Mechanisms of action

The specific mechanisms of action of metformin have not been definitively demonstrated. In the liver, metformin increases insulin-dependent suppression of gluconeogenesis and decreases the glucagon-dependent stimulation of gluconeogenesis, resulting in an overall decrease in hepatic glucose production. Animal models suggest additional mechanisms of action for metformin, including insulin-dependent glucose uptake by muscle61 and adipose tissue,62 with resultant increases in glycogen formation, glucose oxidation, and lipogenesis. De Fronzo et al.63 demonstrated that, in humans, improvement in fasting blood glucose on metformin results from reduction in basal hepatic glucose production. In studies using the glucose/insulin clamp techniques metformin did not improve whole-body insulin sensitivity in individuals with T2DM. Since the glucose-lowering effect of metformin occurs without stimulation of insulin secretion, metformin is not associated with hypoglycemia when used as monotherapy.

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