Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History
Open Access
- 5 March 2021
- journal article
- review article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 22 (5), 2596
- https://doi.org/10.3390/ijms22052596
Abstract
While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.This publication has 109 references indexed in Scilit:
- Vildagliptin preserves the mass and function of pancreatic β cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetesDiabetes, Obesity and Metabolism, 2012
- Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysisPLOS ONE, 2012
- The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetesDiabetologia, 2011
- Regulation of MafA Expression in Pancreatic β-Cells in db/db Mice With DiabetesDiabetes, 2010
- Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4Diabetes, 2010
- Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell functionHuman Molecular Genetics, 2009
- Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell ProliferationOnline Journal of Public Health Informatics, 2008
- MAFA controls genes implicated in insulin biosynthesis and secretionDiabetologia, 2006
- Overweight, obesity and cancer: epidemiological evidence and proposed mechanismsNature Reviews Cancer, 2004
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001