Molecular mechanism of action of metformin: old or new insights?

Graham Rena, Ewan R Pearson, Kei Sakamoto, Graham Rena, Ewan R Pearson, Kei Sakamoto

Abstract

Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin's molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.

Figures

Fig. 1
Fig. 1
(a, b) Schematic diagram of the anti-hyperglycaemic action of metformin on the liver cell. Part (b) shows a simplified version of (a). Metformin is transported into hepatocytes mainly via OCT1, resulting in an inhibition of the mitochondrial respiratory chain (complex I) through a currently unknown mechanism(s). The resulting deficit in energy production is balanced by reducing the consumption of energy in the cell, particularly reduced gluconeogenesis in the liver. This is mediated in two main ways. First, a decrease in ATP and a concomitant increase in AMP concentration occur, which is thought to contribute to the inhibition of gluconeogenesis directly (because of the energy/ATP deficit). Second, increased AMP levels function as a key signalling mediator that has been proposed to (1) allosterically inhibit cAMP–PKA signalling through suppression of adenylate cyclase, (2) allosterically inhibit FBPase, a key gluconeogenic enzyme, and (3) activates AMPK. This leads to inhibition of gluconeogenesis (1 and 2) and lipid/cholesterol synthesis (3), which may contribute to the longer term metabolic and therapeutic responses to the drug. FBPase; fructose-1,6-bisphosphatase

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