaction with glycemic control. 34

The second hybrid closed-loop device in the United States, the Tandem t:slim X2 with Control-IQ using the Dexcom G6 as the input CGM, was approved in 2019 for adults and pediatric patients older than or equal to 6 years. In the 6-month, randomized, controlled pivotal trial of this device, participants were randomized to closed-loop control or usual diabetes care with sensor-augmented pump therapy. 35 Patients randomized to closed-loop control had improvements in target range, mean CGM glucose, and HbA1c, as well as reduced rates of hypoglycemia. Unlike the Medtronic 670G, Control-IQ only reverts to preprogrammed insulin delivery when CGM signal is lost and does not require finger-stick calibration to continue AID. Trials are underway evaluating this device in younger children ( {"type":"clinical-trial","attrs":{"text":"NCT03844789","term_id":"NCT03844789"}} NCT03844789 ).

Experimental Automated Insulin Delivery Systems

Several AID systems that rely on different sets of mathematical algorithms, including proportional integral derivative, fuzzy logic, and model predictive control algorithms, are in development. These AID systems have been associated with increased time in target glucose range (typically 70–180 mg/dL) and in some cases with decreased mean glucose, lower HbA1c, and decreased time in the hypoglycemic range. Pivotal trials for several of these AID systems are currently ongoing, including the Omnipod Horizon hybrid closed-loop system ( {"type":"clinical-trial","attrs":{"text":"NCT04196140","term_id":"NCT04196140"}} NCT04196140 ) and the Beta Bionics iLet Bionic Pancreas ( {"type":"clinical-trial","attrs":{"text":"NCT04200313","term_id":"NCT04200313"}} NCT04200313 ).

One class of AID systems, called bihormonal or dual hormone systems, is capable of delivering a second hormone to further improve glycemic control. Given the kinetics of subcutaneous insulin delivery, the reduction and/or suspension of insulin may be insufficient to prevent hypoglycemia, especially in certain scenarios that may result in changes in insulin sensitivity such as exercise. Several bihormonal systems use microdosing of glucagon to prevent and treat hypoglycemia when suspension of insulin delivery is not sufficient. Glucagon has rapid on and off kinetics, and the addition of glucagon can allow for more aggressive glucose targets compared with insulin-only systems by reducing the potential for hypoglycemia. In short-term studies of bihormonal systems, subjects achieved increased time in target range, lower mean glucose, and decreased rates of hypoglycemia compared with sensor-augmented pump therapy. 31 , 36 Additional studies comparing bihormonal with insulin-only closed-loop systems suggest that bihormonal systems may further improve mean glucose, time in range, as well as reduce the time spent in hypoglycemic ranges. 37

Other classes of dual hormone systems that have been studied administer pramlintide (an amylin analogue) or glucagon-like peptide-1 (GLP-1) receptor agonist in combination with insulin. 38 , 39 Amylin is cosecreted with insulin from pancreatic beta cells and helps moderate postprandial glucose excursions by slowing gastric emptying, inhibiting glucagon secretion, and promoting satiety. A recent study examining an automated system delivering fixed dose ratio of insulin and pramlintide found increase in time in range compared with the insulin-only system. 38 Long-term studies of bihormonal systems are needed to establish their potential benefits.

A recent meta-analysis 37 reviewed published studies of artificial pancreas systems including insulin-only and dual hormone systems delivering glucagon in more than 500 adult and pediatric subjects with T1D. Most of these trials were small and for a short duration, but the analyses showed that AID systems achieved higher TIR compared with conventional pump therapy and that dual hormone systems resulted in greater improvements in TIR than insulin-only systems. Both classes of AID systems deliver improved glycemia overnight, which is a substantial benefit to patients, as fear of nocturnal hypoglycemia is a primary concern for patients and families. 37 , 40

Challenges to Fully Automated Insulin Delivery

One the main challenges to achieving fully automated closed-loop insulin delivery is overcoming the kinetics of nonphysiologic subcutaneous insulin administration related to postprandial glucose excursions. Given the kinetics of subcutaneous insulin delivery, increased insulin dosing that occurs only after the glucose excursion has begun may lead to prolonged hyperglycemia. Furthermore, because of variations in physiologic insulin needs and the kinetics of current insulin formulations, increased insulin delivery can result in late hypoglycemia. Exercise can compound these challenges by altering insulin sensitivity and increasing insulin-independent glucose uptake into muscles. Several approaches have been studied to ameliorate this issue. Adjunctive therapies including pramlintide (an amylin analogue), GLP-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium–glucose cotransporter 2 inhibitors have all been studied in patients with T1D with the goal of decreasing postprandial glycemic excursions and reducing the need for aggressive insulin dosing. 41 Alternate approaches to insulin delivery, such as delivery of insulin directly to intraperitoneal space, enable faster pharmacokinetics/pharmacodynamics than subcutaneous insulin delivery. 42 Studies examining the utility of new ultrarapid-acting insulins in AID systems have suggested decreased glycemic variability with these newer insulin analogues. 43

