Metformin-mechanisms of its glycemia-reducing effect

Metformin currently serves as the basis of oral treatment for patients with type 2 diabetes. While metformin's effect on glycemia is well established, its mode of action remains unclear. In clinical studies, long-term metformin treatment improved glucose disposal and reduced hepatic gluconeogenesis. The effects on gluconeogenesis have been confirmed in experimental animals and cell preparations, but mostly at higher doses than those used in humans. Proposed hepatic mechanisms can be grouped into those with and without AMP-activated protein kinase (AMPK) activation; the latter include inhibition of mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase. Experimental studies on the effects of metformin on skeletal muscles suggest that AMPK activation and anti-inflammatory activities are possible mechanisms for increasing glucose disposal. Inhibition of renal gluconeogenesis may contribute to the extraintestinal glycemia-lowering effects of metformin. Following the observation that short-term intravenous metformin lacks glycemia-lowering effects in humans, intestinal mechanisms have been investigated. Suggested mechanisms include inhibition of intestinal glucose absorption owing to increased glycolysis driven by complex I inhibition in the mitochondria of enterocytes, stimulation of glucose transport into the colon, and stimulation of glucagon-like peptide-1 (GLP-1) secretion. Intestinal GLP-1 activates the gut-brain-liver axis, which impairs hepatic gluconeogenesis through vagal stimulation. Metformin can enhance intestinal GLP-1 secretion by L-cells directly through AMPK activation via complex I inhibition or indirectly by increasing the availability of glucose, bile acids, and/or metabolites produced by intestinal bacteria. Thus, metformin improves muscle glucose disposal, reduces gluconeogenesis, and has several intestinal effects that impact glycemia. Inhibition of mitochondrial complex I in different organs appears to be an important mechanism of metformin's glucose-lowering effect. SIGNIFICANCE STATEMENT: Most previous studies on the mechanism of metformin's glycemia-reducing effect focused on inhibition of hepatic gluconeogenesis. However, clinical studies show that increased glucose transport into skeletal muscle is at least as important. Furthermore, recent studies suggest that intestinal effects, including inhibition of glucose absorption, stimulation of the gut-liver and gut-brain-liver axes, and changes in the intestinal microbiota, contribute to metformin's glycemia-lowering effect. Thus, metformin's glycemia-reducing effect is multifactorial, affecting glucose metabolism in the gut, liver, and skeletal muscle.