research on cure for type 1 diabetes

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

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

Harvard Correspondent

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

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

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

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

GAZETTE: Would you walk us through the approach?

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

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

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

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

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

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

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

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

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

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

GAZETTE: What’s next?

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

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

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Current and future therapies for type 1 diabetes

Bernt johan von scholten.

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

Frederik F. Kreiner

Stephen c. l. gough, matthias von herrath.

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

Associated Data

Graphical abstract.

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

Supplementary Information

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

Introduction

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

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

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

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

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

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

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

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

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

Immune-focused therapies

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

Cell-directed interventions

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

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

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

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

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

Cytokine-directed interventions

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

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

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

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

Antigen vaccination

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

Non-immunomodulatory adjunctives

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

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

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

Sodium-glucose cotransporter inhibitors

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

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

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

Future perspectives

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

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

Immune interventions

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

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

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

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

Management of cardiometabolic complications

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

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

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

Combination therapies

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

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

Stem cell replacement therapy

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

Closing thoughts

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

(PPTX 230 kb)

Authors’ relationships and activities

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

Abbreviations

Contribution statement.

All authors contributed substantially to the preparation of the review and approved the version to be published.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

FDA News Release

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

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

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

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

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

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

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

The FDA granted approval of Lantidra to CellTrans Inc.

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

Breakthrough diabetes study could lead to end of regular insulin injections, researchers say

Researchers say they have made a breakthrough in the treatment of type 1 diabetes which could replace the need for regular insulin injections.

Research published by Baker Heart and Diabetes Institute scientists shows they have manipulated existing pancreatic stem cells to prompt them to produce insulin.

The study from the Melbourne researchers builds on previous work by Monash University scientists, using two existing cancer drugs. 

The research is still in its early days and the next step will be pre-clinical animal trials.

But lead researcher and Baker institute scientist, Sam El-Osta, said the potential treatment could be viable for children and adults in the future.

"What we've discovered is the ability to harness the patient's remaining pancreatic cells to influence those cells to behave like insulin-producing beta cells," Professor El-Osta told ABC Radio Melbourne.

"This could potentially modify the course of diabetes and potentially eliminate the need for round-the-clock insulin injections in some people living with type 1 diabetes."

Broadly, people with diabetes do not naturally produce enough insulin, or their bodies do not use the hormone as they should.

For many people with diabetes, it means multiple insulin injections are required daily to manage the illness.

Research could be 'holy grail'

The two cancer drugs used in the research are already approved by the US Food and Drug Administration.

Researchers said the potential treatment could be "rapid" compared to current treatment options for type 1 diabetes.

"We've been able to repurpose these drugs to determine whether we could influence the trajectory by using these small molecule inhibitors in pancreatic ductal cells," Professor El-Osta said.

"We can quickly influence insulin restoration in a number of days in a dish from tissues derived from type 1 diabetes donors, both children and adults."

Diabetes Australia estimates around 134,000 people in Australia are living with type 1 diabetes, which represents about 10 per cent of all diabetes cases.

The Baker Heart and Diabetes Institute researchers are optimistic their work could potentially help people living with insulin-dependent type 2 diabetes.

The research has been published in a Nature scientific journal, Signal Transduction and Targeted Therapy.

Chief executive of the Australian Diabetes Society and University of Melbourne associate professor, Sof Andrikopoulos, labelled the research as "remarkable". 

"For the 135,000 Australians with type 1 diabetes, this is the holy grail. This is it," he said. 

"There's a potential here that this research might lead to the cure of type 1 diabetes, at some point down the road.

"It also has the potential to make a significant improvement in type 2 diabetes."

Dr Andrikopoulos, who was not involved with the study, said the research would reduce the burden of the disease.

"This research has the potential for the body itself, to produce and secrete insulin. So you can see that you're getting rid of needles, you're getting rid of insulin pumps, you're getting rid of finger pricking, you're getting rid of continuous glucose monitors," he said.

