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New advances in type 1 diabetes

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This article has a correction. Please see:

• New advances in type 1 diabetes - June 03, 2024
• 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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New Type 1 Diabetes Treatment Eliminates Need for Insulin

Key takeaways.

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

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

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

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

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

Small—But Successful—Clinical Trials Led to Approval

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

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

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

What to Know About Lantidra

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

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

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

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

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

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

Lantidra introduces healthy islet cells without requiring a transplant procedure.

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

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

How Lantidra Is Administered

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

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

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

How Does Lantidra Work?

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

Known Side Effects

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

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

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

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

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

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

How to Get Lantidra

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

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

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

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

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

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

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

Food and Drug Administration. Lantidra [drug label].

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

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April 27, 2023

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Study unlocks potential breakthrough in type 1 diabetes treatment

by Silvia Cernea Clark, Rice University

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

FDA News Release

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

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

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

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

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

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

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

The FDA granted approval of Lantidra to CellTrans Inc.

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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 ( 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 ( NCT04196140 ) and the Beta Bionics iLet Bionic Pancreas ( 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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A new therapy for treating Type 1 diabetes

Promising early results show that longstanding harvard stem cell institute (hsci) research may have paved the way for a breakthrough treatment of type 1 diabetes. utilizing research from the melton lab, vertex pharmaceuticals has developed vx-880, an investigational stem cell-derived, fully differentiated pancreatic islet cell replacement therapy for people with type 1 diabetes (t1d). in conjunction with immunosuppressive therapy, vx-880 produced robust restoration of islet cell function on day 90 in the first patient in its phase 1/2 clinical trial..

The patient was treated with a single infusion of VX-880 at half the target dose in conjunction with immunosuppressive therapy. The patient, who was diagnosed with T1D 40 years ago and has been dependent on exogenous (injected) insulin, achieved successful engraftment and demonstrated rapid and robust improvements in multiple measures. These included increases in fasting and stimulated C-peptide, improvements in glycemic control, including HbA1c, and decreases in exogenous insulin requirement, signifying the restoration of insulin-producing islet cells.

VX-880 is not only a potential breakthrough in the treatment of T1D, it is also one of the very first demonstrations of the practical application of embryonic stem cells, using stem cells that have been differentiated into functional islets to treat a patient, explained Doug Melton, Ph.D., co-director of HSCI, is the Xander University Professor at Harvard and an Investigator of the Howard Hughes Medical Institute. Unlike prior treatments, this innovative therapy gives the patient functional hormone producing cells that control glucose metabolism. This potentially obviates the lifelong need for patients with diabetes to self-inject insulin as the replacement cells “provide the patient with the natural factory to make their own insulin,” explained Melton.

These results from the first patient treated with VX-880 are unprecedented. What makes these results truly remarkable is that they were achieved with only half the target dose,” said Bastiano Sanna, Ph.D., Executive Vice President and Chief of Cell and Genetic Therapies at Vertex. “While still early, these results support the continued progression of our VX-880 clinical studies, as well as future studies using our encapsulated islet cells, which hold the potential to be used without the need for immunosuppression.”

“As a surgeon who has worked in the field of islet cell transplantation for decades, this approach, which obviates the need for an organ donor, could be a game changer,” said James Markmann, M.D., Ph.D., Professor of Surgery and Chief of the Division of Transplant Surgery at Massachusetts General Hospital. “We are excited to progress this unique and potentially transformative medicine through clinical trials and to patients.”

“More than a decade ago our lab had a vision for developing an islet cell replacement therapy to provide a functional cure to people suffering from T1D,” said Melton, a founder and one of the first co-chairs of the Harvard Stem Cell and Regenerative Biology Department. “These promising results bring great hope that stem cell-derived, fully differentiated islet cells could deliver a life-changing therapy for people who suffer from the relentless life-long burden of T1D. I'm so grateful that Harvard and the Harvard Stem Cell Institute have supported this work.”

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Stem Cell Therapy Implant Shows Promise For Type 1 Diabetes

Dec. 11, 2023 – An experimental device containing millions of stem cells significantly reduced the need for insulin shots among people with type 1 diabetes , according to a  new study – a treatment researchers say may someday provide a cure for the chronic, life-altering condition.

Researchers from the University of British Columbia and Vancouver Coastal Health used tiny implants filled with lab-grown pancreatic cells known as VC-02. 

The study, published in the journal Nature Biotechnology , involved 10 people who at the start of the study could not produce insulin naturally. After 6 months with the implant, three of them showed significant improvement. Their bodies spent more time within the normal blood sugar range, reducing their need for external insulin. 

“The hope is to get these cells strong enough to help stop requiring insulin injections all together,” said David Thompson, MD, principal investigator at the Vancouver trial site and clinical director of the Vancouver General Hospital Diabetes Centre. “I believe this is going to turn into a cure as soon as 2024.”

Type 1 diabetes is a condition in which the immune system destroys insulin-making cells in the pancreas, known as beta cells. Insulin is a hormone that regulates sugar in the blood. The condition – sometimes called juvenile diabetes – is most commonly diagnosed between the ages of 4 and 6 and in early puberty.

In the United States, people who are non-Hispanic and White are most likely to have type 1 diabetes, and it affects men and women at about the same rates. Having a close family member with the illness increases risk. About 1.24 million people in the United States live with type 1 diabetes; that number is expected to reach 5 million by 2050.

With type 1 diabetes, it's as if the body's insulin factory has shut down. People who have the disease need to take insulin from the start.

This differs from  type 2 diabetes , in which the body doesn't use insulin properly. It can be managed with lifestyle changes, medications, and sometimes external insulin shots.

Until a century ago – when insulin was discovered –  diabetes was a death sentence . A 14-year-old boy who lay dying from diabetes in a Toronto hospital was the first person to receive the new treatment in 1922. Within 24 hours, his high blood glucose levels dropped to near-normal levels.

“Insulin therapy for people with type 1 diabetes is better than it has ever been, but it's still not a cure,” Thompson said. “This is probably the first wave of a new era of medicine using cell therapy.”

