Cellular and molecular mechanisms of metformin: an overview.

By B. Viollet, B. Guigas, Nieves Sanz Garcia, J. Leclerc, M. Foretz, F. Andreelli. Clinical science, 2012

1,680 citations recorded by the source corpus.

Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/f42fc25cd640e13e0233ac17c243919ab13acf4b

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Citations in the corpus

Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness (2018, background): “vating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway(54) or the mitochondrial respiratory chain.(55) The AMPK pathway acts as a central regulator of cellular energy”
Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status (2016, positive): “The key clinical hallmark of metformin’s antihyperglycemic action is suppression of hepatocyte gluconeogenesis.(4,5,9) The most likely cellular effect underlying this response is inhibition of mitochondrial enzymes, including complex I in the electron transport chain.”
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis (2014, positive): “Metformin suppresses liver gluconeogenesis thereby reducing glucose release from the liver (Inzucchi et al., 1998; Viollet et al., 2012).”
Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes (2012, background): “Metformin has been reported to decrease hepatic glucose production, thereby activating AMPK, reducing fatty liver, and decreasing microvascular and macrovascular complications associated with type 2 diabetes (40).”
Metformin promotes antitumor immunity via endoplasmic reticulum-associated degradation of PD-L1 (2018, positive): “In addition, metformin has been reported to exert antitumor effects, as several case-control studies of T2D patients showed that metformin treatment reduced the incidence of various cancer types (Evans et al., 2005; Viollet et al., 2012).”
Metformin: from mechanisms of action to therapies. (2014, background): “The resulting fall in cellular ATP concentration and an increase in both ADP/ATP and AMP/ATP ratios activates the AMP-activated protein kinase (AMPK), a critical energy sensor of cellular energy homeostasis that integrates multiple signaling networks to coordinate a wide array of compensatory, prote”