Exercise activates AMPK in mouse pancreatic islet leading to decreased senescence

Increased beta-cell senescence contributes to the development of type 2 diabetes (T2D). Exercise is critical in the treatment of T2D and can attenuate aging-associated cellular changes, but its effects on beta-cell senescence are unknown. Using two mouse models of insulin resistance, we showed that exercise prevented and reversed beta-cell senescence. Mechanistic studies revealed that these effects were mediated by exercise-induced increases in serum glucagon leading to AMPK activation in beta-cells. Nuclear translocation of NRF2 in mouse islets after exercise and its inversely proportional regulation of p16Ink4a, suggested its role as a molecular mediator between AMPK activation and cellular senescence. C57Bl/6 retired breeder male mice were subjected to a structured running protocol of a single-bout/day of acute treadmill running protocol. After a 3-day acclimatization protocol, animals were trained for 1 hour/day, 5 times per week, for 2 weeks, at 17 cm/s and 5 degree incline. Under anesthesia, mice were injected with collagenase into the pancreatic duct before pancreatectomy. After digestion and centrifugation, islets were hand-picked under a microscope and plated in a petri dish with islet media. Islet media was composed of RPMI medium (11 mM glucose), 10% FBS and 1% Penicillin-Streptomycin. Islets from trained and sedentary C57Bl6 mice were isolated for RNA sequencing.