Sirt1 Activation Attenuates Alpha Cell Hyperplasia, Hyperglucagonaemia And Hyperglycaemia In Stz-Diabetic Mice

The NAD(+)-dependent lysine deacetylase, Sirtuin 1 (SIRT1), plays a central role in metabolic regulation. With type 1 diabetes a disease that is characterised by metabolic dysregulation, we sought to assess the impact of SIRT1 activation in experimental, streptozotocin (STZ)-induced diabetes. CD1 mice with and without STZ-induced diabetes were randomized to receive the SIRT1 activating compound, SRT3025, or vehicle over 20 weeks. Vehicle treated STZ-CD1 mice developed severe hyperglycaemia with near-absent circulating insulin and widespread beta cell loss in association with hyperglucagonaemia and expanded islet alpha cell mass. Without affecting beta-cell mass or circulating insulin, diabetic mice that received SRT3025 had substantially improved glycaemic control with greatly reduced islet alpha cell mass and lower plasma glucagon concentrations. Consistent with reduced glucagon abundance, the diabetes-associated overexpression of key gluconeogenic enzymes, glucose-6-phosphatase and PEPCK were also lowered by SRT3025. Incubating cultured a cells with SRT3025 diminished their glucagon secretion and proliferative activity in association with a reduction in the alpha cell associated transcription factor, Aristaless Related Homeobox (Arx). By reducing the paradoxical increase in glucagon, SIRT1 activation may offer a new, alpha-cell centric approach to the treatment of type 1 diabetes.