Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta cell. DMA also enhances time-dependent potentiation (TDP), and enables TDP to occur in situations where it is normally absent. As we demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus, both DMA and arginine have the potential to correct the secretory defect in diabetes through enabling or enhancing TDP. In the current study we demonstrate the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of nitric oxide synthase is not the only mechanism through which DMA exerts its positive effects. Thus, we have also explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase (KGDH).