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Islets are composed mostly of beta-cells, and therefore stem cell research has concentrated on generating purified beta-cells, neglecting the other endocrine cell types in the islet. We investigated the presence of endocrine non-beta-cells after islet transplantation. In addition, we studied whether the transplantation of pure beta-cells, in volumes similar to that used in islet transplantation, would suffice to reverse hyperglycemia in diabetic mice. Rat islets were dispersed and beta-cells were purified by fluorescence-activated cell sorting according to their endogenous fluorescence. After reaggregation, 600 islet equivalents of the purified beta-cell aggregates were implanted into diabetic SCID mice. In mice implanted with beta-cell-enriched aggregates, the hyperglycemia was reversed and good graft function over a 12-week period was observed with regard to glucose and insulin levels, glucose tolerance tests, and graft insulin content. The endocrine cell composition of the beta-cell-enriched aggregates remained constant; before and 12 weeks after transplantation, the beta-cell-enriched aggregates comprised 95% beta-cells and 5% endocrine non-beta-cells. However, islet grafts, despite originally having comprised 75% beta-cells and 25% endocrine non-beta-cells, comprised just 5% endocrine non-beta-cells after transplantation, indicating a loss of these cells. beta-Cell-enriched aggregates can effectively reverse hyperglycemia in mice, and transplanted intact islets are depleted in non-beta-cells. It is therefore likely that islet non-beta-cells are not essential for successful islet transplantation. [ABSTRACT FROM AUTHOR]

Stimulation of insulin secretion by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) has been found to be diminished in type 2 diabetes. We hypothesized that this impairment is due to a defect at the receptor level induced by the diabetic state, particularly hyperglycemia. Gene expression of incretin receptors, GLP-1R and GIPR, were significantly decreased in islets of 90% pancreatectomized (Px) hyperglycemic rats, with recovery when glucose levels were normalized by phlorizin. Perifused islets isolated from hyperglycemic Px rats showed reduced insulin responses to GLP-1 and GIP. To examine the acute effect of hyperglycemia on incretin receptor expression, a hyperglycemic clamp study was performed for 96 h with reduction of GLP-1 receptor expression but increase in GIP receptor expression. Similar findings were found when islets were cultured at high glucose concentrations for 48 h. The reduction of GLP-1 receptor expression by high glucose was prevented by dominant-negative protein kinase C (PKC)alpha overexpression, whereas GLP-1 receptor expression was reduced with wild-type PKCalpha overexpression. Taken together, GLP-1 and GIP receptor expression is decreased with chronic hyperglycemia, and this decrease likely contributes to the impaired incretin effects found in diabetes. [ABSTRACT FROM AUTHOR]

High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)beta inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and (13)C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium. [ABSTRACT FROM AUTHOR]

Background: Our goal was to convert adult mouse hepatocytes to pancreatic beta-cells.Methods and Results: To facilitate conversion, cultured primary hepatocytes were dedifferentiated by the removal of dexamethasone (Dex) from the culture media. Removal of Dex caused detachment of hepatocytes from the culture dish, but the addition of betacellulin prevented this from happening. With the combination of lack of Dex and addition of betacellulin, albumin mRNA levels decreased. Cultured hepatocytes had a faint expression of insulin 2 mRNA, Nkx 6.1 and Pax 6 mRNA. Dedifferentiated hepatocytes were transduced with adenoviruses expressing NeuroD1, Ngn 3, or Pax 4. NeuroD1 transduction increased the insulin 2 mRNA but caused detachment of cells. However, when hepatocytes were allowed to reaggregate for 4 and 6 days in hydrophobic plates after transduction with NeuroD1, further increases of insulin 2 mRNA were found along with induction of PDX-1, IAPP, NeuroD1, Ngn3, Pax 4, Isl-1, PC1, PC2 and islet glucokinase. Additionally, glucagon, pancreatic polypeptide and somatostatin expression were induced, but neither elastase 1 nor insulin 1 mRNA could be detected. Ngn 3 and Pax 4 had effects similar to NeuroD1, but did not increase insulin 2 mRNA as much as NeuroD1.Conclusion: We conclude that the combination of NeuroD1 and reaggregation promotes cultured dedifferentiated hepatocytes to differentiate towards a pancreatic beta-cell phenotype. [ABSTRACT FROM AUTHOR]

