Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions

Abstract

Type 2 diabetes (T2D) is a very prevalent, multisystemic, chronic metabolic disorder closely related to atherosclerosis and cardiovascular diseases. It is characterised by mitochondrial dysfunction and the presence of oxidative stress. Metformin is one of the safest and most effective anti-hyperglycaemic agents currently employed as first-line oral therapy for T2D. It has demonstrated additional beneficial effects, unrelated to its hypoglycaemic action, on weight loss and several diseases, such as cancer, cardiovascular disorders and metabolic diseases, including thyroid diseases. Despite the vast clinical experience gained over several decades of use, the mechanism of action of metformin is still not fully understood. This review provides an overview of the existing literature concerning the beneficial mitochondrial and vascular effects of metformin, which it exerts by diminishing oxidative stress and reducing leukocyte-endothelium interactions. Specifically, we describe the molecular mechanisms involved in metformin's effect on gluconeogenesis, its capacity to interfere with major metabolic pathways (AMPK and mTORC1), its action on mitochondria and its antioxidant effects. We also discuss potential targets for therapeutic intervention based on these molecular actions.

Keywords: Atherosclerosis; Metformin; Mitochondria; Oxidative stress; Pathophysiology; Treatment; Type 2 diabetes.

Fig. 1

Pathophysiological mechanisms of Type 2 Diabetes Mellitus (T2D). The onset of T2D and its complications can lead to an imbalance in cellular homeostasis such as enhanced oxidative stress levels due to an increase in ROS production and a decrease in levels of antioxidant defenses. This can promote ER stress, which activates the UPR (unfolded protein response) on the one hand and can increase autophagy on the other hand. CVD, cardiovascular disease; ER, endoplasmic reticulum; ROS, reactive oxygen species.

Fig. 2

Molecular mechanisms of the mitochondrial action of metformin. Metformin exerts mild, transient and specific inhibition of complex I (NADH:ubiquinone oxidoreductase) of the respiratory chain, which leads to a change in both AMP/ATP ratio and NAD^+/NADH ratio, effects that lead to downregulation of gluconeogenesis. Metformin also acts as a non-competitive inhibitor of mitochondrial glycerol 3-phosphate dehydrogenase (mGPD), and this inhibition of the glycerol-phosphate shuttle can result in impaired respiration, a reduced cytoplasmic NAD⁺/NADH ratio and undermined glucose production through gluconeogenesis. AMPK, AMP-activated protein kinase; NAMPT, nicotinamide phosphoribosyltransferase.

Fig. 3

Beneficial effects of metformin on cardiovascular system. Metformin inhibits lipogenesis by downregulation of sterol regulatory element-binding protein (SREBP) expression and activity; it confers protection from lipoapoptosis by alleviating ER stress; it ameliorates cardiovascular system function by preventing abnormal vascular smooth muscle cell (VSMCs) proliferation and migration and by increasing AMPK signalling and nitric oxide (NO) production in endothelial vascular cells. Metformin ameliorates tissue insulin sensitivity, which leads to a decrease in glucose serum levels and inhibits NF-κB pathway signalling, thus diminishing inflammation; it prevents the conversion of monocytes into macrophages; it increases ATP cassette transporter type 1 (ABCA-1) activity, promoting the export of cholesterol from lipid-rich macrophages and ameliorating high-density lipoprotein cholesterol (HDL-c) function, thus reducing leukocyte-endothelium interactions and atherosclerotic risk.