Introduction and Objective: Tumor necrosis factor (TNF)-alpha signaling is associated with obesity and insulin resistance, although its role in beta-cell function has not been addressed. The TNFRSF1A gene encodes the tumor necrosis factor receptor 1 (TNFR1;p55), which is bound by the cytokine TNF-alpha. Signaling through this pathway activates the NF-κB pathway and overactive inflammatory pathway signaling is associated with reduced insulin secretion. TNFR1 is expressed in pancreatic beta-cells although its role to regulate islet inflammation and glucose homeostasis in vivo is unclear. With plasma TNF-alpha concentration elevated in obesity and with advancing age, we tested the hypothesis that islet beta-cell TNFR1 negatively regulated glucose homeostasis.Methods: A beta-cell specific TNFRSF1A-deficient (TNFRSF1A Ins1-/-) mouse model was generated on a C57Bl/6 background by crossing Ins1-Cre mice with TNFRSF1A floxed mice. Glucose (GTT) and insulin tolerance tests (ITT) were used to examine metabolic status of all cohorts of mice. Islet β-cell transcription factor abundance was analyzed in isolated pancreatic islets.Results: Islet beta-cell deletion of TNFRSF1A improved glucose tolerance measured by GTT (p < 0.05) without altering body weight in both male and female mice (n = 8-13). This phenotype occurred during aging and in response to a high-fat diet. There were no detectable alterations in insulin sensitivity assessed by ITT between TNFRIns1-/- mice and littermate controls.Conclusion: This novel mouse model with beta-cell deletion of TNFRSF1A reveals an important (patho)physiological role for pancreatic islet beta-cell TNFR1 to regulate whole body glucose homeostasis.
H. Batdorf: None. T. Martin: None. S. Burke: None. J. Collier: None.
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