Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering.

Published on Oct 1, 2021in The Lancet Diabetes & Endocrinology32.069
· DOI :10.1016/S2213-8587(21)00170-4
Nicole A.J. Krentz8
Estimated H-index: 8
(Stanford University),
Lonnie D. Shea83
Estimated H-index: 83
(UM: University of Michigan)
+ 1 AuthorsJames Shaw32
Estimated H-index: 32
(Newcastle University)
Sources
Abstract
Summary null null Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.
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References208
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Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet β cell loss and dysfunction resulting in insulin deficiency and hyperglycemia. During a presymptomatic phase of established β cell autoimmunity, β cell loss may first be evident through assessment of β cell secretory capacity, a measure of functional β cell mass. Reduction in pancreatic islet β cell reserve eventually manifests as impaired first-phase insulin response to glucose and abnormal glucose tolerance...
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OBJECTIVE We evaluated hybrid closed-loop glucose control with faster-acting insulin aspart (Fiasp) in adults with type 1 diabetes (T1D). We hypothesised that closed-loop with Fiasp provides similar efficacy as closed-loop with standard insulin aspart. RESEARCH DESIGN AND METHODS In a double-blind, multinational, randomised, crossover study, 25 adults with T1D using insulin pump therapy (mean ± SD, age 38 ± 9 years, HbA1c 7.4 ± 0.8% [57 ± 8 mmol/mol]) underwent two 8-week periods of unrestricted...
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Tremendous progress has been made over the last two decades in the field of pancreatic beta cell replacement therapy as a curative measure for diabetes. Transplantation studies have demonstrated therapeutic efficacy, and cGMP-grade cell products are currently being deployed for the first time in human clinical trials. In this perspective, we discuss current challenges surrounding the generation, delivery, and engraftment of stem cell-derived islet-like cells, along with strategies to induce dura...
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Inhibition of mitochondrial reactive oxygen species (ROS) and subsequent damage-associated molecular patterns (DAMPs)-induced inflammatory responses could be a novel target in clinical islet transplantation. We investigated the protective effects of NecroX-7, a novel clinical-grade necrosis inhibitor that specifically targets mitochondrial ROS, against primary islet graft failure. Islets from heterozygote human islet amyloid polypeptide transgenic (hIAPP+/- ) mice and nonhuman primates were isol...
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Summary Background Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. Methods This randomised, parallel-group, placebo-controlled, double-dummy, do...
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We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty...
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Islet transplantation is an emerging treatment for type 1 diabetes which offers the prospect of physiological control of blood glucose and reductions in acute hypoglycaemic episodes. However, current protocols are limited by a rapid decline in islet functional viability during the isolation process, culture period, and post-transplantation. Much of this can be attributed to the deleterious effects of hypoxic and cytokine stressors on β cells. One experimental strategy to improve the functional v...
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Background And Aims Destroying visceral sensory nerves impacts pancreatic islet function, glucose metabolism, and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied. Methods We characterized the anatomical pattern of pancreatic sensory innervation by combining viral tracing, immunohistochemistry, and reporter mouse models. To assess the functional interactions of β-cells with vagal sensory neurons, we recorded Ca2+ responses in individual nodose neur...
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AIMS/HYPOTHESIS Pancreatic beta cells are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce reactive oxygen species to protect against apoptosis. While impaired islet autophagy has been demonstrated in human type 2 diabetes, it is unknown if islet autophagy is perturbed in the pathogenesi...
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Summary null null The first insulin preparation capable of consistently lowering blood glucose was developed in 1921. But 100 years later, blood glucose control with insulin in people with diabetes is nearly universally suboptimal, with essentially the same molecule still delivered by the same inappropriate subcutaneous injection route. Bypassing this route with oral administration appears to have become technologically feasible, accelerating over the past 50 years, either with packaged insulin ...
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