A hallmark of type 2 diabetes is decreased insulin secretion and a loss of functional beta-cells, leading to dysregulation of blood glucose control. The elevated average blood glucose concentrations consequently exert harmful effects on the insulin secreting beta-cells, so called glucotoxicity. Since beta-cell mitochondria play a central role in the coupling of glucose metabolism to insulin secretion, their dysfunction has been implicated in the defective hormone release in type 2-diabetes. A key regulator of mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), a multi-functional protein located on the outer mitochondrial membrane (OMM) mediating the fluxes of nucleotides and metabolites across the OMM. Changes in the VDAC1 or VDAC2 function have been related to impaired mitochondrial metabolism and apoptosis. The present project aims to identify the mechanisms underlying pancreatic beta-cell dysfunction during episodes of glucotoxicity and to dissect the complex signaling network involved in hyperglycemia-induced beta-cell dysfunction in human islets and also in relevant animal models of type 2 diabetes.