title: Activation of Melatonin Signaling Promotes β-Cell Survival and Function.
abstract: Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-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 β-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 β-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 β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼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 β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.
authors.affiliation: Department of Medicine (S.C., M.B., A.P.T., A.V.M.), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095; and Department of Physiology and Biomedical Engineering (A.V.M.), Mayo Clinic School of Medicine, Mayo Clinic Rochester, Minnesota 55905.
authors.forename: Safia
authors.initials: S
authors.lastname: Costes
authors.forename: Marti
authors.initials: M
authors.lastname: Boss
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Thomas
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Matveyenko
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008550:Melatonin / Q000502:physiology*; D051381:Rats; D044094:Receptors, Melatonin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D044094:Receptors, Melatonin; D008550:Melatonin