318-OR: Intermittent Fasting Improves ß-cell Function in Nonobese KATP-Induced Neonatal Diabetes through Reduction of Cellular Stress and Enhanced Autophagy

Abstract

Diabetes progression is characterized by loss of functional β-cell mass. Non-obese KATP-GOF mouse models of human neonatal diabetes developed severe diabetes due to lack of insulin secretion; with a marked loss of β-cell mass/identity and dedifferentiation as diabetes progresses. Intermittent fasting (IF) reduces body weight, improves diabetes and autophagy in humans and obese mice, but the mechanisms underlying this in lean individuals remains elusive. Upon diabetes development, non-obese KATP-GOF mice were divided in two groups: i) fed chow diet ad libitum (AL) , ii) subjected to IF (24h fast/24hr feed cycles) . IF-KATP-GOF mice showed reduced blood glucose without changes in body weight or lean-fat mass compared to AL-KATP-GOF mice. The markedly reduced insulin and increased proinsulin levels in islets from AL-KATP-GOF mice were restored to normal levels in IF-KATP-GOF islets. IF-KATP-GOF islets showed reduced ATF6 and sXBP1 message levels and decreased sXBP1 and TXNIP protein levels compared to AL-KATP-GOF islets, suggesting reduced oxidative and ER stress. Strikingly, the markedly increased autophagy markers LC3II and P62 in AL-KATP-GOF islets were reduced to control levels in IF-KATP-GOF, suggesting improved autophagy. Electron microscopy confirmed increased insulin granules, reduced mitochondrial and ER damage, and decreased autophagosome accumulation in IF-KATP-GOF. While liver G6PC and PCK1 (gluconeogenesis) , FAS (lypogenesis/lipolysis) , and CPT1 and ATGL (β-oxidation/lipolysis) messages were increased, CRCT2 and FOXO1 (gluconeogenesis) , GCK (glycolysis) and PPARα (β-oxidation) were decreased. PPARγ and PPARα were decreased in brown adipose tissue. In conclusion, our studies in KATP-GOF mice indicate the beneficial effects of IF not only on improving functional β-cell mass through decreasing oxidative and ER stress and enhancing autophagy, but also improving liver and adipose tissue function. Disclosure E.Castelblanco: None. Z.A.Shyr: None. Z.Yan: None. A.Diwan: Consultant; Biomedical systems (ERT) , Dewpoint Therapeutics. M.S.Remedi: None. Funding National Institutes of Health (GDK123163)