Cellular and molecular mechanisms of metformin: an overview

Abstract

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.

Figures

Figure 1. The mitochondrial respiratory-chain complex 1 is the primary target of metformin

Due to its high acid dissociation constant (pKa=12.4) metformin exists in a positively charged protonated form under physiological conditions and, as a result, can only marginally cross the plasma membrane by passive diffusion. Thus, its intracellular transport is mediated by different isoforms of the organic cation transporters (OCT) depending of the tissue considered (e.g. OCT1 in liver or OCT2 in kidney). Once inside the cytosolic compartment, mitochondria then constitute the primary target of metformin. The positive charge of metformin was proposed to account for its accumulation within the matrix of energized mitochondria, driven by the membrane potential (Δϕ), whereas the apolar hydrocarbon side-chain of the drug could also promote binding to hydrophobic structures, especially the phospholipids of mitochondrial membranes [31]. Although the exact mechanism(s) by which metformin acts at the molecular level remains unknown, it has been shown that the drug inhibits mitochondrial respiratory-chain specifically at the complex 1 level without affecting any other steps of the mitochondrial machinery. This unique property of the drug induces a decrease in NADH oxidation, proton pumping across the inner mitochondrial membrane and oxygen consumption rate, leading to lowering of the proton gradient (Δϕ) and ultimately to a reduction in proton-driven synthesis of ATP from ADP and inorganic phosphate (Pi).

Figure 2. Potential molecular mechanisms of metformin action on hepatic gluconeogenesis

After hepatic uptake through OCT1, the mitochondria is the primary target of metformin which exerts specific and AMPK-independent inhibition of respiratory-chain complex 1. The resultant mild decrease in energy status leads to acute and transient inhibition of energy-consuming gluconeogenic pathway. In addition, through AMPK-dependent and -independent regulatory points, metformin can lead to the inhibition of glucose production by disrupting gluconeogenesis gene expression. In parallel, the LKB1-dependent activation of AMPK triggered by ATP depletion could reduce hepatic lipogenesis and exert an indirect effect on hepatic insulin sensitivity to control hepatic glucose output.

Figure 3. Control of cell proliferation and tumor growth by metformin

The anti-neoplastic action of metformin appears to be exerted by several pathways. Metformin inhibits the growth of cancer cells by the reversal of hyperglycemia, insulin resistance and hyperinsulinemia, resulting in reduced levels of glucose, insulin and IGFs and activation of growth signaling pathways through their respective receptors. The anti-tumor effects of metformin seems regulated by both AMPK-dependent or -independent mechanisms leading to the inhibition of mTOR signaling, cell cycle by decrease of cyclin D1 level, stimulation of p53/p21 axis, fatty acid synthesis, angiogenesis and inflammation. Adapted from [104] and reproduced from [163].