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

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

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