title: GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells from glucolipotoxicity.
abstract: Type 2 diabetes, often associated with obesity, results from a deficiency of insulin production and action manifested in increased blood levels of glucose and lipids that further promote insulin resistance and impair insulin secretion. Glucolipotoxicity caused by elevated plasma glucose and lipid levels is a major cause of impaired glucose-stimulated insulin secretion from pancreatic β-cells, due to increased oxidative stress, and insulin resistance. Glucagon-like peptide-1 (GLP1), an insulinotropic glucoincretin hormone, is known to promote β-cell survival via its actions on its G-protein-coupled receptor on β-cells. Here, we report that a nonapeptide, GLP1(28-36)amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 β-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor. The nonapeptide appears to enter preferably stressed, glucolipotoxic cells compared with normal unstressed cells. It targets mitochondria and improves impaired mitochondrial membrane potential, increases cellular ATP levels, inhibits cytochrome c release, caspase activation, and apoptosis, and enhances the viability and survival of INS-1 β-cells. We propose that GLP1(28-36)amide might be useful in alleviating β-cell stress and might improve β-cell functions and survival.
authors.affiliation: Laboratory of Molecular Endocrinology, Their 306, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Zhengu
authors.initials: Z
authors.lastname: Liu
authors.forename: Violeta
authors.initials: V
authors.lastname: Stanojevic
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Brindamour
authors.forename: Joel F
authors.initials: JF
authors.lastname: Habener
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000627:therapeutic use*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000633:toxicity; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019301:Oleic Acid / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000633:toxicity
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C560057:glucagon-like peptide-1(28-36)amide; D019301:Oleic Acid; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D000077270:Exenatide; D006861:Hydrogen Peroxide; D005947:Glucose