Mechanisms of Action of Metformin

The mechanism by which metformin exerts its antihyperglycaemic effects is still not entirely clear, but may be mediated by activation of hepatic and muscle adenosine monophosphate-activated protein kinase [2], which is a major regulator of lipid and glucose metabolism. Metformin improves fasting and postprandial glucose levels during an oral glucose tolerance test, whereas the plasma insulin response to glucose is unchanged or may be decreased in patients with hyperinsulinemia [3]. Metformin ameliorates hyperglycaemia by reducing hepatic glucose production and gastrointestinal glucose absorption and improving peripheral sensitivity to insulin [4-7]. Unlike sulfonylureas, it does not stimulate insulin secretion, aggravate hyperinsu-linemia or cause hypoglycaemia [3-7]. However, the insulin-sensitizing effect of metformin is much smaller compared with that of thiazolidine-diones [7]. The insulin-sensitizing action of met-formin on peripheral tissues may be mainly explained by glucose toxicity. It is well known that chronic hyperglycaemia causes deterioration of both beta-cell function and insulin action and that these effects are reversed by improved gly-caemic control.

The major action of metformin in patients with diabetes is to decrease hepatic glucose output, primarily by decreasing gluconeogenesis, but it may also, as a lesser effect, increase glucose uptake by skeletal muscles [6,7].

Rise, fall and revival of metformin in the therapy of type 2 diabetes

Discovery of glucose lowering effect

UGDP Study

AHA/EASD guidelines Metformin as first line therapy

UGDP Study

AHA/EASD guidelines Metformin as first line therapy

Discovery of glucose lowering effect

1982 Metformin „Insulin Sensitizer"

1996

Metformin in the USA

1929

1957 Clinical application

1982 Metformin „Insulin Sensitizer"

1996

Metformin in the USA

1950 1970 1990 2000

Fig. 1. Rise, fall and revival of metformin in the therapy of type 2 diabetes.

2007

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