The trial tested an experimental cell therapy developed by biotechnology company ViaCyte.

Thompson and his colleagues used devices implanted just beneath the skin, about the size of a small bandage. Unlike a  glucose monitor – which is also inserted beneath the skin but only estimates blood glucose levels – the stem cell device delivers a steady supply of insulin to the body. 

The trial builds off of a  2021 study that showed this approach could help the human body produce insulin. The latest study increased the number of devices for each person and improved the design to help the lab-grown cells survive. 

All the people in the study started out with no insulin production and had surgery at sites in Vancouver, Belgium, and the U.S. to get up to 10 device implants each. After 6 months, three of them showed clear signs of insulin production that stayed steady throughout the yearlong study. One person in the study had showed notable improvement, spending more time in the target blood sugar range and reducing their need for extra daily insulin by 44%.

“Each device is like a miniature insulin-producing factory,” said co-author Timothy Kieffer, PhD, a professor with the departments of surgery and cellular and physiological sciences at the University of British Columbia, and past chief scientific officer of ViaCyte. The cells are “packaged into the device to essentially re-create the blood sugar-regulating functions of a healthy pancreas.”

A cure for type 1 diabetes would also mean preventing several other health complications related to the illness: blindness, kidney problems, limb loss, and even life-threatening blood sugar drops during sleep. Diabetes also significantly heightens the chances of having a heart attack or stroke.

The trial has two big limitations, said Robert Gabbay, MD, chief scientific and medical officer of the American Diabetes Association, who was not involved in the trial.   Not only is it small, but the technology failed to normalize blood glucose levels, which is the goal. 

But it shows promise, he said. Cell replacement therapies have previously faced a major barrier: The immune system attacks the implanted cells, requiring potentially harmful immunosuppressive drugs.

“This is particularly problematic for people with type I diabetes since the initial cause of type 1 is an autoimmune destruction of beta cells,” Gabbay said. “Placing beta cells sequestered from the immune system has been something that a number of investigative teams have worked on. This early study shows some proof of concept.”

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

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 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 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, PhD , 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, which was funded by the Juvenile Diabetes Research Foundation (JDRF) and used DMFO provided by Panbela Therapeutics, 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, also funded by JDRF – with UChicago among the trial sites – 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.

The study, “Inhibition of Polyamine Biosynthesis Preserves β-Cell Function in Type 1 Diabetes,” was published in Cell Medicine Reports in November 2023. Co-authors include Emily K. Sims, Abhishek Kulkarni, Audrey Hull, Stephanie E. Woerner, Susanne Cabrera, Lucy D. Mastrandrea, Batoul Hammoud, Soumyadeep Sarkar, Ernesto S. Nakayasu, Teresa L. Mastracci, Susan M. Perkins, Fangqian Ouyang, Bobbie-Jo Webb-Robertson, Jacob R. Enriquez, Sarah A. Tersey, Carmella Evans-Molina, S. Alice Long, Lori Blanchfield, Eugene W. Gerner, Raghavendra Mirmira, and Linda A. DiMeglio.

Apr. 27, 2023

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 mellitus describes a condition where the body cannot produce insulin which leads to a very high level of blood sugar and associated complications. The condition, which usually develops in childhood or adolescence, affects millions of people worldwide.

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Best exercises for people with type 1 diabetes outlined in new research

Conor Seery

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Researchers have revealed what types of exercise suit people living with type 1 diabetes .

Academics from the Universidade Federal do Vale do São Francisco in partnership with Staffordshire University have outlined that gender determines what exercise an individual with type 1 diabetes should do.

Senior author Dr Pooya Soltani said: “This study is important because people with diabetes often lack motivation to exercise as a means of managing their condition.

“One reason for this is that physical activity can lead to blood sugar drops, causing discomfort and demotivation. We investigated whether the type of physical activity could mitigate these blood sugar drops .”

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A total of 19 adults with type 1 diabetes took part in the study. The research team looked at each participant’s glycaemic and cardiovascular responses following interval exercise sessions and continuous exercise sessions.

Each person involved in the trial participated in half an hour of moderate aerobic exercise on a treadmill.

Meanwhile, the interval aerobic exercise session included alternating one-minute intervals at 40% and 60% of estimated maximal oxygen consumption (VO 2max ). Whereas the participants performed the continuous exercise session at 50% of VO 2max .

The researchers analysed the participant’s blood pressure, heart rate and blood glucose levels prior to and instantly after the exercise sessions, as well as 20 minutes after.

According to the study, greater blood glucose reductions were seen in men than women after continuous aerobic exercise and interval exercise.

Women only reduced their blood glucose values after continuous exercise, and not interval exercise, the results have reported.

Fellow author Dr Jorge Luiz de Brito-Gomes said: “Our study shows that for male patients, interval exercise, such as short bursts of walking, is preferable when starting with low blood sugar levels.

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“Conversely, continuous exercise, like running, is more suitable for those with higher initial blood sugar levels. These approaches can help prevent sudden blood sugar drops.”

Dr Luiz de Brito-Gomes added: “For female patients, both interval and continuous aerobic exercise appear to be effective starting points.

“We hope these findings show that gender-specific recommendations should be considered for aerobic exercise prescription, especially for men with irregular physical activity levels.”

Read the study here .

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Diabetes control and complications trial/epidemiology of diabetes interventions and complications study: continuing to build on 40 years of diabetes research.