This article reports on the developemnt of new insulin delivery systems and blood glucose monitors, as well as on the latest research in islet-cell transplantation aimed at a cure for diabetes [ABSTRACT FROM AUTHOR]

Scientific endeavors may actually put an end to diabetes mellitus some day. Even better, prevention may also be possible. New techniques seek to preserve, assist, or allow replacement of ailing beta cells. [ABSTRACT FROM AUTHOR]

Long-term -- often lifelong -- care of patients with chronic disease is always a challenge. Measure what you do against our experts' clinical protocols for six common conditions. [ABSTRACT FROM AUTHOR]

Predicting and preventing diabetes are realistic goals for the 1990s. Meanwhile, advances in therapy will improve the life-style and prognosis of those who must live with the disease. [ABSTRACT FROM AUTHOR]

This article reports on the development of new insulin delivery systems and blood glucose monitors, as well as on the latest research in islet-cell transplantation aimed at a cure for diabetes. [ABSTRACT FROM AUTHOR]

Human islets can be transplanted into the portal vein for T1 diabetes, and a similar procedure is being used in a clinical trial for stem cell-derived beta-like cells. Efforts have been underway to find an alternative transplant site that will foster better islet cell survival and function. Although conceptually attractive, the subcutaneous (SC) site has yielded disappointing results, in spite of some improvements resulting from more attention paid to vascularization and differentiation factors, including collagen. We developed a method to transplant rat islets in a disk of type 1 collagen gel and found improved efficacy of these transplants. Survival of islets following transplantation (tx) was determined by comparing insulin content of the graft to that of the pre-transplant islets from the same isolation. At 14 days after transplantation, grafts of the disks had more than double the recovered insulin than islets transplanted in ungelled collagen. SC grafts of disks had similar insulin content to grafts in a kidney site and in epididymal fat pads. In vivo disks underwent contraction to 10% of initial volume within 24 h but the islets remained healthy and well distributed. Whole mount imaging showed that residual donor vascular cells within the islets expanded and connected to ingrowing host blood vessels. Islets (400 rat islet equivalents (IEQ)) in the collagen disks transplanted into an SC site of NOD scid IL2R gammanull (NSG) mice reversed streptozotocin (STZ)-induced diabetes within 10 days as effectively as transplants in the kidney site. Thus, a simple change of placing islets into a gel of collagen 1 prior to transplantation allowed a prompt reversal of STZ-induced diabetes using SC site., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In type 1 diabetes, the reduced glucagon response to insulin-induced hypoglycemia has been used to argue that β-cell secretion of insulin is required for the full glucagon counterregulatory response. For years, the concept has been that insulin from the β-cell core flows downstream to suppress glucagon secretion from the α-cells in the islet mantle. This core-mantle relationship has been supported by perfused pancreas studies that show marked increases in glucagon secretion when insulin was neutralized with antisera. Additional support comes from a growing number of studies focused on vascular anatomy and blood flow. However, in recent years this core-mantle view has generated less interest than the argument that optimal insulin secretion is due to paracrine release of glucagon from α-cells stimulating adjacent β-cells. This mechanism has been evaluated by knockout of β-cell receptors and impairment of α-cell function by inhibition of Gi designer receptors exclusively activated by designer drugs. Other studies that support this mechanism have been obtained by pharmacological blocking of glucagon-like peptide 1 receptor in humans. While glucagon has potent effects on β-cells, there are concerns with the suggested paracrine mechanism, since some of the supporting data are from isolated islets. The study of islets in static incubation or perifusion systems can be informative, but the normal paracrine relationships are disrupted by the isolation process. While this complicates interpretation of data, arguments supporting paracrine interactions between α-cells and β-cells have growing appeal. We discuss these conflicting views of the relationship between pancreatic α-cells and β-cells and seek to understand how communication depends on blood flow and/or paracrine mechanisms., (© 2023 by the American Diabetes Association.)