Data management and telehealth

Technology including CGM, smartphones, smartwatches, and activity trackers generate large amounts of high-density data that can be difficult for clinicians to synthesize in the limited time available during visits. At present, SMBG, CGM, and pump data can be downloaded to review for patterns and make adjustments in treatment. Currently available software allows patients to download their pump and CGM at home and then share these data via cloud-based services with the patient’s clinical team to review, potentially allowing for more frequent patient contact between in-person visits. With advancement of artificial intelligence and machine learning, these data could be analyzed for automated generation of recommendations for therapy adjustment. Software systems have been developed to automatically generate insulin dose decision support recommendations. 44

The prevalence of technology at home and in clinics has led to great interest in telehealth—a broad term used to describe health care delivery with the aid of technology, which includes video visits, web-based portals, or text messaging. Telehealth has been applied across multiple specialties and conditions and can be used to conduct remote patient visits and patient education and behavioral management sessions. Telehealth strategies can help increase access to health care and reduce barriers to reaching providers, especially in resource limited settings or for those living far from treatment facilities. A recent meta-analysis found that telehealth intervention in patients with diabetes led to HbA1c improvements. 45 Concerns about spread of SARS-CoV-2 have dramatically increased use of telehealth visits for diabetic patients over a very short period of time in the first quarter of 2020 and will likely accelerate the movement of diabetes management visits to virtual formats.

Availability of data in the cloud has allowed companies to publish “real world” studies describing glycemic control in patients using their technologies. 46 The development of virtual diabetes clinics is likely on the horizon, as patient data are obtained from wearable devices including CGM and insulin pumps and then transmitted into the electronic health record for analysis with machine learning and decision support. 47

Diabetes technology holds promise for improving glycemic outcomes and decreasing burden of disease for patients and families with T1D. Rapid advancement of diabetes therapeutics and technologies have enhanced diabetes monitoring and insulin delivery capabilities. Devices that partially automate insulin delivery improve glycemic control, and more capable automated closed-loop systems will likely be available in the near future. Further research should determine the long-term benefits of these devices on glycemic control and quality of life in T1D.

J.S. Sherwood has nothing to disclose. S.J. Russell has patents and patents pending on aspects of the bionic pancreas that are assigned to Massachusetts General Hospital and are licensed to Beta Bionics, has received honoraria and/or travel expenses for lectures from Novo Nordisk, Roche, and Ascensia, serves on the scientific advisory boards of Unomedical and Companion Medical, has received consulting fees from Beta Bionics, Novo Nordisk, Senseonics, and Flexion Therapeutics, has received grant support from Zealand Pharma, Novo Nordisk, and Beta Bionics, and has received in-kind support in the form of technical support and/or donation of materials from Zealand Pharma, Ascencia, Senseonics, Adocia, and Tandem Diabetes. M.S. Putman has nothing to disclose.

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Study provides preliminary evidence in favor of a new type 1 diabetes treatment

by University of Chicago Medical Center

Type 1 diabetes is an autoimmune disease that causes the body's immune system to attack and destroy insulin-producing beta cells in the pancreas. Traditional management of type 1 diabetes has primarily involved replacing the missing insulin with injections which, though effective, can be expensive and burdensome.

A new study , published in Cell Reports Medicine , led by researchers at the University of Chicago Medicine and Indiana University suggests that an existing drug could be repurposed to treat type 1 diabetes , potentially reducing dependence on insulin as the sole treatment. The study is titled "Inhibition of Polyamine Biosynthesis Preserves β-Cell Function in Type 1 Diabetes,"

The research centers on a medication known as α-difluoromethylornithine (DFMO), which inhibits an enzyme that plays a key role in cellular metabolism. The latest translational results are a culmination of years of research. In 2010, while corresponding author Raghu Mirmira, MD, Ph.D., was at Indiana University, he and his lab performed fundamental biochemistry experiments on beta cells in culture.

