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.