title: Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion.
abstract: Incretin-related drugs and sulfonylureas are currently used worldwide for the treatment of type 2 diabetes. We recently found that Epac2A, a cAMP binding protein having guanine nucleotide exchange activity toward Rap, is a target of both incretin and sulfonylurea. This suggests the possibility of interplay between incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion. In this study, we examined the combinatorial effects of incretin and various sulfonylureas on insulin secretion and activation of Epac2A/Rap1 signaling. A strong augmentation of insulin secretion by combination of GLP-1 and glibenclamide or glimepiride, which was found in Epac2A(+/+) mice, was markedly reduced in Epac2A(-/-) mice. In contrast, the combinatorial effect of GLP-1 and gliclazide was rather mild, and the effect was not altered by Epac2A ablation. Activation of Rap1 was enhanced by the combination of an Epac-selective cAMP analog with glibenclamide or glimepiride but not gliclazide. In diet-induced obese mice, ablation of Epac2A reduced the insulin secretory response to coadministration of the GLP-1 receptor agonist liraglutide and glimepiride. These findings clarify the critical role of Epac2A/Rap1 signaling in the augmenting effect of incretin and sulfonylurea on insulin secretion and provide the basis for the effects of combination therapies of incretin-related drugs and sulfonylureas.
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Shibasaki
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Dalseo-Gu, Daegu, Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Shihomi
authors.initials: S
authors.lastname: Hidaka
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Ono
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, Dalseo-Gu, Daegu, Korea.
authors.forename: Dae-Kyu
authors.initials: DK
authors.lastname: Song
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan seino@med.kobe-u.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D054795:Incretins / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D054795:Incretins; D007328:Insulin; C486707:Rapgef4 protein, mouse; D013453:Sulfonylurea Compounds; D052216:Glucagon-Like Peptide 1; D020827:rap1 GTP-Binding Proteins; D002118:Calcium