As diabetes continues to grow as major health problem, there has been great progress in understanding the important role of pancreatic beta-cells in its pathogenesis. Diabetes develops when the normal interplay between insulin secretion and the insulin sensitivity of target tissues is disrupted. With type 2 diabetes (T2D), glucose levels start to rise when beta-cells are unable to meet the demands of insulin resistance. For type 1 diabetes (T1D) glucose levels rise as beta-cells are killed off by autoimmunity. In both cases the increased glucose levels have a toxic effect on beta-cells. This process, called glucose toxicity, has a major inhibitory effect on insulin secretion. This beta-cell dysfunction can be reversed by therapies that reduce glucose levels. Thus, it is becoming increasingly apparent that an opportunity exists to produce a complete or partial remission for T2D, both of which will provide health benefit., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Weir and Bonner-Weir.)

Biomedical devices comprise a major component of modern medicine, however immune-mediated fibrosis and rejection can limit their function over time. Here, we describe a humanized mouse model that recapitulates fibrosis following biomaterial implantation. Cellular and cytokine responses to multiple biomaterials were evaluated across different implant sites. Human innate immune macrophages were verified as essential to biomaterial rejection in this model and were capable of cross-talk with mouse fibroblasts for collagen matrix deposition. Cytokine and cytokine receptor array analysis confirmed core signaling in the fibrotic cascade. Foreign body giant cell formation, often unobserved in mice, was also prominent. Last, high-resolution microscopy coupled with multiplexed antibody capture digital profiling analysis supplied spatial resolution of rejection responses. This model enables the study of human immune cell-mediated fibrosis and interactions with implanted biomaterials and devices.

β cells in the hyperglycemic environment of diabetes have marked changes in phenotype and function that are largely reversible if glucose levels can be returned to normal. A leading hypothesis is that these changes are caused by the elevated glucose levels leading to the concept of glucose toxicity. Support for the glucose toxicity hypothesis is largely circumstantial, but little progress has been made in defining the responsible mechanisms. Then questions emerge that are difficult to answer. In the very earliest stages of diabetes development, there is a dramatic loss of glucose-induced first-phase insulin release (FPIR) with only trivial elevations of blood glucose levels. A related question is how impaired insulin action on target tissues such as liver, muscle and fat can cause increased insulin secretion. The existence of a sophisticated feedback mechanism between insulin secretion and insulin action on peripheral tissues driven by glucose has been postulated, but it has been difficult to measure increases in blood glucose levels that might have been expected. These complexities force us to challenge the simplicity of the glucose toxicity hypothesis and feedback mechanisms. It may turn out that glucose is somehow driving all of these changes, but we must develop new questions and experimental approaches to test the hypothesis., Competing Interests: Declaration of competing interest All of the authors contributed to the writing of this manuscript and none of the authors have any conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

During progression to both types 1 and 2 diabetes (T1D, T2D), there is a striking loss of glucose-induced first-phase insulin release (FPIR), which is known to predict the onset of T1D. The contribution of reduced β cell mass to the onset of hyperglycemia remains unclear. In this issue of the JCI, Mezza et al. report on their study of patients with pancreatic neoplasms before and after partial pancreatectomy to evaluate the impact of reduced β cell mass on the development of diabetes. The authors found that reduced FPIR predicted diabetes when 50% of the pancreas was removed. These findings suggest that low or absent FPIR indicates that β cell mass can no longer compensate for increased insulin needs. Notably, clinicians may use reduction of FPIR as a warning that progression to T2D is underway.

There are strong reasons to say that pancreatic islets are organs before they are isolated and that they should be considered to be organs once transplanted. Thus, taking into account how much we have learned about the structure and function of islet micro-organs, it seems highly illogical to on one hand consider autologous islets be regulated as organ transplants and alloislets to be regulated with the very restrictive rules used for cell transplantation. It is particularly problematic that this policy has led to restrictions that have made it next to impossible for transplants of alloislets to be carried out in the US, which is a very sad situation for the country that made so many of the advances that brought islet transplantation to the clinic., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest to disclose.

The long-term function of transplanted therapeutic cells typically requires systemic immune suppression. Here, we show that a retrievable implant comprising a silicone reservoir and a porous polymeric membrane protects human cells encapsulated in it after implant transplantation in the intraperitoneal space of immunocompetent mice. Membranes with pores 1 µm in diameter allowed host macrophages to migrate into the device without the loss of transplanted cells, whereas membranes with pore sizes <0.8 µm prevented their infiltration by immune cells. A synthetic polymer coating prevented fibrosis and was necessary for the long-term function of the device. For >130 days, the device supported human cells engineered to secrete erythropoietin in immunocompetent mice, as well as transgenic human cells carrying an inducible gene circuit for the on-demand secretion of erythropoietin. Pancreatic islets from rats encapsulated in the device and implanted in diabetic mice restored normoglycaemia in the mice for over 75 days. The biocompatible device provides a retrievable solution for the transplantation of engineered cells in the absence of immunosuppression.

Objective: As diabetes develops, marked reductions of insulin secretion are associated with very modest elevations of glucose. We wondered if these glucose changes disrupt beta cell differentiation enough to account for the altered function., Methods: Rats were subjected to 90% partial pancreatectomies and those with only mild glucose elevations 4 weeks or 10 weeks after surgery had major alterations of gene expression in their islets as determined by RNAseq., Results: Changes associated with glucose toxicity demonstrated that many of the critical genes responsible for insulin secretion were downregulated while the expression of normally suppressed genes increased. Also, there were marked changes in genes associated with replication, aging, senescence, stress, inflammation, and increased expression of genes controlling both class I and II MHC antigens., Conclusions: These findings suggest that mild glucose elevations in the early stages of diabetes lead to phenotypic changes that adversely affect beta cell function, growth, and vulnerability., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

For patients with type 1 diabetes, it is accepted among the scientific community that there is a marked reduction in β-cell mass; however, with type 2 diabetes, there is disagreement as to whether this reduction in mass occurs in every case. Some have argued that β-cell mass in some patients with type 2 diabetes is normal and that the cause of the hyperglycaemia in these patients is a functional abnormality of insulin secretion. In this Personal View, we argue that a deficient β-cell mass is essential for the development of type 2 diabetes. The main point is that there are enormous (≥10 fold) variations in insulin sensitivity and insulin secretion in the general population, with a very close correlation between these two factors for any individual. Although β-cell mass cannot be accurately measured in living patients, it is highly likely that it too is highly correlated with insulin sensitivity and secretion. Thus, our argument is that a person with type 2 diabetes can have a β-cell mass that is the same as a person without type 2 diabetes, but because they are insulin resistant, the mass is inadequate and responsible for their diabetes. Because the abnormal insulin secretion of diabetes is caused by dysglycaemia and can be largely reversed with glycaemic control, it is a less serious problem than the reduction in β-cell mass, which is far more difficult to restore., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Reduction of β-cell mass and function is central to the pathogenesis of type 2 diabetes. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity are used to describe potentially responsible processes. The premise is that chronically elevated glucose levels are toxic to β-cells, that elevated lipid levels in the form of circulating free fatty acids (FFA) also have toxic effects, and that the combination of the two, glucolipotoxicity, is particularly harmful. Much work has shown that high concentrations of FFA can be very damaging to β-cells when used for in vitro experiments, and when infused in large amounts in humans and rodents they produce suppression of insulin secretion. The purpose of this Perspective is to raise doubts about whether the FFA levels found in real-life situations are ever high enough to cause problems. Evidence supporting the importance of glucotoxicity is strong because there is such a tight correlation between defective insulin secretion and rising glucose levels. However, there is virtually no convincing evidence that the alterations in FFA levels occurring during progression to diabetes are pathogenic. Thus, the terms lipotoxicity and glucolipotoxicity should be used with great caution, if at all, because evidence supporting their importance has not yet emerged., (© 2019 by the American Diabetes Association.)

