Metformin Modulates GLP-1- and GIP-Mediated Intracellular Signaling under Normoglycemic Conditions

Kyoko Shinmura, Takaharu Negoro, Shunichi Shimizu, Giovanna Roncador, Tsutomu Hirano, Yasuko Nakano

Department of Pathophysiology, Showa University School of Pharmacy, Tokyo, Japan.
Department of Pharmacogenomics, Showa University School of Pharmacy, Tokyo, Japan.
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Monoclonal Antibodies Unit, Biotechnology Program, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain.

DOI: 10.4236/ojemd.2013.37036                

Abstract

GLP-1 and GIP promote insulin secretion from pancreatic β-cells by inducing intracellular signals such as Ca²⁺ and cAMP. Metformin primarily acts by inhibiting glucogenesis in the liver and promoting glucose metabolism in the muscle. It is used as a concomitant drug with the incretin in the treatment of T2D. We focused on intracellular signals under various glucose concentrations and assessed the effects of metformin on incretin signaling in MIN6 β-cells. Metformin inhibited incretin-induced [Ca²⁺]_i in the presence of 5.5 mM glucose but not 16.7 mM glucose. In accordance with low [Ca²⁺]_i, insulin secretion from MIN6 cells declined, despite enhanced incretin-induced cAMP production. Abundant expressions of Adcy 6 and 9, which are negatively controlled by Ca²⁺ signals, were detected in MIN6 cells. Thus, increasing cAMP production was associated with the inhibition of Ca²⁺ mobilization by metformin. However, we show that metformin controls insulin secretion by inhibiting incretin-mediated [Ca²⁺]_i under normoglycemic conditions.

Keywords

Metformin; GLP-1; GIP; Calcium; cAMP; Insulin Secretion

Conflicts of Interest

The authors declare no conflicts of interest.

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