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William T. Cefalu , Griffin P. Rodgers; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study: Continuing to Build on 40 Years of Diabetes Research. Diabetes Care 27 August 2024; 47 (9): 1518–1521. https://doi.org/10.2337/dci24-0030

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Over a hundred years ago, the discovery of insulin—one of the most notable scientific advances of the 20th century—ushered in a new era in chronic disease management. Specifically, with the clinical availability of insulin, an incredible paradigm shift emerged that changed type 1 diabetes from a rapidly progressive disease associated with significant morbidity and mortality to a more manageable chronic condition. With the shift to a chronic condition, questions then emerged as to how to best manage the disease and prevent the development of devastating complications. It was critical to test the hypothesis that managing the hyperglycemia associated with diabetes would delay the development and progression of the complications and improve the health outcomes of people with type 1 diabetes. Fortunately, definitive clinical trial evidence proving the “glucose hypothesis” of diabetes complications was indeed obtained and the data presented for the first time in June 1993 at the 53rd American Diabetes Association Annual Meeting and Scientific Sessions in Las Vegas, NV ( 1 ). At this meeting, many of us were in awe as we heard the presentation of the initial results of the Diabetes Control and Complications Trial (DCCT) (supported by the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] of the National Institutes of Health), demonstrating that the risk of microvascular complications over an average of 6.5 years of follow-up was reduced by 26–63% with intensive versus conventional therapy.

After the initial results of the DCCT were presented, the first principal results publication appeared in the New England Journal of Medicine in September 1993 and remains one of the most cited publications in the diabetes literature ( 1 , 2 ). After the close of the DCCT, the NIDDK launched the Epidemiology of Diabetes Interventions and Complications (EDIC) study, for which the original cohort has been longitudinally assessed for the development of significant microvascular disease and the development of cardiovascular and other macrovascular diseases. It is truly incredible how this landmark study has continued to present novel results 40 years since the feasibility study was first launched and 30 years after the initial scientific findings. Thus, in this issue of Diabetes Care are five new reports from DCCT/EDIC that continue to show how stable long-term investment in research provides significant public health benefits. These reports are the latest in DCCT/EDIC’s long history of providing new knowledge on diabetes complications and the effects of intensive glycemic management. Here, DCCT/EDIC researchers specifically provide more in-depth understanding of diabetes-associated retinal structure abnormalities, bone microarchitecture, neuropathic pain, and plasma biomarkers of brain injury and kidney tubular function ( 3–7 ).

From data obtained during EDIC, it is well known that intensive as opposed to conventional therapy during the DCCT resulted in a significant decrease in the cumulative incidence of individuals showing retinopathy progression and progression to more severe levels of retinopathy that require intervention ( 8 ). In the study from Blodi et al. ( 3 ) in this issue of Diabetes Care , the authors provided a further evaluation of the effects of glycemic control on retinopathic changes in the DCCT/EDIC cohort. Specifically, they investigated changes in retinal structure (both quantitative and qualitative) using optical coherence tomography (OCT), which visualizes intraretinal structures at micron resolution, and evaluated associations with systemic and other risk factors in participants of the EDIC study cohort. Interestingly, they reported that participants originally in the conventional treatment group were more likely to have structural macular abnormalities, as reflected by more disorganization of retinal inner layers (DRIL) and more intraretinal fluid or intraretinal cysts. Of great clinical significance, the authors noted that DRIL, as a morphological abnormality, was associated with a history of macular edema, a history of ocular surgery, and worse visual acuity. The authors reported that early intensive glycemic management decreased risk of DRIL in DCCT/EDIC participants. The significance of this study is that it continues to emphasize the importance of metabolic memory by demonstrating that intensive glycemic management in DCCT/EDIC participants had benefits on the retina beyond features detected by fundus photographs and ophthalmoscopy routinely obtained in clinical practice. This important observation contributes to our understanding of retinopathy development in type 1 diabetes.

Previous reports on DCCT/EDIC have demonstrated significant declines in memory and psychomotor and mental efficiency and concluded that cognitive function declines with aging in type 1 diabetes ( 9 ). In this issue, Karger et al. ( 4 ) took the next logical step to understand mechanisms of brain injury by evaluating the associations between plasma biomarkers of brain injury and brain MRI and cognitive measures. The authors stated that in previously reported smaller studies, plasma biomarkers of brain injury revealed potential associations between the biomarker and brain structural abnormalities and/or cognitive function. Thus, in 373 participants in the EDIC study, the authors assessed plasma biomarkers (i.e., amyloid-β-40, amyloid-β-42, neurofilament light chain [NfL], phosphorylated Tau-181 [pTau-181], and glial fibrillary acidic protein [GFAP]) along with cognitive measures and MRI assessments. The authors reported the most notable biomarker results from their study were with NfL, a cytoskeletal filament protein in neurons released secondary to neuropathological processes ( 4 ). They found that NfL was the only biomarker significantly associated with accelerated brain aging in their models and that it significantly declined in individuals with type 1 diabetes with cognitive impairment. In addition, amyloid-β-42 measures were not associated with cognitive symptoms or MRI measures, and elevated NfL and pTau-181, but not amyloid-β-42, may reflect accelerated neurodegeneration without a prototypical Alzheimer disease pattern. Thus, this study provides important insights into the pathophysiology of cognitive dysfunction in older individuals with type 1 diabetes. Such novel observations clearly would not have been possible without DCCT/EDIC’s focus on closely following the DCCT/EDIC cohort over decades.

The long-term benefits of intensive glycemic management on nephroprotection in diabetes has also been clearly demonstrated in DCCT/EDIC ( 10 ). The promise and potential for using biomarkers to identify underlying renal dysfunction and clinical disease is that they may allow for earlier implementation of effective protective strategies. Therefore, Limonte et al. ( 5 ) sought to advance our understanding of renal dysfunction in long-term type 1 diabetes by examining tubular biomarkers reflecting kidney tubular injury and dysfunction in EDIC. Again, the significance of this report lies in the ability to leverage EDIC’s longevity and assess biomarkers over an extended period of time, allowing for an extensive assessment of temporal relationships with meaningful clinical renal outcomes. As stated by the authors, most studies to date that have assessed tubular biomarkers with kidney outcomes were measured at a single point in time. In a case-cohort study, the authors measured biomarkers across seven time points spanning ∼30 years and reported associations with diabetic kidney disease development. They observed that levels of two serum /plasma biomarkers, KIM-1 and sTNFR1, rising together over time better predicted the development of macroalbuminuria and poor kidney function than did measuring individual biomarkers alone. The novel information from serial measures from long-term follow-up of EDIC participants suggests that tubular biomarkers were more strongly associated with these clinically relevant outcomes over medium-term follow-up. The authors concluded that serial monitoring of biomarkers of kidney tubular injury and dysfunction may be useful for detecting early indicators of ongoing, progressive kidney damage in diabetic kidney disease.

