Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
Open Access
- 27 August 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 24 (9), 1395-1406
- https://doi.org/10.1038/s41591-018-0159-7
Abstract
Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5′-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet–fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.This publication has 89 references indexed in Scilit:
- Molecular mechanism of action of metformin: old or new insights?Diabetologia, 2013
- Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liverJournal of Lipid Research, 2012
- Measuring Deuterium Enrichment of Glucose Hydrogen Atoms by Gas Chromatography/Mass SpectrometryAnalytical Chemistry, 2011
- Metformin Activates AMP Kinase through Inhibition of AMP DeaminaseOnline Journal of Public Health Informatics, 2011
- Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy stateJCI Insight, 2010
- Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK ActivationCell Metabolism, 2010
- Role of KLF15 in Regulation of Hepatic Gluconeogenesis and Metformin ActionDiabetes, 2010
- Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 DiabetesProceedings of the National Academy of Sciences of the United States of America, 2009
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001