They found that suppressing the metabolic pathway altered by DFMO helped protect the beta cells from environmental factors, hinting at the possibility of preserving and even restoring these vital cells in patients diagnosed with type 1 diabetes.

The researchers confirmed their observations preclinically in zebrafish and then in mice before senior author Linda DiMeglio, MD, MPH, Edwin Letzter Professor of Pediatrics at Indiana University School of Medicine and a pediatric endocrinologist at Riley Children's Health, launched a clinical trial to evaluate the safety and tolerability of the drug in type 1 diabetes patients. The results of the trial indicated that the drug is safe for type 1 diabetes patients and can help keep insulin levels stable by protecting beta cells.

"As a physician-scientist, this is the kind of thing we've always strived for—to discover something at a very basic, fundamental level in cells and find a way to bring it into the clinic," said Mirmira, who is now Professor of Medicine and an endocrinologist at UChicago Medicine. "It definitely underscores the importance of supporting basic science research."

"It's been truly thrilling to witness the promising results in the pilot trial after this long journey, and we're excited to continue our meaningful collaboration," said DiMeglio.

Importantly, DFMO has already been FDA-approved as a high dose injection since 1990 for treating African Sleeping Sickness and received breakthrough therapy designation for neuroblastoma maintenance therapy after remission in 2020. Pre-existing regulatory approval could potentially facilitate its use in type 1 diabetes, saving effort and expense and getting the treatment to patients sooner.

"For a drug that's already approved for other indications, the approval timeline can be a matter of years instead of decades once you have solid clinical evidence for safety and efficacy," said Mirmira. "Using a new formulation of DFMO as a pill allows patients to take it by mouth instead of needing to undergo regular injections, and it has a very favorable side effect profile. It's exciting to say we have a drug that works differently from every other treatment we have for this disease."

To follow up on the recently published results, first and co-corresponding author Emily K. Sims, MD, Associate Professor of Pediatrics at IU School of Medicine and a pediatric endocrinologist at Riley Children's Health, launched a multi-center clinical trial to gather even stronger data regarding the efficacy of DFMO as a type 1 diabetes treatment.

"With our promising early findings, we hold hope that DFMO, possibly as part of a combination therapy, could offer potential benefits to preserve insulin secretion in individuals with recent-onset type 1 diabetes and ultimately also be tested in those who are at risk of developing the condition," said Sims.

"A new era is dawning where we're thinking of novel ways to modify the disease using different types of drugs and targets that we didn't classically think of in type 1 diabetes treatment," said Mirmira.

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Type 1 Research Highlights

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

Smart Insulin Patch

American Diabetes Association Pathway to Stop Diabetes Scientist Zhen Gu, PhD, recently published a paper describing the development of an innovative "smart insulin" patch that imitates the body's beta cells by both sensing blood glucose levels and releasing insulin.

A Possible Trigger for Type 1 Diabetes

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

Enhancing Survival of Beta Cells for Successful Transplantation

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

Explore: Type 1 Research Highlights

Investments in type 1 diabetes research

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

Identifying type 1 diabetes before beta cell loss

Dr. Hessner is investigating so-called “biomarkers,” which are components in blood or tissue samples that can be measured to predict which individuals are most likely to develop type 1 diabetes. 

Beta cell replacement

Both type 1 and type 2 diabetes result from a complete or partial loss of beta cell number and function. Finding a way to successfully replace functional beta cell is key to efforts to one day cure diabetes.

Enhancing survival of beta cells for successful transplantation

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


New insight into how diabetes leads to blindness

New research is uncovering how diabetes changes the kinds of proteins that are made in the eye. These changes may lead to diabetic retinopathy, a leading cause of blindness. This information is allowing researchers to identify new targets for therapies that could delay or prevent the development of diabetic retinopathy.

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Type 1 diabetes: New findings on the development of the autoimmune disease in children

Study provides novel insights on dynamics of blood sugar levels and autoimmunity in early childhood.

When and why does type 1 diabetes manifest in children? For the first time, researchers conducted a long-term study on infants and young children with increased genetic risk of type 1 diabetes. The results have now been published in the Journal of Clinical Investigation. The authors provide a unique picture of the dynamics of blood sugar regulation during early childhood and its relationship to the development of autoimmunity.

