Metformin enhances glucagon-like peptide 1 via cooperation between insulin and Wnt signaling.
One aspect of the effects of metformin on glucagon-like peptide (GLP)-1 might be associated with the mechanism by which the cross talk between insulin and Wnt signaling enhances GLP1 secretion, due to the action of metformin as an insulin sensitizer. However, this remains completely unknown. In this study, we have investigated the mechanisms of the action of metformin on cross talk between insulin and Wnt signaling. GLP1 enhancement by meformin was determined in human NCI-H716 intestinal L-cells and hyperglycemic db/db mice treated with metformin (0.25 and 0.5 mM and/or 12.5 mg/kg body weight) for 24 h and 2 months. Metformin increased GLP1 secretion in L-cells and db/db mice. Metformin stimulated the nuclear translocation of β-catenin and TOPflash reporter activity, and gene depletion of β-catenin or enhancement of mutation of transcription factor 7-like 2 binding site offset GLP1. In addition, insulin receptor substrate 2 gene depletion blocked metformin-enhanced β-catenin translocation. These effects were preceded by an increase in glucose utilization and calcium influx, the activation of calcium-dependent protein kinase, and, in turn, the activation of insulin signaling, and the inhibition of glycogen synthase kinase 3β, a potent inhibitor of β-catenin. Furthermore, high blood glucose levels were controlled via GLP1 receptor-dependent insulinotropic pathways in db/db mice, which were evidenced by the increase in GLP1 and insulin levels at 30 min after oral glucose loading and pancreatic insulinotropic gene expression. Our findings indicate that the cooperation between Wnt and its upstream insulin signaling pathways might be a novel and important mechanism underlying the effects of metformin on GLP1 production.
Division of Endocrinology and Metabolism, Samsung Biomedical Research Institute, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea Division of Endocrinology and Metabolism, Department of Medicine Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.
Mi-Hyun
MH
Kim
Jae-Hwan
JH
Jee
Sunyoung
S
Park
Myung-Shik
MS
Lee
Kwang-Won
KW
Kim
Moon-Kyu
MK
Lee
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004357:Drug Synergism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology
D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D005947:Glucose; D002118:Calcium
GLP1; Wnt signaling; insulin signaling; metformin