New Insight into the Mechanisms of the Anti-hyperglycemic Action of Metformin

Abstract

Although metformin is currently one of the most frequently prescribed drugs for the treatment of type 2 diabetes, the precise mechanism of its molecular action is not fully understood. Metformin induces mild and transient inhibition of mitochondrial respiratory-chain complex I activity, resulting in the activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of hepatic gluconeogenesis. However, recent studies provide evidence that several AMPK-independent pathways may be involved in the action of metformin. The aim of this review is to summarize novel findings on the mechanisms of the anti-hyperglycemic action of metformin, with a special attention paid to AMPK-independent pathways. The results of recent studies with gut-restricted delayed-release metformin formulation demonstrating dissociation of its glucose-lowering effect from plasma exposure are also discussed. The role of the gastrointestinal tract in the action of metformin is summarized focusing on the enhanced secretion of glucagon-like peptide-1 and modulation of gut microbiota. Recent scientific evidence extends our understanding of the complex mechanisms of metformin action, points towards potential new molecular targets for the treatment of diabetes and may promote the development of new antidiabetic therapies.