The POInT study is uniquely poised to study blood sugar levels during the development of autoimmunity

Within the framework of the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD), the clinical primary prevention study POInT (Primary Oral Insulin Trial) is conducted multicentrically at seven clinical sites in five countries. POInT aims to prevent the formation of islet autoantibodies, and thus the induction of type 1 diabetes. As a result of a misdirected immune reaction, the insulin-producing beta cells of the pancreas are destroyed in people with type 1 diabetes. It was previously thought that metabolic changes occur close to the onset of clinical disease and that the pancreatic beta cells are destroyed by the autoimmunity. However, no-one had looked closely at what happens when the autoimmunity starts. Therefore, the POInT study conducted a frequent follow-up in the first years of life -- starting at four months of age -- in over 1,000 children with a genetically determined 10 percent risk to develop type 1 diabetes. This enabled the researchers to precisely correlate changes in blood glucose with the timing of islet autoantibody development.

"Our results change our understanding of the development of type 1 diabetes. We show that metabolic changes occur in an earlier phase of the disease than previously anticipated," explains Anette-Gabriele Ziegler, Director at the Helmholtz Munich Institute of Diabetes Research (IDF). Together with an international team of researchers, she conducted the POInT study. The team examined the pre- and post-prandial blood sugar levels together with islet autoantibodies in the participating children.

Results provide new approaches for research

First, and in contrast to the previous assumption, the results showed that the blood sugar concentrations shortly after birth are not stable. Instead they decrease in the first year of life, and then increase again at around 1.5 years of age. "The dynamic changes in glucose metabolism in the first years of life were a surprise to us. They very likely reflect changes in the pancreatic islets and signal that we need to study glucose metabolism and the pancreas in early life more intensely" says Katharina Warncke, Chief Physician for Paediatric Endocrinology / Diabetology at the Department of Pediatrics and scientist at the IDF. Importantly, the scientists found that in the children who developed autoimmunity compared to children who did not, blood sugar levels after meals were already higher two months before the formation of islet antibodies. This difference persisted and was also followed by increases in pre-meal values after the autoimmunity.

Puzzle around the key event inducing the autoimmune reaction

The researchers were able to determine that blood sugar levels of infants and young children behave dynamically and reflect the concentration peak of islet autoantibodies -- this indicates a phase of activity and susceptibility of islet cells. "The change in post-meal blood sugar levels shortly before the initial detection of autoantibodies points to the likelihood that there is an event impairing the function of the islets preceding and contributing to the autoimmune reaction. As glucose values further increase after seroconversion, the impairment or damage seems to be sustained leading to further glucose instability," explains Warncke.

"The observed changes in blood sugar levels in relation to autoantibody formation are exciting. Now we know that the start of the disease process is likely to be acting at the pancreatic islets and we can focus our research to find the cause of this chronic illness," says Ezio Bonifacio, Professor at the Center for Regenerative Therapies Dresden at the Technische Universität Dresden.

In summary, the scientists discovered that metabolic alterations occur in a much earlier stage of the disease than previously assumed: changes can occur in parallel to autoimmunity or even precede it. The researchers suggest that the excess increase in blood sugar levels after eating and shortly before the formation of antibodies is connected to a change in islet cell function.

The goal: prevention of new cases

"Changes in glucose levels could thus serve as an indicator of islet cell dysfunction and a potential onset of autoimmunity against beta cells in the future," summarizes Ziegler. However, this requires intensive further research of glucose metabolism and additional biomarkers in early childhood. The scientists ultimately strive to reduce the number of new cases of type 1 diabetes. Four out of every 1,000 children in Western, industrialised nations are currently affected.

• Hypertension
• Immune System
• Children's Health
• Diet and Weight Loss
• Hormone Disorders
• Heart Disease
• Diabetes mellitus type 1
• Personalized medicine
• Diabetes mellitus type 2
• Diabetic diet
• Hyperglycemia
• Molecular biology

Story Source:

Materials provided by Helmholtz Munich . Note: Content may be edited for style and length.

Journal Reference :

• Katharina Warncke, Andreas Weiss, Peter Achenbach, Thekla von dem Berge, Reinhard Berner, Kristina Casteels, Lidia Groele, Konstantinos Hatzikotoulas, Angela Hommel, Olga Kordonouri, Helena Elding Larsson, Markus Lundgren, Benjamin A. Marcus, Matthew D. Snape, Agnieszka Szypowska, John A. Todd, Ezio Bonifacio, Anette-G. Ziegler. Elevations in blood glucose before and after the appearance of islet autoantibodies in children . Journal of Clinical Investigation , 2022; 132 (20) DOI: 10.1172/JCI162123

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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.

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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

A mother’s cautionary tale -, losing will hauver -, how diabetes impacts your mental health -, one day in the life of type 1 diabetes -.

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