Glucagon-like peptide 1 stimulates insulin secretion via inhibiting RhoA/ROCK signaling and disassembling glucotoxicity-induced stress fibers

Endocrinology. 2014 Dec;155(12):4676-85. doi: 10.1210/en.2014-1314. Epub 2014 Sep 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytochalasin B
  • Female
  • Glucagon-Like Peptide 1 / physiology*
  • Glucose / toxicity*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology*
  • Mice, Inbred C57BL
  • Rats
  • Signal Transduction
  • Stress Fibers / metabolism*
  • Thiazolidines
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism


  • Actins
  • Bridged Bicyclo Compounds, Heterocyclic
  • Insulin
  • Thiazolidines
  • Cytochalasin B
  • Glucagon-Like Peptide 1
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • rhoA GTP-Binding Protein
  • Glucose
  • latrunculin B