title: Glucagon-like peptide 1 stimulates insulin secretion via inhibiting RhoA/ROCK signaling and disassembling glucotoxicity-induced stress fibers.
abstract: Chronic hyperglycemia leads to pancreatic β-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic β-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared with β-cells cultured at a low glucose level. β-Cells at high glucose were refractory to glucose-induced actin cytoskeleton remodeling and insulin secretion. Importantly, F-actin depolymerization by either cytochalasin B or latrunculin B restored glucotoxicity-diminished GSIS. The effects of glucotoxicity on increasing stress fibers and reducing GSIS were reversed by Y-27632, a Rho-associated kinase (ROCK)-specific inhibitor, which caused actin depolymerization and enhanced GSIS. Notably, glucagon-like peptide-1-(7-36) amide (GLP-1), a peptide hormone that stimulates GSIS at both normal and hyperglycemic conditions, also reversed glucotoxicity-induced increase of stress fibers and reduction of GSIS. In addition, GLP-1 inhibited glucotoxicity-induced activation of RhoA/ROCK and thereby resulted in actin depolymerization and potentiation of GSIS. Furthermore, this effect of GLP-1 was mimicked by cAMP-increasing agents forskolin and 3-isobutyl-1-methylxanthine as well as the protein kinase A agonist 6-Bnz-cAMP-AM whereas it was abolished by the protein kinase A inhibitor Rp-Adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt. To establish a clinical relevance of our findings, we examined the association of genetic variants of RhoA/ROCK with metabolic traits in homeostasis model assessment index of insulin resistance. Several single-nucleotide polymorphisms in and around RHOA were associated with elevated fasting insulin and homeostasis model assessment index of insulin resistance, suggesting a possible role in metabolic dysregulation. Collectively these findings unravel a novel mechanism whereby GLP-1 potentiates glucotoxicity-diminished GSIS by depolymerizing F-actin cytoskeleton via protein kinase A-mediated inhibition of the RhoA-ROCK signaling pathway.
authors.affiliation: Shenzhen University Diabetes Center (X.K., D.Y., X.W., X.H., X.M.) and Shenzhen University, Shenzhen 518060, People's Republic of China; Lund University Diabetes Centre (J.S., H.M.), Unit of Molecular Metabolism, SE-205 02 Malmö, Sweden; and University of Pennsylvania Perelman School of Medicine (X.H.), Philadelphia, Pennsylvania 19104.
authors.forename: Xiangchen
authors.initials: X
authors.lastname: Kong
authors.forename: Dan
authors.initials: D
authors.lastname: Yan
authors.forename: Jiangming
authors.initials: J
authors.lastname: Sun
authors.forename: Xuerui
authors.initials: X
authors.lastname: Wu
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003571:Cytochalasin B; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D005947:Glucose / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D051381:Rats; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism*; D053778:Thiazolidines; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007328:Insulin; D053778:Thiazolidines; D003571:Cytochalasin B; D052216:Glucagon-Like Peptide 1; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein; D005947:Glucose; C037068:latrunculin B