An understudied complication related to type 1 diabetes is its effect on skeletal health, and it has been documented that type 1 diabetes is associated with increased risk of fractures ( 11 ). In this regard, EDIC has also furthered our understanding of bone health, demonstrating that type 1 diabetes is associated with lower bone mineral density (BMD) and that diabetes-related factors such as poorer glycemic control, advanced glycated end product (AGE) accumulation, and kidney disease are independent risk factors for lower hip BMD ( 11 ). A new report from EDIC researchers on this issue provides more key data on the adverse effect of type 1 diabetes on skeletal health. Specifically, Sinha Gregory et al. ( 6 ) describe a cross-sectional study embedded in EDIC where they sought to determine whether type 1 diabetes and its complications are associated with specific bone geometry or deficits in bone microarchitecture. They evaluated 183 individuals with type 1 diabetes from the EDIC cohort and 94 individuals without diabetes, obtaining high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal and diaphyseal tibia. The authors report that, compared with control participants, EDIC participants with type 1 diabetes had lower total BMD at the distal radius and distal tibia and larger total area at distal radius, distal tibia, and diaphyseal tibia. Individuals with type 1 diabetes in EDIC had poorer radius trabecular and cortical microarchitecture, but estimated failure load was similar. They concluded that suboptimal glycemic control, AGE accumulation, and microvascular complications, particularly reduced renal function, were associated with deficits in bone microarchitecture as well as lower BMD in the EDIC participants. The clinical significance of this report suggests that maintenance of adequate glycemic control resulting in reduced AGE accumulation and prevention of microvascular complications such as renal disease may reduce fracture risk by preventing loss of bone density and preserving healthy bone microarchitecture. This study continues to confirm the benefits of early glycemic control and importantly expands our understanding of the less-studied interactions between type 1 diabetes and bone health.

Diabetic peripheral neuropathy (DPN) remains a challenging complication to manage clinically given the risk for severe pain, lower limb amputations, and impact on daily function and quality of life. In addition, data obtained in DCCT/EDIC demonstrated that DPN is significantly related to glycemic control ( 12 ). Specifically, prior research from EDIC participants noted that a higher mean HbA 1c was the most significant risk factor for DPN, followed by older age, longer duration of type 1 diabetes, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria ( 12 ). In the final article in this series in Diabetes Care , Braffett et al. ( 7 ) sought to characterize the features and burden of neuropathic pain in type 1 diabetes. For this report, the authors evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for neuropathic pain during EDIC. Specifically, they administered the Michigan Neuropathy Screening Instrument annually between 1994 and 2020 and defined neuropathic pain with clinical signs of diabetic peripheral neuropathy by self-reported neuropathic pain plus an examination score >2, while neuropathic pain without clinical signs of DPN was defined by self-reported neuropathic pain and an examination score ≤2. The authors report that by year 26, the cumulative incidence of neuropathic pain was 57% regardless of clinical presence of diabetic peripheral neuropathy. Interestingly, they also noted there may be frequent remission, as the prevalence of neuropathic pain at 26 years was 20%. Remission was associated with several modifiable and nonmodifiable risk factors, but interestingly use of pain medication did not affect annualized remission rates. These findings highlight the high incidence of neuropathic pain in individuals with type 1 diabetes, even in the absence of accompanying clinical signs of DPN. This report further demonstrated that intensive glucose control in those with type 1 diabetes, applied early as done in the DCCT, lowers the risk of later developing neuropathic pain—findings that have not been available from any other cohort. These novel results may be key to improving clinical care of people with type 1 diabetes and to development of new management strategies for this common and burdensome disease complication.

A major strength of all five of the studies presented in this issue is the leveraging of the extremely well-characterized cohort of participants with type 1 diabetes in EDIC. All of these studies provided a better understanding of the already well-known but sometimes poorly understood clinical complications associated with diabetes. Some of the studies sought to further evaluate the effect of metabolic memory on development of their specific complication of interest, whereas the others leveraged the cohort to further characterize complications in the population with long-term type 1 diabetes. EDIC continues to provide unique opportunities to improve the lives of those with type 1 diabetes. The long-standing EDIC cohort allows investigators to propose novel hypotheses and answer meaningful research and clinical questions that cannot be addressed by shorter studies.

Collectively, these five reports add to the enduring legacy of the DCCT/EDIC studies, which continue to inform the diabetes community and provide new findings on the benefits of early glycemic control. These reports highlight how EDIC’s unique and extremely well-characterized cohort of participants with type 1 diabetes continues to contribute new knowledge on the natural history of this disease and its complications. For over four decades, the EDIC study has provided an extraordinarily detailed assessment of microvascular and macrovascular complications as well as a comprehensive assessment of long-term diabetes-related risk factors, including HbA 1c and other markers of glycemic control.

After 40 years, DCCT/EDIC remains an incredibly unique resource that still inspires and informs the current direction of diabetes research. The hundreds of published reports from DCCT/EDIC—and the resulting findings that have become accepted clinical standards of care—have been incredibly impressive contributions to public health. They also have stood as testaments to the benefits of sustained, long-term funding for medical research, demonstrating how investments in research today can yield dividends for years to come. These landmark findings, though, would not have been possible without the DCCT/EDIC investigators, study staff, and volunteer research participants. NIDDK applauds their dedication in contributing to this unique and uniquely successful research effort. Because of their vision, DCCT/EDIC’s legacy continues to grow, and we continue to celebrate the release of new findings that aim to improve the lives of those with type 1 diabetes.

This article is part of a special article collection available at diabetesjournals.org/collection/2296/DCCT-EDIC-40th-Anniversary-Collection .

