2101-LB: Restoring ß-Cell Mass and Identity in KATP-Induced Neonatal Diabetes—The Synergy of Autophagy and Intermittent Fasting

Pancreatic β-cell dysfunction is central to diabetes pathogenesis. Autophagy, which degrades damaged organelles and proteins, has emerged as a key player in β-cell function, but its role in preserving β-cell mass and identity remains poorly understood. Here, we investigated the interplay between autophagy and β-cell identity in the tamoxifen-inducible KATP gain-of-function (GOF) mouse model of neonatal diabetes. As expected due to the expression of overactive channels, non-obese KATP-GOF mice developed severe diabetes due to a lack of insulin secretion. As diabetes progressed, they showed increased β-cell endoplasmic reticulum (ER) stress and a decline in β-cell mass and identity, accompanied by dysregulated autophagy with impaired autophagic flux and autophagosome accumulation. KATP-GOF mice showed altered liver architecture with hepatocytes containing lipid droplets, but no changes in liver autophagy markers were observed. Strikingly, KATP-GOF mice exposed to alternate-day intermittent fasting (IF) showed improved glycemic control and glucose tolerance, mitigation of β-cell ER stress and mitochondrial abnormalities, and restored β-cell mass and identity. IF KATP-GOF mice demonstrated normalization of β-cell autophagic flux and reduction of autophagosome accumulation, accompanied by restored liver architecture and enhanced expression of genes involved in gluconeogenesis and lipolysis. These studies demonstrate, for the first time, impaired autophagy in non-obese KATP-induced diabetes and suggest that IF preserved β-cell identity via improved autophagy in the absence of body-weight loss or insulin secretion, implying similar mechanisms occurring in different forms of diabetes. These findings not only increase our understanding of the mechanisms underlying β-cell demise in diabetes but also offer insights into therapeutic strategies aimed at preserving functional β-cell mass.