Metformin, Glucotoxicity And Islet Dysfunction
Abstract
METFROMIN, GLUCOTOXICITY AND ISLET DYSFUNCTION by SARTAJ BAIDWAN MAY 2017 Advisor: Dr. Anjaneyulu Kowluru Major: Pharmaceutical Sciences Degree: Master of Science Glucotoxicity is the leading cause for β-cell dysfunction [e.g., defective glucose-stimulated insulin secretion] in Type 2 Diabetes [T2DM]. Recent studies from our lab have shown sustained Rac1 activation leading to the activation of downstream signaling steps including stress kinase [p53, p38MAPK] activation and mitochondrial dysregulation [caspase-3 activation] in pancreatic islet beta-cells exposed to glucotoxic [HG] conditions [20 mM; 24 hrs]. Metformin [MF] is an oral anti-diabetic drug that is being widely prescribed to T2DM. MF works by suppressing hepatic glucose production and increasing glucose uptake by the target tissues. However, potential beneficial effects of MF on pancreatic beta-cell dysfunction under HG conditions have not been studied to date. Therefore, in the current studies, we asked if MF [0-30 μM; clinically relevant concentrations] affords protective effects against HG-induced metabolic dysfunction of the pancreatic beta [INS-1 832/13] cells. Since recent studies from our laboratory have demonstrated activation of Rac1, a small G-protein, as an upstream signaling event to stress kinase activation, we asked if protective effects of MF may, in part, be due to inhibition of HG-induced Rac1 activation in INS-1 832/13 cells. Data from these studies have suggested nearly 40% inhibition in…
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