This article is featured in a podcast available at diabetesjournals.org/care/pages/diabetes_care_on_air .

Acknowledgments. We acknowledge and recognize Dr. Rebecca Cerio, Dr. Julie Wallace, and Dr. Heather Rieff from NIDDK’s Office of Scientific Program & Policy Analysis for their careful review and editing support.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Steven E. Kahn.

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The association of weight-adjusted waist index with the risk of osteoporosis in patients with type 2 diabetes: a cross-sectional study

• Runzhou Pan 1 , 2 &
• Yukun Li 1  

Journal of Orthopaedic Surgery and Research volume  19 , Article number:  518 ( 2024 ) Cite this article

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The relationship between obesity and type 2 diabetes with bone health has always been a topic of debate. The weight-adjusted waist index has become a commonly used indicator for assessing central obesity, fat, and muscle mass. However, currently there is no research reporting the association between weight-adjusted waist index and risk of osteoporosis in populations of type 2 diabetes. Therefore, this study aims to provide new information on the association between weight-adjusted waist index and risk of osteoporosis in type 2 diabetes.

This cross-sectional study involved 963 patients with type 2 diabetes who were admitted to the Department of Endocrinology of Cangzhou Central Hospital. Multivariate logistic regression models were used to assess the association between weight-adjusted waist index and osteoporosis. The potential nonlinear association was evaluated. The effects of interaction between subgroups were assessed using the likelihood ratio test.

Weight-adjusted waist index was positively associated with the risk of osteoporosis, regardless of traditional confounding factors. For each 1 unit increased in weight-adjusted waist index, the risk of osteoporosis increased by 67%. Furthermore, there was a nonlinear relationship between weight-adjusted waist index and osteoporosis. The subgroup analysis did not reveal any significant interactions.

Conclusions

Our study indicated a positive association between weight-adjusted waist index and the risk of osteoporosis in adult Chinese type 2 diabetes patients, and this relationship was nonlinear.

Due to its severity, chronic nature, and progression, osteoporosis (OP) has become a public health problem. In China, the prevalence of OP among adults over 20 years of age has reached 18.2% [ 1 ]. The clinical and economic burden of fractures related to OP is significant [ 2 , 3 ]. Therefore, the treatment and prevention of osteoporosis and osteoporotic fractures are of significant clinical and public health importance. In recent years, the latest evidence on the modern management of OP has been presented, in order to provide patients with more treatment options [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Similarly, actively exploring innovative approaches to prevent OP is also crucial to maintaining public health.

As two common metabolic disorders, the relationship between obesity and type 2 diabetes (T2D) with bone health has always been a topic of debate. T2D is associated with normal or higher bone mineral density (BMD), but paradoxically increases the risk of fractures [ 10 ]. Several factors related to diabetes are associated with increased fracture risk, including exogenous insulin therapy, vascular complications, and poor glycaemic control, although detailed comprehensive studies to identify the independent contributions of these factors are lacking [ 10 ]. Similarly, although the view that obesity is positively associated with BMD or bone mass was once widely accepted [ 11 , 12 ], recent research suggests that the relationship between the two may be the opposite [ 13 ]. The presence of metabolic syndrome and/or high waist circumference seems to be playing a role in the loss of bone mass in obesity [ 14 ]. Obesity is a risk factor for T2D, so bone phenotypes in both conditions may overlap a lot.

In recent years, a type of obesity phenotype known as sarcopenic obesity (SO), characterised by increased fat accumulation, decreased muscle mass and strength, has been found to be prevalent in some clinical settings [ 15 ]. Individuals with SO are at increased risk of developing T2D compared to individuals who are obese but do not have SO [ 16 ]. Osteosarcopenic obesity (OSO) combines the characteristics of low bone mass with SO, and has been proposed as a new disease [ 17 ]. As traditional measures of obesity, body mass index (BMI) and waist have limitations in distinguishing between muscle and fat mass, which may lead to less accurate estimates of individual health risks, including bone health [ 18 , 19 ]. In recent years, a new obesity measure called the weight-adjusted waist index (WWI) has been introduced and has become a commonly used indicator for assessing central obesity, fat, and muscle mass [ 20 ]. The relationship between WWI and bone health has been investigated in the general population [ 21 , 22 , 23 , 24 , 25 ]. However, currently there is no research reporting the association between WWI and risk of OP in T2D populations. Therefore, this population-based study aims to provide new information on the association between WWI and risk of OP in patients with T2D. Therefore, this population-based study aims to explore the relationship between WWI in T2D patients and the risk of OP, to provide new information for the prevention of OP in patients with T2D.

Study design and sample

This study is a cross-sectional study. Based on data from nearby cities, the prevalence of T2D in adults is 9.2% [ 26 ]. Assuming a two-sided α = 0.05 and a permissible error of 3%, using PASS 15 to calculate the sample size, we obtain N  = 390. This study involved 963 patients with T2D who were admitted to the Endocrinology Department of Cangzhou Central Hospital between October 2018 and December 2023. The inclusion criteria were adults aged 18 years or older, individuals diagnosed with T2D according to the 1999 World Health Organization (WHO) criteria [ 27 ]. The BMD levels of patients’ total hip, femoral neck, and lumbar spine were measured using Hologic’s DXA equipment. The diagnostic criteria for OP are based on the WHO diagnostic criteria: T-scores ≤ -2.5 were defined as OP, -2.5 < T-scores ≤ -1.0 were defined as osteopenia, T-scores > -1.0 were defined as normal BMD [ 28 ]. Patients with osteopenia and normal BMD are considered non-OP. Excluded from the study were patients with acute diabetes complications, a history of endocrine disorders affecting bone metabolism (such as thyroid disease, hypopituitarism, Addison’s disease, Cushing syndrome, pituitary adenoma, parathyroid disease or hypogonadism), severe infections, inflammatory diseases, malignant tumours, severe liver or kidney dysfunction, or other secondary OP. Patients taking medications that affect bone metabolism were also excluded. This study was approved by the Ethics Committee of Cangzhou Central Hospital and was conducted according to the Helsinki Declaration guidelines, including all relevant details. As this study was retrospective, informed consent was not required.

