Metformin: what cellular target?
Metformin, discovered in the 1920s appeared on the market in 1957. It belongs to one of the major families of products acting on insulin resistance in patients suffering from type 2 diabetes.
The target of its action is the mitochondrion1, more specifically complex 1, the entry point of NADH reduction which allows preservation of the proton gradient required for ATP production at the level of the mitochondrial membrane. However, the molecular target of metformin within complex 1 remains unknown.
Metformin is considered to have as a dominant cell action the activation of AMP kinase (AMPK) to which the inhibition of hepatic neoglucogenesis by metformin is attributed. Finally, metformin acts selectively on the liver; a transport protein from the Organic Cation Transporter (OCT), family,OCT1, being in control of the entry of metformin into hepatocytes.2,3
A work that has just been published in J Clin Invest4 questions the role of AMPK in the action of metformin on hepatic neoglucogenesis. Metformin continues to block hepatic glucose production.2 This is observed in the presence and absence of catalytic AMPK subunits in mouse hepatocyte primary cultures at concentrations comparable to those obtained under treatment in humans. It is a fast effect, noticeable as soon as the 4th hour. The inhibition of hepatic production takes place irrespective of the presence or absence of glucose in AMPK-deficient hepatocytes, the absence of phosphorylation of CRTC2, central mediator of neoglucogenesis in the liver, and without modification of the levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase, conversely strongly altered in the absence of LKB1. These data indicate that the basal regulation of CRTC2 phosphorylation is dependent on LKB1, but independent of AMPK. CRTC2 phosphorylation is abolished in the absence of AMPK or LKB1, but without abolishing the action of metformin, both on glucose production and on the inhibition of glucose-6-phosphatase. Comparable results were obtained in vivo; metformin improved insulin sensitivity both in deficient and control mice. Furthermore, the deficient mice are normoglycemic, respond normally to glucose, and have blood insulin levels comparable to those of control mice, indicating a normal insulin sensitivity.
The effect of metformin in deficient mice thus seems independent of the effect of AMPK and CRTC2 phosphorylation observed in control mice. In this model, it is independent of the genes controlling neoglucogenesis, suggesting more an inhibitor effect on neoglucogenic fluxes than an effect on neoglucogenesis transcription genes.5
C. Boitard – France
1- El-Mir MY et al. J Clin Biochem. 2001;275:223.
2- Wang DS et al. J Pharmacol Exp Ther. 2002;302:510.
3- Shu Y et al. J Clin Invest. 2007;117:1422.
4- Foretz M et al. J Clin Invest. 2010,120:2355.
5- Miller RA et Bimbaum J. J Clin Invest.2010;120:2267.
Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.
Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B.
J Clin Invest. 2010 Jul 1;120(7):2355-69. doi: 10.1172/JCI40671. Epub 2010 Jun 23.