While he was hopeful for the future, Dr Andrikopoulos warned steps towards a cure would require consistent funding for diabetes research.

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New advances in type 1 diabetes

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

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

Introduction

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

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

Sources and selection criteria

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

Epidemiology

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

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

Autoantibody characteristics associated with increased risk of type 1 diabetes 10

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

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

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

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

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

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

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

Advances in monitoring

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

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

Summary of trials for each topic covered

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

Standardized continuous glucose monitoring metrics for adults with diabetes 52

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

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

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

Advances in treatments

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

Pharmacokinetics of commonly used insulin preparations

Ultra-long acting basal insulins

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

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

Ultra-rapid acting prandial insulins

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

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

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

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

Pulmonary inhaled insulin

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

Insulin delivery systems

Approved automated insulin delivery systems.

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

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

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

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

Comparison of commercially available hybrid closed loop systems 75

Unapproved systems

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

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

β cell replacement therapies

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

Pancreas transplantation

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

Islet transplantation

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

Disease modifying treatments for β cell preservation

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

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

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

Non-immunomodulatory adjunctive therapies

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

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

Glucagon-like peptide receptor agonists

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

Sodium-glucose cotransporter inhibitors

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

Updates in acute complications of type 1 diabetes

Diabetic ketoacidosis.

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

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

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

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

Hypoglycemia

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

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

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

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

Management in under-resourced settings

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

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

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

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

Emerging technologies and treatments

Monitoring systems.

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

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

Insulin and delivery systems

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

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

Immunotherapy for type 1 diabetes

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

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

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

Guidelines in type 1 diabetes

Conclusions

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

Glossary of abbreviations

ADA—American Diabetes Association

AID—automated insulin delivery

BGM—blood glucose monitoring

CGM—continuous glucose monitoring

CKM—continuous ketone monitoring

DCCT—Diabetes Control and Complications Trial

DIY—do-it-yourself

FDA—Food and Drug Administration

GADA—glutamic acid decarboxylase antibody

GLP-1—glucagon-like peptide 1

GRS—genetic risk scoring

HbA1c—glycated hemoglobin

HCL—hybrid closed loop

LADA—latent autoimmune diabetes of adults

LMIC—low and middle income country

PAKT—pancreas after kidney transplant

RCT—randomized controlled trial

SGLT-2—sodium-glucose cotransporter 2

SPKT—simultaneous pancreas-kidney transplant

Questions for future research

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

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

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

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

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

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

How patients were involved in the creation of this manuscript

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

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

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

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

Provenance and peer review: Commissioned; externally peer reviewed.

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

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The Long, Long Wait for a Diabetes Cure

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

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

Supported by

By Andrew Jacobs

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What to Know About Diabetes

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Speedy squeeze

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

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

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

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

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

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

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

Tissue challenges

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

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

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

This means BuBble Gun has potential uses beyond insulin delivery.

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

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

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

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

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

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

Planned prototype

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

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

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

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

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• EU health research and innovation

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New Startup Develops Potential Cure for Type 1 Diabetes

Nov 03, 2022 — atlanta, ga.

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

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

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

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

The Insulin Issue

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

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

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

How iTOL-100 Works

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

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

Introducing iTolerance

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

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

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

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

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

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

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

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

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

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

Tess Malone, Research Writer/Editor 

Siblings with unique genetic change help scientists progress drug search for type 1 diabetes

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

• Immune System
• Personalized Medicine
• Diseases and Conditions
• Hormone Disorders
• Medical Topics
• Diabetes mellitus type 1
• Diabetes mellitus type 2
• Erectile dysfunction
• Gene therapy
• Alzheimer's disease

Story Source:

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

Journal Reference :

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

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Strange & offbeat.

Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials

Affiliations.

