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has been cited by the following article:

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

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

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

  JOURNAL NAME: Open Journal of Endocrine and Metabolic Diseases, Vol.3 No.7, November 18, 2013

  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.