Pancreatic {beta}-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises {beta}-cell identity is largely unknown. We show that under reversible, chronic ER stress, {beta}-cells undergo a distinct transcriptional and translational reprogramming. During reprogramming, expression of master regulators of {beta}-cell function and identity and proinsulin processing is impaired. Upon recovery from stress, {beta}-cells regain their identity, highlighting a high-degree of adaptive {beta}-cell plasticity. Remarkably, when stress episodes exceed a certain threshold, {beta}-cell identity is gradually lost. Single cell RNA-seq analysis of islets from type 1 diabetes (T1D) patients, identifies the severe deregulation of the chronic stress-adaptation program, and reveals novel biomarkers for progression of T1D. Our results suggest {beta}-cell adaptive exhaustion ({beta}EAR) is a significant component of the pathogenesis of T1D.

https://biorxiv.org/content/10.1101/2021.05.24.445193v1.full.pdf

Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Theacute effects ofcontraction andinsulin ontheglucose transport andGLUT4glucose transporter translocation wereinvestigated inratsoleus muscles byusing a3-O-methylglucose transport assay andthesensitive exofa- ciallabeling technique withtheimpermeant photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethy l)benzoyl-1,3-bis(D- mannose-4-yloxy)-2-propylamine (ATB-BMPA), respectively. Addition ofwortmannin, whichinhibits phosphatidylinositol 3-kinase, reduced insulin-stimulated

Contraction stimulates translocation ofglucose transporter GLUT4inskeletal musclethrough a mechanismdistinct fromthatofinsulin

The insulin resistance of diet-induced obesity (DIO) is accompanied by inflammation. Previous studies suggest that the anti-inflammatory effects of infliximab, an anti-TNFα chimeric monoclonal antibody, decreases DIO-associated inflammation in mice fed a 60% fat diet. The effectiveness of infliximab at 10 mg/kg Infliximab (IF10) and 100 mg/kg infliximab (IF100) in C57Bl/6J DIO mice was studied in comparison to C57Bl/6J DIO mice administered chimeric IgG (IgG; 10 mg/kg). Treatment consisted of IP injections of infliximab or IgG once per week for 4 weeks. Body weight and fasting arterial glucose was not different in IF10, IF100, and IgG. IF10 and IF100 mice had a decreased presence of crown-like structures in white adipose tissue compared to IgG treated mice. Infliximab resulted in a dose-dependent reduction in macrophage F4/80 staining in white adipose tissue (4.3±0.7% and 1.8±0.2% in IF10 and IF100, respectively) compared to 8.1±1.6% in IgG, validating the anti-inflammatory effect. Insulin action was measured in mice with arterial and venous catheters using the hyperinsulinemic, euglycemic clamp method (insulin dose of 4 mU/kg/min) combined with [3-3H]glucose in conscious, unstressed mice. Glucose infusion rates (GIR) in IgG mice were higher (25±3 mg/kg/min) as compared to IF10 (17±2 mg/kg/min) and IF100 (19±2 mg/kg/min). The greater GIR in IgG as compared to IF10 was due to changes in hepatic endogenous glucose production (suppression of 12±3 mg/kg/min and 5±1 mg/kg/min, respectively) without a difference in glucose utilization. IF100 exhibited small reductions in both hepatic and peripheral insulin action, neither of which reached significance. Mice treated with saline alone were used as an additional control, but neither IF10 nor IF100 had significant effects on insulin action compared to saline controls. In summary, despite profound anti-inflammatory effects of the anti-TNFα drug, Infliximab causes a paradoxically greater hepatic insulin resistance. Disclosure D.A. Roby: None. C. Guan: None. F. James: None. D. Bracy: None. L. Lantier: None. D. Wasserman: None.

1749-P: The TNFa Inhibitor Infliximab Decreases Inflammation in High-Fat Fed Mice but Does Not Alleviate Insulin Resistance

Skeletal Muscle Insulin Resistance in Obesity and Type 2 Diabetes: Studies With Dynamic Interactions Among Glucose Delivery, Transport, and Phosphorylation That Underlie

effects of exercise and acute insulin infusion Gut and liver fat metabolism in depancreatized dogs

The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. However, acute effect was absent in mice fed a high fat (HF) diet for 13 weeks. In contrast, mice fed a HF diet for 13 weeks and continuously treated with relaxin for the final 3 weeks of the diet exhibit decreased fasting glucose. Insulin-stimulated whole-body glucose disappearance and percent suppression of hepatic glucose production are corrected by chronic relaxin. The increase in peripheral glucose utilization is a result of augmented in vivo skeletal muscle glucose uptake. Relaxin intervention improves endothelial-dependent vascular reactivity and induces a 2-fold proliferation in skeletal muscle capillarity. The metabolic effects of the treatment are not attributed to changes in myocellular insulin signaling. Relaxin intervention reverses the accumulation of collagen-III in the liver and collagen-III and -IV in the heart induced by high fat-feeding. These studies show the potential of relaxin in the treatment of diet-induced insulin resistance and vascular dysfunction. Relaxin provides a novel therapeutic approach targeting the extramyocellular barriers to insulin action, which are critical to the pathogenesis of insulin resistance. Page 2 of 35 Diabetes

Relaxin Treatment Reverses Insulin Resistance in High Fat-Fed Mice Running title: Relaxin Reverses Insulin Resistance

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1749-P: The TNFa Inhibitor Infliximab Decreases Inflammation in High-Fat Fed Mice but Does Not Alleviate Insulin Resistance

Skeletal Muscle Insulin Resistance in Obesity and Type 2 Diabetes: Studies With Dynamic Interactions Among Glucose Delivery, Transport, and Phosphorylation That Underlie

effects of exercise and acute insulin infusion Gut and liver fat metabolism in depancreatized dogs

Relaxin Treatment Reverses Insulin Resistance in High Fat-Fed Mice Running title: Relaxin Reverses Insulin Resistance