• 1 Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL.
• 2 Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL.
• 3 Health Informatics Institute, University of South Florida, Tampa, FL.
• 4 Pediatric Endocrinology, Children's Mercy Hospital/University of Missouri-Kansas City Mercy, Kansas City, MO.
• 5 Vanderbilt University Medical Center, Nashville, TN.
• 6 University of California San Francisco, San Francisco, CA.
• 7 Yale University School of Medicine, New Haven, CT.
• 8 Baylor College of Medicine, Texas Children's Hospital, Houston, TX.
• 9 Department of Pediatrics, Indiana University, Indianapolis, IN.
• 10 Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
• 11 Department of Pediatrics, University of Minnesota, Minneapolis, MN.
• 12 Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA.
• 13 Barbara Davis Center, University of Colorado School of Medicine, Aurora, CO.
• 14 Division of Endocrinology, University of Miami, Miami, FL.
• PMID: 38621411
• DOI: 10.2337/dc24-0171

Objective: Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy.

Research design and methods: We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial.

Results: Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants.

Conclusions: Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials.

© 2024 by the American Diabetes Association.

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• U01 DK061010/DK/NIDDK NIH HHS/United States

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Research on a cure for type 1 diabetes

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

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

What are islet cell transplants?   

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

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

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

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

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

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

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

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

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

Beta cells, a challenge for the future

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

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

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

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

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Is There a Cure for Type 1 Diabetes?

One of the first things people ask when they’ve been diagnosed with type 1 diabetes is: is there a cure? The truth is, while type 1 diabetes can be managed with insulin, diet and exercise, there is currently no cure. However, researchers with the Diabetes Research Institute are now working on treatments to reverse the disease, so that people with type 1 diabetes can live healthy lives without medication.

What is type 1 diabetes?

With type 1 diabetes, your pancreas stops making insulin, a hormone that helps the body convert blood sugar into energy. Without insulin, sugar builds up in the blood and can damage your internal organs, including your heart, kidneys, eyes, nervous system, and other parts of the body. This can lead to serious or life-threatening complications over time.

Type 1 diabetes is not caused by a person’s diet or lifestyle. It is an autoimmune disorder, where the body’s immune system mistakenly attacks and destroys healthy cells in the pancreas. While it’s most commonly diagnosed in children and young adults, people can develop type 1 diabetes at any age.

How close are we to a cure?

For a century, treatment for type 1 diabetes has focused on managing the disease. Thanks to past advancements in medicine, patients are able to control their blood glucose levels with regular insulin injections or an insulin pump.

Now clinical trials are underway for treatments to reverse type 1 diabetes and restore the body’s ability to produce insulin naturally. These trials are already allowing some patients to live insulin-free, significantly improving their quality of life.

What is a biological cure?

DRI researchers are working toward a biological cure for type 1 diabetes. A biological cure means treatment that would help the body start producing its own insulin again, restoring blood sugars to normal levels without introducing other risks.

This research focuses on a process called islet transplantation. Islets are clusters of cells found in the pancreas that work together to regulate blood sugar. In an islet transplant, doctors take healthy islets from the pancreas of an organ donor, and inject them into someone with type 1 diabetes. In studies, some patients who had this procedure have been able to reduce the need for insulin injections, or stop injecting insulin altogether.

DRI scientists have already shown that islet transplantation can eliminate the need for insulin injections. Now they are working to improve the science so that more people can benefit from this treatment.

The BioHub Strategy

DRI’s BioHub strategy is a three-step approach to overcoming the current limitations of islet transplantation.

First, scientists focus on the transplant site. While the liver is the traditional site for islet transplantation, this location is not ideal. Scientists are investigating other possible transplant sites and options, including a bio-engineered platform that acts as an artificial pancreas.

Second, they are looking for ways to sustain the islets’ long-term survival and protecting them from the autoimmune attack that caused the type 1 diabetes in the first place. Some options include creating barriers to protect the cells, or adding oxygen or other agents to the transplant site.

Finally, researchers are investigating how to increase the supply of islets available for transplant. This could include finding a method to regenerate a patient’s own pancreatic cells, so cells don’t have to be taken from a donor.