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites-subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type-I diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in diabetic rodent models; yet human patients transplanted with equivalent microsphere formulations have experienced only transient islet-graft function, owing to a vigorous foreign-body reaction (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing, in non-human primate (NHP) models, of seven alginate formulations that were efficacious in rodents, including three that led to transient islet-graft function in clinical trials. Although one month post-implantation all formulations elicited significant FBR and PFO, three chemically modified, immune-modulating alginate formulations elicited reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.

The in vivo microenvironment of tissues provides myriad unique signals to cells. Thus, following isolation, many cell types change in culture, often preserving some but not all of their in vivo characteristics in culture. At least some of the in vivo microenvironment may be mimicked by providing specific cues to cultured cells. Here, we show that after isolation and during maintenance in culture, adherent rat islets reduce expression of key β-cell transcription factors necessary for β-cell function and that soluble pancreatic decellularized matrix (DCM) can enhance β-cell gene expression. Following chromatographic fractionation of pancreatic DCM, we performed proteomics to identify soluble factors that can maintain β-cell stability and function. We identified Apolipoprotein E (ApoE) as an extracellular protein that significantly increased the expression of key β-cell genes. The ApoE effect on beta cells was mediated at least in part through the JAK/STAT signaling pathway. Together, these results reveal a role for ApoE as an extracellular factor that can maintain the mature β-cell gene expression profile., Competing Interests: The authors have declared that no competing interests exist.

Objective: To determine the safety and pharmacokinetics of alpha-1 antitrypsin (AAT) in adults and children., Research Design and Methods: Short-term AAT treatment restores euglycemia in the non-obese mouse model of type 1 diabetes. A phase I multicenter study in 16 subjects with new-onset type 1 diabetes studied the safety and pharmacokinetics of Aralast NP (AAT). This open-label, dose-escalation study enrolled 8 adults aged 16 to 35 years and 8 children aged 8 to 15 years within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for 6 weeks, followed by a higher dose of 90 mg/kg for 6 weeks., Results: C-peptide secretion during a mixed meal, hemoglobin A1c (HbA1c), and insulin usage remained relatively stable during the treatment period. At 72 hours after infusion of 90 mg/kg, mean levels of AAT fell below 2.0 g/L for 7 of 15 subjects. To identify a plasma level of AAT likely to be therapeutic, pharmacodynamic ex vivo assays were performed on fresh whole blood from adult subjects. Polymerase chain reaction (PCR) analyses were performed on inhibitor of IKBKE, NOD1, TLR1, and TRAD gene expression, which are important for activation of nuclear factor-κB (NF-κB) and apoptosis pathways. AAT suppressed expression dose-dependently; 50% inhibition was achieved in the 2.5 to 5.0 mg/mL range., Conclusions: AAT was well tolerated and safe in subjects with new-onset type 1 diabetes. Weekly doses of AAT greater than 90 mg/kg may be necessary for an optimal therapeutic effect., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: There is considerable interest in using macroencapsulation devices as a delivery strategy for transplanting insulin-producing cells. This review aims to summarize recent advances, to highlight remaining challenges, and to provide recommendations for the field., Recent Findings: A variety of new device designs have been reported to improve biocompatibility and to provide protection for islet/beta cells from immune destruction while allowing continuous secretion of insulin. Some of these new approaches are in clinical trials, but more research is needed to determine how sufficient beta-cell mass can be transplanted in a clinically applicable device size, and that insulin is secreted with kinetics that will safely provide adequate controls of glucose levels. Macroencapsulation is a potential solution to transplant beta cells without immunosuppression in diabetes patients, but new strategies must be developed to show that this approach is feasible.