Weight and waist were measured by well-trained hospital healthcare technicians. The subjects stood upright with their arms crossed in front (hands placed on opposite shoulders). A bilateral iliac palpation was performed and a horizontal line was drawn above the outermost part of the right iliac bone. Subsequently, the midline of the axilla was marked on the right side. The tape measure was placed at the intersection point of the two lines in a horizontal plane. The waist was then measured at the end of a normal exhalation by the individual. The participants’ shoes and bulky clothing were removed to calculate their weight. WWI was determined by dividing the waist (cm) by the square root of weight (kg). The methodology to establish WWI was previously described in a separate study [ 29 ].

Drawing from the existing literature [ 22 , 24 ], multiple potential covariates were assessed, encompassing sex, age, hypertension, metabolic syndrome (MetS), smoking history, glycated hemoglobin (HbA1c), total cholesterol (TC), calcium, phosphorus, 25-hydroxy vitamin D (VID), serum creatinine (Cre), uric acid (UA), and insulin use. A definitive smoking history was established by current smoking and previous smoking (quit smoking after a total of more than 100 cigarettes). Hypertension was confirmed with a systolic blood pressure of 130 mmHg or higher or a diastolic blood pressure of 80 mmHg or higher (or through antihypertensive medications). Laboratory data was obtained from the hospital information system.

Statistical analysis

The characteristics of the patients were calculated according to the WWI quartiles. Continuous variables were presented as mean ± SD or median (interquartile range), while categorical variables were expressed as frequencies or percentages. One-way analysis of variance (normal distribution), Kruskal-Wallis test (skewed distribution), and Chi-square test (categorical variables) were used to determine statistical differences in group means and proportions. The multiple logistic regression model was used to investigate the linear association between WWI and the risk of OP. WWI was treated as both a categorical variable (quartiles) and a continuous variable input. The study comprised four models: Model 1 did not require variable adjustment. Model 2 adjusted for sex, age, hypertension, MetS, and smoking history. Model 3 adjusted for sex, age, hypertension, MetS, smoking history, HbA1c, TC, calcium, phosphorus, VID, Cre, and UA. Model 4 adjusted for Model 3 plus insulin use. A generalised additive model (GAM) with a natural spline function incorporating 4 knots was utilised to examine the nonlinear relationship between WWI and the risk of OP. In the cases where a nonlinear association was identified, a two-piece regression model was employed to determine the threshold effect. Subgroup analyses were performed to explore potential variations within different subgroups. For continuous variables, they were initially transformed into categorical variables based on clinical cut-off points, followed by an interaction test. The effects of interaction between subgroups were assessed using the likelihood ratio test. All statistical analyses were carried out using R Statistical Software (Version 4.2.2, The R Foundation, http://www.R-project.org ) and the Free Statistics Analysis Platform (Version 1.9, Beijing, China, http://www.clinicalscientists.cn/freestatistics ).

Characteristics of the study population

This study enrolled 963 eligible T2D patients, aged 58.7 ± 12.1 years. The mean levels of total hip BMD, femoral neck BMD, and lumbar spine BMD were 0.982 ± 0.159 g/cm 2 , 0.820 ± 0.151 g/cm 2 , and 1.047 ± 0.166 g/cm 2 , respectively. The incidence of OP was approximately 9.4%. The baseline characteristics of the participants, stratified by WWI, are presented in Table  1 . As the WWI quartiles increase, total hip BMD, femoral neck BMD, and lumbar spine BMD show a gradual decreasing trend, and the incidence rate of OP is showing an increasing trend. Compared to patients in the first or second quartiles of WWI, patients in the third or fourth quartiles of WWI were older, had higher BMI levels, a higher proportion of female patients, more cases of hypertension, MetS, history of smoking, and insulin use. Laboratory indicators such as TG, UA, and phosphorus levels were higher, while HDL-C levels were lower in patients in the third or fourth quartiles of WWI ( P  < 0.05). No significant differences were found between the groups in other laboratory indicators including TC, LDL-C, Cre, FBG, HbA1c, calcium and VID ( P  > 0.05) (Table  1 ).

Association between WWI and the risk of OP

In univariate logistic regression analyses, WWI expressed as a continuous variable (Per 1 cm/√kg) was increased associated with the risk of OP [odds radio (OR) = 2.36, 95% confidence interval (CI) = 1.71 ~ 3.26, P  < 0.001] (Table  2 , model 1). This association was attenuated but remained statistically significant (OR = 1.69, 95% CI = 1.15 ~ 2.48, P  = 0.007), independent of potential confounders (Table  2 , model 4). When WWI was expressed in quartiles in logistic regression analysis, patients in the highest quartile of WWI had a 3.26-fold increased risk of OP compared to those in the lowest quartile of WWI (OR = 4.26, 95% CI = 2.19 ~ 8.3, P  < 0.001) (Table  2 , model 1). Even after adjusting for potential confounders, this association remained significant and independent (OR = 2.20, 95% CI = 1.02 ~ 4.77, P  = 0.045) (Table  2 , model 4). In addition, multivariable-adjusted restricted cubic spline analyses indicated nonlinear relationship between WWI and the risk of OP ( P  = 0.029) (Fig.  1 ). when the WWI < 11.14 cm/√kg, there appears to be a decreasing trend in the risk of OP for patients with T2D with increasing WWI, but this difference is not significant. However, when WWI ≥ 11.14 cm/√kg, there is a significant positive association between WWI and the risk of OP, with an OR of 4.29 (95% CI, 1.66–11.07; P  = 0.003) (Table  3 ).

