Activation of Melatonin Signaling Promotes β-Cell Survival and Function

Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of beta-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of beta-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced beta-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on beta-cell function. MT signaling in beta-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced beta-cell apoptosis evidenced by reduced caspase-3 cleavage (similar to 40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (similar to 50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that beta-cell MT signaling is important for the regulation of beta-cell survival and function and implies a preventative and therapeutic potential for preservation of beta-cell mass and function in T2DM.