3115-LB: Reversal Therapy for Diet-Induced Diabetes Linked to Insulin Biosynthesis

Introduction and Objective: Predisposition to proinsulin misfolding increases susceptibility to diet-induced diabetes by impairing insulin biosynthesis and exacerbating β-cell endoplasmic reticulum (ER) stress. We investigated whether intermittent Alternate-Day Feeding of a high-fat diet (ADF-HFD) could reverse obesity-induced diabetes in Ins2-proinsulin-R(B22)E heterozygous mice compared with equivalent caloric reduction achieved by ad libitum normal chow (NC). Methods: Male Ins2-proinsulin-R(B22)E mice fed 60% high-fat diet (HFD) for 6 weeks induced weight gain and diabetes. Diabetic mice were then treated (5 weeks) with ADF-HFD or NC. Calorie consumption, body weight, energy expenditure, insulin sensitivity, glucose tolerance, circulating hormones, islet insulin content, GSIS, ultrastructure, β-cell maturity markers, and phospho-eIF2α were evaluated. Results: Both cohorts consumed the same total calories, maintained the same energy expenditure, body weight, insulin sensitivity by insulin-tolerance-test, average islet size, and β-cell cytosolic calcium response to increased extracellular glucose. However, only ADF-HFD reversed diabetes, accompanied by decreased islet phospho-eIF2α, increased islet proinsulin synthesis, increased islet insulin content, glucose-stimulated insulin release, and circulating insulin — restoring glycemic control. Nutrient (and blood glucose) fluctuations on fasting versus feeding day reduces insulin secretory demand and promotes islet recovery. Conclusion: In addition to the reported beneficial β-cell circadian transcriptomic effects, intermittent fasting enhances islet insulin production with diminished β-cell stress and enhanced β-cell maturity, with increased islet insulin storage. These findings support intermittent fasting paradigms as a potential strategy to alleviate β-cell stress and restore glycemic control in type 2 diabetes. Disclosure M. Alam: None. A. Arunagiri: None. L. Haataja: None. C. Liu: None. M. Torres: None. E.S. Mastroianni: None. J. Monickaraj: None. L. Satin: None. P. Arvan: None. Funding 141038-Sub of F078201-MNORC P/F grant (Primary sponsor-Health and Human Services, Department of-National Institutes of Health)