The association of WWI(cm/√kg) and the risk of OP. (Solid and dashed lines represent the predicted value and 99.9% confidence intervals) Abbreviations: WWI, waist circumference index; OP, osteoporosis. Adjust for age, sex, hypertension, metabolic syndrome (MetS), smoking history, glycogen hemoglobin (HbA1c), total cholesterol (TC), calcium, phosphorus, 25-hydroxy vitamin D (VID), serum creatinine (Cre), uric acid (UA) and insulin use

Stratified analyses were carried out in several subgroups (Male or Female, Age < 50 years or Age ≥ 50 years, BMI < 24 kg/m 2 , 24 kg/m 2  ≤ BMI < 28 kg/m 2 or BMI > 28 kg/m 2 , MetS or not, insulin use or not, VID < 50 nmol/L or VID > 50 nmol/L) to assess the potential impact of the relationship between WWI and OP in the population with T2D. The results of the subgroup analysis did not reveal any significant interactions ( P  > 0.05) (Fig.  2 ).

Association between WWI and the risk of OP according to the general characteristics. p-Value < 0.05 was considered significant. Abbreviations: WWI, waist circumference index; OP, osteoporosis; BMI, body mass index; MetS, metabolic syndrome; VID, 25-hydroxy vitamin D; OR, odds radio; CI, confidence interval. Except for the stratification factor itself, the stratifications were adjusted for all variables, including age, sex, hypertension, MetS, smoking history, glycogen hemoglobin (HbA1c), total cholesterol (TC), calcium, phosphorus, VID, serum creatinine (Cre), uric acid (UA) and insulin use

This cross-sectional study indicates that there is a nonlinear association between WWI and OP among adult T2D patients in China. This relationship remains stable in subgroup analysis based on different sex, BMI, MetS, ages, insulin use and vitamin D levels.

Obesity and overweight have previously been identified as preventive factors for fractures and OP. Excess body fat can not only promote the secretion of various hormones, including oestrogen, insulin, and leptin, which can prevent bone loss, but also exert more static mechanical stress on the bones, promoting the formation of cortical bone in obese individuals [ 30 ]. BMI and waist are two internationally recognized parameters for identifying obesity, and many early studies have found a positive association between BMI, waist, and BMD [ 11 , 12 ]. As traditional body measurement indices, BMI and waist have a stronger association with high fat mass and are valuable in predicting health risks related to obesity [ 14 , 31 ]. However, these indices cannot be used as accurate indicators of obesity due to their inability to differentiate between fat and muscle mass, as well as their limitations influenced by age, gender, and race [ 32 ]. In recent years, the viewpoint that obesity is a protective factor for OP has gradually shifted [ 13 ]. A simple linear association cannot fully reflect the relationship between BMI and BMD [ 33 ]. Previous studies have shown that SO, rather than simple obesity, significantly increases the risk of morbidity and mortality. This elevated risk of mortality is not only related to obesity [ 34 , 35 ]. Recently, as a new entity, OSO combines excessive fat accumulation (obesity), decreased muscle mass and strength (sarcopenia), and low bone mass (osteopenia/OP), and is increasingly gaining attention [ 17 ]. This highlights the need to consider the complex effects of fat and muscle mass on the body when calculating bone health risks. WWI shows minimal differences between races and is widely applicable in multiethnic environments. It is positively associated with body fat and negatively associated with muscle mass [ 20 ]. It represents the complex condition of SO, reflecting changes in abdominal components with age and excluding interference from muscle mass in high body weight [ 36 ]. Therefore, when assessing various health outcomes, especially bone health, WWI can perform better than traditional indicators such as BMI and waist.

Some studies based on the NHANES and KNHANES database have found a negative association between WWI and total hip BMD, femoral neck BMD, and lumbar spine BMD in adult populations in the United States (US) and South Korea [ 21 , 22 , 25 ], and a negative association between WWI and total femoral BMD in adolescent populations [ 24 ]. Recently, a study in the US population aged 65 and older found a U-shaped relationship between WWI and OP [ 23 ]. Compared to previous studies, this study adjusted for potential confounders and used multivariate regression analysis of data from Chinese patients with T2D, making the results generalisable to the Chinese population with T2D. We found a positive association between WWI and OP. To evaluate the effects of age, sex, blood pressure, smoking history, lipid metabolism, calcium, phosphorus, VID, Cre, UA, and insulin on the association between WWI and OP, we constructed four models and compared the results before and after adjusting for the above covariates. In Model 2, which considers age, sex, hypertension, MetS, and smoking, and Model 3, which further considers TC, calcium, phosphorus, VID, Cre, and UA on the basis of Model 2, this association remains stable. Additionally, it should be noted that insulin is closely associated with both obesity and bone [ 37 , 38 ]. Therefore, in Model 4, we adjusted for whether the patients used insulin and the results confirmed that the relationship between WWI and OP remains robust. The exact underlying cause of the association between WWI and OP remains uncertain. Potential mechanisms may include the following: The presence of fat in bone and muscle is a key pathophysiological factor in low bone mass [ 39 ]. A key mechanism of bone loss involves bone marrow mesenchymal stem cells (BMSCs) that expend bone marrow adipose tissue at the expense of osteoblasts. The ‘fattening’ of bones, coupled with reduced bone formation, lowers trabecular bone density, leading to a higher risk of fractures [ 40 ]. Fat inflammation leads to redistribution of fat from subcutaneous spaces to intra-abdominal fat (visceral fat) and skeletal muscle (fat infiltration), resulting in decreased muscle strength and function [ 41 ]. The central pathway shared by muscles and bones is the growth hormone/insulin-like growth factor-1 axis, which plays a crucial role in regulating bone and muscle growth [ 42 ]. Complex bidirectional crosstalk between muscles and bones, including mechanical interactions and paracrine and endocrine communication, functions in the homeostasis of bones and muscles. Decreased muscle function and performance lead to reduced skeletal loading and subsequent deterioration of BMD. Muscle paralysis, atrophy, or immobilisation can promote bone loss and OP [ 39 , 43 ]. The coexistence of obesity and sarcopenia under the so-called ‘SO’ phenotype may have a synergistic effect, chronic inflammation being a common factor in both conditions, potentially playing a significant role in bone remodelling, especially driving and accelerating the transition to a resorptive state, leading to decreased bone mass [ 44 ]. Furthermore, although the underlying mechanisms are not yet clear, both T2D and obesity can induce oxidative stress and inflammation. T2D further exacerbates the damage to the bones due to obesity [ 45 ]. Studies have shown that T2D is associated with the transition from osteogenesis to fat generation, with an increase in bone marrow adiposity leading to the replacement of cell marrow by fat. BMSCs may be involved in the shared pathological processes of obesity, diabetes, and skeletal fragility [ 45 , 46 ].

