Metformin: new insights into an archetypal cardiometabolic drug
Abstract
Although metformin has been in clinical use as a diabetes medication for six decades, its mechanism of action remains uncertain 1. Hepatic gluconeogenesis is reduced by metformin without increasing insulin secretion, inducing weight gain, or risking hypoglycemia. Widely regarded as an insulin sensitizer, the main glucose-lowering effect of metformin is to reduce inappropriate rates of hepatic glucose production 2; effects on whole-body insulin sensitivity appear to be secondary to lowered blood glucose concentrations 3. Suggestions that metformin reduces glucose production by the activation of enzyme AMP-activated protein kinase were subsequently challenged by genetic loss-of-function studies 4. While rodent and tissue culture studies reported that metformin inhibited the stimulatory effect of glucagon on hepatic glucose production 5 clinical studies suggest a more complex picture 6. Results of in-vitro and in-vivo studies from Gerald Shulman’s Yale group propose that metformin noncompetitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase 7. In turn, this results in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and hence decreased hepatic gluconeogenesis. Clinical studies with delayed-release metformin, formulated to deliver the drug to the lower bowel, have implicated gut hormones (glucagon-like peptide-1, peptide YY) in the glucose-lowering effect of metformin 8,9. Beyond glucose-lowering,…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 537 participants or records.
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