Metabolic Effects Independent of Improved Glycemia

The interpretation of the above experiments is limited by the fact that treatment with metformin was always accompanied by improvement in glycemic control and sometimes also by reduction of body weight. It can not be excluded; therefore, that the effects on endogenous glucose production and glucose disposal at least in part were secondary to reduced glucose toxicity (39) and/or weight loss (40) rather than metformin per se. Only four studies have examined the metabolic actions of metformin in the absence of any changes in glycemic control or body weight.

In one study 1 g of metformin was administered acutely to patients with type 2 diabetes and after 12 hours no effect on insulin-stimulated glucose disposal was seen while the excessive endogenous glucose production in the basal state was significantly reduced (32). This suggests that in patients with type 2 diabetes improvement in insulin-stimulated glucose disposal is predominantly due to alleviation of glucose toxicity while endogenous glucose production is immediately affected by metformin. In another study lean, normal glucose-tolerant, insulin-resistant first-degree relatives of patients with type 2 diabetes acutely received 1 g of metformin and the exact opposite was observed (38). In subjects with impaired glucose tolerance (IGT) 6-week metformin treatment improved basal homeostasis model

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