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Diabetes. 2015 Apr;64(4):1262-72. doi: 10.2337/db14-0576. Epub 2014 Oct 14.

Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion.

Author information

1
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
2
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
3
Department of Physiology, Keimyung University School of Medicine, Dalseo-Gu, Daegu, Korea.
4
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.
5
Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan seino@med.kobe-u.ac.jp.

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.

PMID:
25315008
DOI:
10.2337/db14-0576
[Indexed for MEDLINE]
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