Prevention of Post-Transplant Diabetes Mellitus: Towards a Personalized Approach

Post-transplant diabetes is a frequent complication after transplantation. Moreover, patients suffering from post-transplant diabetes have increased cardiovascular morbidity and reduced survival. Pathogenesis mainly involves beta-cell dysfunction in presence of insulin resistance. Both pre- and post-transplant risk factors are well-described, and some of them may be corrected or prevented. However, the frequency of post-transplant diabetes has not decreased in recent years. We realized a critical appraisal of preventive measures to reduce post-transplant diabetes.

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

Aims/hypothesis Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. Conclusions/interpretation Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes. Graphical abstract

Pancreas Pathology in Type 1 Diabetes: An evolving Story

We review the current knowledge of pancreas pathology in type 1 diabetes. During the last two decades dedicated efforts towards the recovery of pancreas from deceased patients with type 1 diabetes have promoted significant advances in the characterization of the pathological changes associated with this condition. The implementation autoantibody screening among organ donors has also allowed examining pancreas pathology in the absence of clinical disease, but in the presence of serological markers of autoimmunity. The assessment of key features of pancreas pathology across various disease stages allows driving parallels with clinical disease stages. The main pathological abnormalities observed in the pancreas with type 1 diabetes are beta cell loss, insulitis, and more recently hyperexpression of HLA class I and class II molecules have been reproduced and validated. Additionally, there are changes affecting extracellular matrix components, evidence of viral infections, inflammation, and ER stress, which could contribute to beta cell dysfunction and the stimulation of apoptosis and autoimmunity. The increasing appreciation that beta cell loss can be less severe at diagnosis than previously estimated, the coexistence of beta cell dysfunction, and the persistence of key features of pancreas pathology for years after diagnosis impact the perception of the dynamics of this chronic process. The emerging information is helping identifying novel therapeutic targets and have implications for the design of clinical trials.

Modulation of Autophagy Signal Pathway in Type 2 Diabetes Mellitus Rat Model Using Phytochemical Extracts

Background Type 2 DM is a chronic metabolic disease characterized by insulin resistance and beta cell dysfunction. It is an extremely heterogeneous disease in which the insulin resistance and beta cell dysfunction resulted from environmental and genetic factor. Type 2 diabetes is the most prevalent form of diabetes worldwide and account for 90% of cases globally. It represents a major public health threat and considered as a principal cause of morbidity and mortality affecting almost 6% of the world’s population. Patients with type 2 diabetes usually have insulin resistance and relative insulin deficiency and are often associated with a strong genetic predisposition. Objective To retrieve potential miRNA-associated ceRNAs Linked to autophagy, insulin resistance and type 2 DM from Public microarray databases followed by validation of the chosen network in animal model. To evaluate the efficacy of Isorhamentin as a potential therapeutic strategy to modulate the autophagy pathway and IR in type 2 DM. Patients and Methods This study was done at Medical Biochemistry Department, Faculty of Medicine, Ain Shams University during the period from December 2019 – June 2020 and included 50 wistar male rats. 50 Male Wistar rats weighed (140-150g), age nearly two months, were purchased from the Holding Company for Biological Products and Vaccines. They were acclimatized to laboratory environment for at least one week with free access to water and food before induction of diabetes. Experiment for eight weeks duration was planned after a pilot study was performed for determination of the most effective and least toxic STZ dose. Results Our study demonstrated that “Isorhamentin” can be potential treatment in type 2 diabetes mellitus through modulation of Autophagy signaling pathway related genes and ceRNA network. Isorhamentin down-regulates the expression of m-tor mRNA and it up-regulates the expression of miR-1. Conclusion The results of our study Support our previous hypothesis that miR-1 miRNA and mTOR mRNA act as ceRNA network and might play an important role in the pathogenesis of autophagy and insulin resistance and T2DM.And could be potential therapeutic target by isorhamentin to modulate the expression of the deregulated network in type 2 DM.

Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.

Visceral Fat Accumulation Is Related to Impaired Pancreatic Blood Perfusion and Beta-Cell Dysfunction in Obese Women

<b><i>Aims/Hypothesis:</i></b> Beta-cell failure plays a fundamental role in type 2 diabetes mellitus (T2DM) development. It has been shown that the beta-cells are among the most sensitive to hypoxia. We aimed to analyze whether decrease in pancreatic perfusion relates to 1/decline in beta-cell function and 2/visceral fat accumulation in patients with T2DM. <b><i>Methods:</i></b> Fifteen women with T2DM on metformin therapy alone and fifteen women of comparable age and BMI without prediabetes/diabetes were cross-sectionally examined: clinical and anthropometric examination, fast sampled intravenous glucose tolerance test (FSIVGTT), dynamic contrast-enhanced magnetic resonance imaging to assess pancreatic perfusion (area under the curve of postcontrast saturation, AUC_TSIC), and visceral adiposity (VAT, calculated from transverse sections at the level L2–L5 vertebrae). <b><i>Results:</i></b> Pancreatic blood perfusion (AUC_TSIC) did not differ between groups (<i>p</i> = 0.273), but it negatively correlated with BMI (<i>r</i> = −0.434, <i>p</i> = 0.017), WHR (<i>r</i> = −0.411, <i>p</i> = 0.024), and VAT (<i>r</i> = −0.436, <i>p</i> = 0.016) in both groups. Moreover, AUC_TSIC in the head of the pancreas negatively correlated with the level of fasting glycemia (<i>r</i> = −0.401, <i>p</i> = 0.028) and HOMA-IR (<i>r</i> = −0.376, <i>p</i> = 0.041). <b><i>Discussion/Conclusion:</i></b> We showed that decreased pancreatic perfusion did not relate to beta-cell dysfunction in early stages of T2DM development, but it was related to VAT, insulin resistance, and higher fasting glycemia. Furthermore, lower pancreatic perfusion was related to VAT, insulin resistance, and higher fasting glycemia.

The pathophysiology of glucose intolerance in newly diagnosed, untreated T2DM

Aims The two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays. Materials and methods A total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis. Results The MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function. Conclusion This study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution.