Striking a gut–liver balance for the antidiabetic effects of metformin

Despite the widespread use of metformin in the treatment of type 2 diabetes mellitus, its mechanism of action remains to be completely elucidated. Historically, the major site of action of metformin has been thought to be the liver, but recent findings confirm that it also has notable effects in the gut. Metformin promotes intestinal glucose uptake, establishing a gut–liver crosstalk that inhibits hepatic glucose production, increases the secretion of glucagon-like peptide-1 and the expression of growth differentiation factor 15, and alters the microbiota. All these effects contribute to reducing hyperglycemia. Since most of the glucose-lowering effects of metformin depend on its action on the intestines, research over the past few years has suggested a switch from the liver to the gut as its primary site of action. Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects. Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects. shortest fatty acid derived from the diet or fiber fermentation in the gut, which supports acetyl-coenzyme A metabolism and, thus, lipogenesis and protein acetylation. central regulator of energy homeostasis, which coordinates metabolic pathways and, thus, balances nutrient supply with energy demand. It is a serine/threonine protein kinase complex comprising a catalytic α-subunit (α1 or α2), a scaffolding β-subunit (β1 or β2), and a regulatory γ-subunit (γ1, γ2, or γ3). cells secreting GLP1, GLP2, and peptide YY (PYY). These cells are widely distributed in the distal small intestine and colon (mainly in the proximal portion). gastrointestinal peptide that is released in response to nutrients, neuronal or hormonal stimuli. The main actions of GLP-1 are stimulating insulin secretion and inhibiting glucagon secretion. anabolic process that produces glucose primarily from lactate, pyruvate, amino acids, and glycerol. energy-generating process that converts glucose into pyruvate in the presence of oxygen, or into lactate in the absence of oxygen. divergent member of the transforming growth factor β (TGFβ) superfamily. GDF15 serum levels increase in response to cell stress. The endogenous receptor for GDF15 is glial-derived neurotrophic factor-family receptor α-like (GFRAL), detected selectively in the brain. Binding of GDF15 to GFRAL regulates energy balance by reducing food intake. process by which the liver produces and releases glucose into the blood by regulating the two primary glucose production metabolic pathways, glycogenolysis and gluconeogenesis. Excessive hepatic glucose production is a major contributor to the hyperglycemia observed in T2DM. defect in the ability of insulin to drive glucose into its target tissues. major gluconeogenic precursor in the liver. major gluconeogenic precursor in the liver.