Transplantation of encapsulated islets can cure diabetes without immunosuppression, but oxygen supply limitations can cause failure. We investigated a retrievable macroencapsulation device wherein islets are encapsulated in a planar alginate slab and supplied with exogenous oxygen from a replenishable gas chamber. Translation to clinically-useful devices entails reduction of device size by increasing islet surface density, which requires increased gas chamber pO 2. Here we show that islet surface density can be substantially increased safely by increasing gas chamber pO 2 to a supraphysiological level that maintains all islets viable and functional. These levels were determined from measurements of pO 2 profiles in islet-alginate slabs. Encapsulated islets implanted with surface density as high as 4,800 islet equivalents/cm 3 in diabetic rats maintained normoglycemia for more than 7 months and provided near-normal intravenous glucose tolerance tests. Nearly 90% of the original viable tissue was recovered after device explantation. Damaged islets failed after progressively shorter times. The required values of gas chamber pO 2 were predictable from a mathematical model of oxygen consumption and diffusion in the device. These results demonstrate feasibility of developing retrievable macroencapsulated devices small enough for clinical use and provide a firm basis for design of devices for testing in large animals and humans.

We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β cells at different stages of their life cycle with different functional capacities and that further changes occur with metabolic stress and aging. We identified new markers of aging in β cells, including IGF1R. In β cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16 ink4a , p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of β cells. These novel findings about β cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Isolated islets used for transplantation are known to be stressed, which can result from the circumstances of death, in particular brain death, the preservation of the pancreas with its warm and cold ischemia, from the trauma of the isolation process, and the complex events that occur during tissue culture. The current study focused upon the events that occur before the islet isolation procedure. Pancreases were obtained from brain dead donors (n = 7) with mean age 50 (11) and normal pancreatic tissue obtained at surgery done for pancreatic neoplasms (n = 7), mean age 69 (9). Frozen sections were subjected to laser capture microdissection (LCM) to obtain β-cell rich islet tissue, from which extracted RNA was analyzed with microarrays. Gene expression of the 2 groups was evaluated with differential expression analysis for genes and pathways. Marked changes were found in pathways concerned with endoplasmic reticulum stress with its unfolded protein response (UPR), apoptotic pathways and components of inflammation. In addition, there were changes in genes important for islet cell identity. These findings advance our understanding of why islets are stressed before transplantation, which may lead to strategies to reduce this stress and lead to better clinical outcomes.

This commentary explores the hypothesis that when autoimmunity leads to a fall of beta cell mass during the progression of type 1 diabetes (T1D), rising glucose levels cause major changes in beta cell identity. This then leads to profound changes in secretory function and less well-understood changes in beta cell susceptibility to autoimmune destruction, which may influence of rate of progression of beta cell killing.

GABA and the antimalarial drug artemether, which acts on GABAergic pathways, can drive pancreatic cells with an α-cell phenotype toward a β-cell-like phenotype. As reported in two papers (Ben-Othman et al. and Li et al.), these drugs can stimulate the production of sufficient numbers of new β-like cells to reverse severe diabetes in mice., (Copyright © 2017. Published by Elsevier Inc.)

Objective: Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states., Research Design and Methods: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT)., Results: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations., Conclusions: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use., (© 2016 by the American Diabetes Association.)

Injectable hydrogels have been widely used for a number of biomedical applications. Here, we report a new strategy to form an injectable and glucose-responsive hydrogel using the boronic acid-glucose complexation. The ratio of boronic acid and glucose functional groups is critical for hydrogel formation. In our system, polymers with 10-60% boronic acid, with the balance being glucose-modified, are favorable to form hydrogels. These hydrogels are shear-thinning and self-healing, recovering from shear-induced flow to a gel state within seconds. More importantly, these polymers displayed glucose-responsive release of an encapsulated model drug. The hydrogel reported here is an injectable and glucose-responsive hydrogel constructed from the complexation of boronic acid and glucose within a single component polymeric material., Competing Interests: Notes The authors declare no competing financial interest.

The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.

After birth the endocrine pancreas continues its development, a complex process that involves both the maturation of islet cells and a marked expansion of their numbers. New beta cells are formed both by duplication of pre-existing cells and by new differentiation (neogenesis) across the first postnatal weeks, with the result of beta cells of different stages of maturation even after weaning. Improving our understanding of this period of beta cell expansion could provide valuable therapeutic insights.