Research Progress

Research has come a long way since the first islet transplant in a human was performed in 1985. Recent work by DRI scientists has included the discovery of pancreatic stem cells that can be stimulated to create insulin-producing beta cells, and a study that demonstrated that abdominal tissue called the omentum could work as a transplant site. And in 2019, a study by DRI scientists showed that a small group of patients who received islet transplants had been able to live without insulin injections for 10 years, while maintaining blood sugar levels that were in the same range as people who had never had type 1 diabetes.

Clinical Trials

A clinical trial is a study that takes treatments that have been developed in lab and pre-clinical research, and tests them in human patients. DRI scientists have a number of clinical trials currently underway, including an islet transplant study that is testing the omentum as an alternative transplant site to the liver. Other ongoing clinical trials include the POSEIDON Trial , which tests whether high doses of vitamin D and Omega-3 fatty acids can help slow or stop the progression of type 1 diabetes in newly diagnosed children and adults.

While past studies have shown that islet transplantation can reduce or eliminate the need for patients to inject insulin, so far this treatment has only been available to people with the most severe cases of type 1 diabetes. At the Diabetes Research Institute, we have one goal: a cure. With more research, our goal is to effectively reverse type 1 diabetes, restoring the body’s ability to normalize blood sugar levels naturally.

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

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

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• Patient Care & Health Information
• Diseases & Conditions
• Type 1 diabetes

Diagnostic tests include:

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

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

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

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

After the diagnosis

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

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

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

More Information

• Blood pressure test

Treatment for type 1 diabetes includes:

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

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

Insulin and other medications

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

There are many types of insulin, including:

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

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

• Insulin pump

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

Insulin delivery options

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

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

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

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

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

Blood sugar monitoring

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

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

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

Continuous glucose monitoring

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

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

Closed loop system

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

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

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

Other medications

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

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

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

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

Healthy eating and monitoring carbohydrates

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

• Whole grains

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

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

Physical activity

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

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

Activities of concern

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

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

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

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

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

Potential future treatments

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

Signs of trouble

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

Low blood sugar (hypoglycemia)

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

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

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

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

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

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

Severe hypoglycemia may cause:

• Convulsions or seizures
• Unconsciousness
• Death, rarely

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

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

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

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

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

Hypoglycemia unawareness

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

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

High blood sugar (hyperglycemia)

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

• Frequent urination
• Increased thirst
• Blurred vision
• Irritability

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

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

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

Increased ketones in your urine (diabetic ketoacidosis)

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

Symptoms of this serious condition include:

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

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

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Lifestyle and home remedies

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

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

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

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

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

Coping and support

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

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

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

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

Preparing for your appointment

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

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

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

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

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

What you can do

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

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

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

What to expect from your doctor

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

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

What you can do in the meantime

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

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• Levitsky LL, et al. Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents. https://www.uptodate.com/contents/search. Accessed May 4, 2022.
• Diabetes mellitus (DM). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed May 4, 2022.
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• Insulin resistance & prediabetes. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance. Accessed May 4, 2022.
• Blood sugar and insulin at work. American Diabetes Association. https://www.diabetes.org/tools-support/diabetes-prevention/high-blood-sugar. Accessed May 4, 2022.
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• Weinstock DK, et al. Management of blood glucose in adults with type 1 diabetes mellitus. https://www.uptodate.com/contents/search. Accessed May 7, 2022.
• FDA proves first automated insulin delivery device for type 1 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-automated-insulin-delivery-device-type-1-diabetes. Accessed May 4, 2022.
• Boughton CK, et al. Advances in artificial pancreas systems. Science Translational Medicine. 2019; doi:10.1126/scitranslmed.aaw4949.
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• FDA approves first-of-its-kind automated insulin delivery and monitoring system for use in young pediatric patients. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-automated-insulin-delivery-and-monitoring-system-use-young-pediatric#:~:text=Today, the U.S. Food and,by individuals aged 2 to. Accessed May 8, 2022.
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• What is type 1 diabetes? A Mayo Clinic expert explains

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

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

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

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

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

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

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

There are several types of diabetes:

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

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

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

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

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

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

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

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

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

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

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Research Gaps Around Type 1 Diabetes

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

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

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

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

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

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

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

Are Type 1 and Type 2 diabetes different diseases?

