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Abstract
Metformin can improve patients' hyperglycemia through significant suppression of hepatic
glucose production. However, up to 300 times higher concentrations of metformin accumulate
in the intestine than in the circulation, where it alters nutrient metabolism in intestinal
epithelial cells and microbiome, leading to increased lactate production. Hepatocytes
use lactate to make glucose at the cost of energy expenditure, creating a futile intestine-liver
cycle. Furthermore, metformin reduces blood lipopolysaccharides and its initiated
low-grade inflammation and increased oxidative phosphorylation in liver and adipose
tissues. These metformin effects result in the improvement of insulin sensitivity
and glucose utilization in extrahepatic tissues. In this review, I discuss the current
understanding of the impact of metformin on systemic metabolism and its molecular
mechanisms of action in various tissues.