{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:34:48Z","timestamp":1790426088646,"version":"4.1.0"},"reference-count":33,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:p>Chronic hyperglycemia leads to pancreatic \u03b2-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic \u03b2-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared with \u03b2-cells cultured at a low glucose level. \u03b2-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\u201336) 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\u2032,5\u2032-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.<\/jats:p>","DOI":"10.1210\/en.2014-1314","type":"journal-article","created":{"date-parts":[[2014,9,22]],"date-time":"2014-09-22T17:46:40Z","timestamp":1411408000000},"page":"4676-4685","source":"Crossref","is-referenced-by-count":34,"title":["Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA\/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers"],"prefix":"10.1210","volume":"155","author":[{"given":"Xiangchen","family":"Kong","sequence":"first","affiliation":[{"name":"Shenzhen University Diabetes Center (X.K., D.Y., X.W., X.H., X.M.) and Shenzhen University, Shenzhen 518060, People\u2019s Republic of 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