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

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

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

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

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

Can you talk about the different treatments?

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

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

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

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

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

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

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

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

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

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

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

Where is this research going next?

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

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

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

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

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

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

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

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

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

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

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Type 1 diabetes: What you need to know

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

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

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

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

What are the symptoms?

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

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

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

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

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

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

How is it diagnosed?

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

How is it treated?

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

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

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

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

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

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

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

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

April 23, 2024

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JDRF Celebrates Research Award Winners and Recognizes Type 1 Diabetes Research Leaders

New York, April 18, 2024— JDRF, the leading global type 1 diabetes (T1D) research and advocacy organization, proudly presented awards to five outstanding leaders in T1D research whose impact has pushed JDRF’s mission forward. Award recipients include:

• Linda DiMeglio, M.D. and Moshe Phillip, M.D., co-recipients, George Eisenbarth Award for Type 1 Diabetes Prevention
• Colin Dayan, M.D., Ph.D., JDRF Rumbough Award
• Kirstine Bell, Ph.D., Dr. Robert Goldstein Award
• Viral Shah, M.D., Mary Tyler Moore and S. Robert Levine, M.D., Excellence in Clinical Research Award

“Since our inception, JDRF’s mission has been focused on accelerating research and breakthroughs to cure, prevent, and treat type 1 diabetes and its complications. Our progress has been driven by the exceptional work and commitment of T1D researchers across the globe,” said JDRF Chief Scientific Officer Sanjoy Dutta, Ph.D. “It’s an honor to recognize and celebrate these dedicated individuals for their leadership and clinical implementation in research and the tangible impacts they have had on their fields and the millions of people who live with or are at risk of T1D.”

George Eisenbarth Award for Type 1 Diabetes Prevention

Named after esteemed researcher George Eisenbarth, M.D., Ph.D., who provided the foundation for predicting T1D and identifying novel approaches toward prevention and cures, this award recognizes researchers who have made great contributions to preventing T1D.

Dr. Moshe Phillip and Dr. Linda DiMeglio have led the development of international consensus guidance for monitoring of T1D in its early stages prior to clinical diagnosis. As chair and vice chair of this effort, they helped convene a broad range of global experts and co-led the writing of the guidance document, which will provide actionable information for healthcare providers to monitor early-stage T1D in the clinical setting.

Dr. Phillip is the director of the Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes at Schneider Children’s Medical Center, Petah Tikva, where he has served since 1997, and leads the Diabetes Technologies Center at the institute. Under Dr. Phillip’s leadership, the institute was leading the first multinational multicenter study with automatic insulin delivery (AID) outside of a hospital. Dr. Phillip is currently engaged in studies for national screening of diabetes in the general population and in family members. He remains active in clinical and applied research, focusing on childhood diabetes and growth.

In addition to maintaining an active clinical practice, Dr. DiMeglio serves as the Edwin Letzter Professor of Pediatrics at Indiana University School of Medicine and Chief of the Division of Pediatric Endocrinology and Diabetology at Riley Children’s Health. She began her career with a JDRF career development award to support one of her first research projects on insulin pump therapy in very young children with diabetes. Now, she directs local and national research teams focused on preventing T1D, preserving beta cell function, and improving metabolic control and quality of life for persons living with the disease.

JDRF Rumbough Award

The JDRF David Rumbough Award acknowledges an individual who has made outstanding contributions in the field of T1D that have significantly accelerated the JDRF mission.

For over 20 years, Dr. Colin Dayan has been a leader in T1D immunotherapy research, and his work has been central to JDRF’s research strategy and overall mission. He is leading efforts to bring teplizumab, the first disease-modifying therapy approved by the U.S. Food and Drug Administration that can delay clinical T1D in individuals in early stages, to Europe and the UK to expand treatment options available in these areas. He is a leading member of the JDRF-funded UK T1D Research Consortium, through which he has brought the research community together to accelerate critical research, leverage collective resources, and collaborate to improve T1D clinical trial delivery. Currently, Professor Dayan serves as chair of Clinical Diabetes and Metabolism and head of section at Cardiff University School of Medicine and as part-time senior clinical researcher in the Nuffield Department of Medicine at the University of Oxford.

Dr. Robert Goldstein Award

Named for Dr. Robert Goldstein, who played a key role in developing JDRF’s Research department and served as chief scientific officer for JDRF International and JDRF Canada for decades, this award recognizes early career T1D researchers who show great promise for future work in the field.

Dr. Kirstine Bell is a diabetes educator, dietitian, and the principal research fellow at the Charles Perkins Centre at the University of Sydney. She leads the Australian T1D National Screening Pilot, a national feasibility, acceptability, and cost-effectiveness program to determine the optimal method for routine, publicly funded national screening program for all Australian children. She has served in a critical role as a co-first author on the 2022 ISPAD Clinical Practice Consensus Guideline: Stages of T1D in children and adolescents.

Mary Tyler Moore and S. Robert Levine, M.D., Excellence in Clinical Research Award

This award was established in honor of the late actress, Mary Tyler Moore, who served as chairman of JDRF International from 1984 until her passing in 2017, and her husband, Dr. Levine, who remains committed to JDRF’s mission. The award recognizes leaders and innovators of outstanding clinical and translational T1D research.

Dr. Viral Shah is currently leading a JDRF-funded trial to examine the effects of semaglutide, a GLP-1 agonist, in people with T1D and hybrid closed-loop systems, and he recently published the first report on use of the GLP1-GIP agonist Mounjaro in T1D that demonstrated promising results. His research has also shown the association between time in range and retinopathy progression in T1D, which provides necessary evidence to support future therapy development.

Dr. Shah is a professor of medicine in endocrinology and metabolism and the director of diabetes clinical research at the Center for Diabetes and Metabolic Diseases at Indiana University whose research focuses on improving glycemic control and reducing complications in people with T1D.

JDRF Research award recipients were recognized at a ceremony in New York City earlier in April 2024.

JDRF recognizes and appreciates all of the dedicated researchers who are committed to finding cures and improving the lives of those living with T1D.

JDRF’s mission is to accelerate life-changing breakthroughs to cure, prevent and treat T1D and its complications. To accomplish this, JDRF has invested more than $2.5 billion in research funding since our inception. We are an organization built on a grassroots model of people connecting in their local communities, collaborating regionally and globally for efficiency and broader fundraising impact, and uniting on a global stage to pool resources, passion, and energy. We collaborate with academic institutions, policymakers, and corporate and industry partners to develop and deliver a pipeline of innovative therapies to people living with T1D. Our staff and volunteers throughout the United States and our five international affiliates are dedicated to advocacy, community engagement, and our vision of a world without T1D. For more information, please visit jdrf.org or follow us on Twitter (@JDRF), Facebook (@myjdrf), and Instagram (@jdrfhq).

About Type 1 Diabetes (T1D)

T1D is an autoimmune condition that causes the pancreas to make very little insulin or none at all. This leads to dependence on insulin therapy and the risk of short or long-term complications, which can include highs and lows in blood sugar; damage to the kidneys, eyes, nerves, and heart; and even death if left untreated. Globally, it impacts nearly 9 million people. Many believe T1D is only diagnosed in childhood and adolescence, but diagnosis in adulthood is common and accounts for nearly 50% of all T1D diagnoses. The onset of T1D has nothing to do with diet or lifestyle. While its causes are not yet entirely understood, scientists believe that both genetic factors and environmental triggers are involved. There is currently no cure for T1D.

Casey Fielder

[email protected]

509-651-0087

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IU endocrinologists receive esteemed JDRF awards for contributions to type 1 diabetes research

Jackie Maupin Apr 23, 2024

Linda DiMeglio, MPH, MD, and Viral Shah, MD

Jackie Maupin

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