title: Glucagon-like peptide 1 potentiates glucotoxicity-diminished insulin secretion via stimulation of cAMP-PKA signaling in INS-1E cells and mouse islets.
abstract: Glucagon-like peptide-1 (GLP-1)-enhanced insulin secretion is mainly mediated by cAMP-PKA and cAMP-Epac2 signaling pathways at physiological glucose concentrations. However the cellular mechanisms underlying the insulinotropic action of GLP-1 at glucotoxicity remain largely unknown. In the present study, we examined the effects of GLP-1 on glucotoxicity-diminished insulin secretion and explored the roles of these two cAMP-linked pathways in mediating the effects of GLP-1 under glucotoxic conditions. Consistent with the previous reports, exposure of INS-1E cells and mouse islets to 30 mM glucose for 72 h almost abolished glucose-stimulated insulin secretion. Addition of 10nM GLP-1 significantly increased glucose-stimulated insulin secretion. This was not due to a protective effect of GLP-1 against glucotoxicity-induced apoptosis but instead improvement of the secretory capacity of the insulin-secreting β-cells. It is of note that GLP-1 preferentially increased the expression and activity of PKA, whereas had no effects on Epac2 at high glucose. In correlation with the observations, treatment of INS-1E cells with the specific PKA inhibitor Rp-cAMPS completely abolished the insulinotropic action of GLP-1, whereas knock-down of Epac2 did not interfere the effects of GLP-1. Moreover, GLP-1 did not increase further insulin secretion in the presence of the PKA agonist 6-Bnz-cAMP-AM. By contrast, it produced additional enhancement of insulin secretion when Epac2 was maximally stimulated by its selective agonist 8-pCPT-2'-O-Me-cAMP-AM. Taken together, our results suggest that GLP-1 potentiates glucotoxicity-diminished insulin secretion mainly through cAMP-PKA signaling pathway.
authors.affiliation: Shenzhen University Diabetes Centre, Shenzhen 518060, PR China.
authors.forename: Guochun
authors.initials: G
authors.lastname: Luo
authors.forename: Xiangchen
authors.initials: X
authors.lastname: Kong
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D015290:Second Messenger Systems
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C486707:Rapgef4 protein, mouse; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose