Antihyperglycemic Mechanism of Metformin Occurs Via the AMPK/LXRα/POMC Pathway

Overview

Journal Sci Rep

Specialty Science

Date 2015 Jan 31

PMID 25634597

Citations 40

Authors

Kumsun Cho

Jae Yong Chung

Sung Kweon Cho

Hyun-Woo Shin

In-Jin Jang

Jong-Wan Park

Kyung-Sang Yu

Joo-Youn Cho

Affiliations

Soon will be listed here.

Abstract

Metformin is a first-line drug for treating type 2 diabetes. Although metformin is known to phosphorylate AMP-activated protein kinase (AMPK), it is unclear how the glucose-lowering effect of metformin is related to AMPK activation. The aim of this study was to identify the urinary endogenous metabolites affected by metformin and to identify the novel underlying molecular mechanisms related to its anti-diabetic effect. Fourteen healthy male subjects were orally administered metformin (1000 mg) once. First morning urine samples were taken before and after administration to obtain metabolomic data. We then further investigated the anti-diabetic mechanism of metformin in vitro and in vivo. The fluctuation of the metabolite cortisol indicated that the neuroendocrine system was involved in the anti-diabetic effect of metformin. Actually we found that metformin induced AMPK/liver X receptor α (LXRα) phosphorylation, followed by pro-opiomelanocortin (POMC) suppression in rat pituitary cells. We confirmed this result by administering metformin in an animal study. Given that cortisol stimulates gluconeogenesis, we propose the anti-hyperglycemic effect of metformin is attributed to reduced POMC/adrenocorticotropic hormone (ACTH)/cortisol levels following AMPK/LXRα phosphorylation in the pituitaries.

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