It should be noted that our results showed a nonlinear relationship between WWI and OP in the T2D population, with a critical value of 11.14 cm/√kg. When WWI < 11.14 cm/√kg, we did not find an association between WWI and OP. However, when WWI ≥ 11.14 cm/√kg, there was a significant positive association between WWI and an increased risk of OP. Therefore, we speculate that in a low WWI state, the increase in weight and the positive effects of hormone secretion on the skeleton may counteract the decrease in the negative impact of decreased muscle mass, increased body fat and T2D on bones. However, as WWI increases beyond the threshold, this negative impact can become more prominent, leading to an increased risk of OP in patients. Interestingly, this nonlinear relationship is different from the U-shaped relationship found in a previous study of the general elderly population in the US [ 23 ]: When WWI is below the threshold, WWI does not show a negative association with OP, as observed in the previous study. However, when WWI exceeds the threshold, the OR of OP reaches 4.13, exceeding the previously reported OR value of 2.23. The difference may be attributed to the different study populations. Firstly, unlike previous studies that included the general population, our study includes T2D patients, so we need to consider the adverse effects of T2D on bone metabolism. The impact of diabetes on bones is multifaceted. In cases where BMD is normal or increased, various factors in T2D patients such as central obesity, insulin resistance, hyperinsulinemia, hyperglycemia, accumulation of advanced glycation end-products, occurrence of microvascular and macrovascular complications, and the use of exogenous insulin lead to impaired bone parameters (reduced bone turnover, cortical defects such as increased cortical porosity, decreased cortical volumetric BMD, reduced cortical cross-sectional area), and decreased bone quality [ 10 ]. Secondly, unlike previous studies that included US populations, our study includes Chinese populations. Research indicates that compared to western populations, Asians have a higher percentage of body fat, prominent abdominal obesity, and a significantly higher visceral fat [ 47 ]. Compared to general obesity, central obesity can have more inflammatory markers, visceral fat can be more active than other fats, secreting a greater variety of cytokines, such as inflammatory cytokines that disrupt the bone remodelling process [ 48 ]. Increased in insulin resistance caused by central obesity can inhibit insulin-like growth factor-1, thereby reducing the proliferation and differentiation of osteoblasts [ 49 ]. Whether the negative impact of T2D itself, as well as abdominal obesity and increased visceral fat on bone, is the cause of this difference deserves further exploration.

No significant interactions were observed in the subgroup analysis, demonstrating that the positive association between WWI and OP risk in T2D patients is robust across different subgroups. It is important to note that the prevalence of OP varies among different subgroups. Epidemiological studies suggest that age and female gender are independent risk factors for osteoporosis [ 50 , 51 ]. A recent study on T2D patients in Japan without a history of fractures or OP treatment has confirmed that elderly women have the highest risk of bone loss and OP [ 52 ]. Our result shows that the prevalence of OP is higher in patients over 50 years of age, as well as in female patients, consistent with previous research findings. In addition, compared to patients with a low BMI, the prevalence of OP is lower in patients with a high BMI, possibly due to the positive effects that obesity and overweight can have on the bones [ 30 ].

The strength of this article is that previous studies have focused primarily on the skeletal health of the general population, with limited information on the relationship between WWI and the risk of OP in patients with T2D. Our study selected adult T2D patients to elucidate some of these issues. However, there are several limitations that need attention. Firstly, since this study used a cross-sectional design, it cannot establish a causal relationship between WWI and the risk of OP. Secondly, despite adjusting for several potential confounding factors, there may be other unknown or unmeasured factors that could affect our research results. Future studies should consider these limitations to improve understanding and applicability of using WWI as a measure to evaluate bone health.

This study indicated a positive association between WWI and OP risk in Chinese adult patients with T2D, and this relationship was nonlinear. This indicates that in T2D patients, maintaining WWI within the optimal range is crucial to effectively managing bone metabolism health. More prospective studies will be needed in the future to confirm these conclusions.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

• Osteoporosis
• Type 2 diabetes

Bone mineral density

Sarcopenic obesity

Osteosarcopenic obesity

Body mass index

• Weight-adjusted waist index

World Health Organization

Metabolic syndrome

Glycated hemoglobin

Total cholesterol

25-hydroxy vitamin D

Serum creatinine

Fasting blood glucose

Triglyceride

High-density lipoprotein cholesterol

Low-density lipoprotein cholesterol

Standard deviation

Interquartile range

Confidence interval

United States

Bone marrow mesenchymal stem cells

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Acknowledgements

The authors acknowledge Jie Liu of the Department of Vascular and Endovascular Surgery, Chinese PLA General Hospital for his contribution to the statistical support, study design consultations, and comments regarding the manuscript.

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Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China

Runzhou Pan & Yukun Li

Department of Endocrinology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China

Runzhou Pan

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RP performed data analysis and wrote the document. YL performed modifed the paper. RP interpreted data. YL designed the investigation and reviewed the document. All authors participated in the essay and accepted the submitted version.

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Pan, R., Li, Y. The association of weight-adjusted waist index with the risk of osteoporosis in patients with type 2 diabetes: a cross-sectional study. J Orthop Surg Res 19 , 518 (2024). https://doi.org/10.1186/s13018-024-04991-7

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Received : 13 June 2024

Accepted : 08 August 2024

Published : 29 August 2024

DOI : https://doi.org/10.1186/s13018-024-04991-7

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