Other Mechanisms of Action

It has been suggested that part of the antihyperglycemic effect of metformin is due to decreased release of free fatty acids (FFA) from adipose tissue and/or decreased lipid oxidation (32,54). However, reduced FFA levels after metformin treatment have only been shown in some (28,36,54) but not all studies (24,25,38). Moreover, in vitro studies have shown that metformin does not enhance the antilipolytic action of insulin on adipose tissue (55). Only two studies have examined FFA turnover using isotope techniques and found either no difference (24) or a 17% reduction (34) after metformin treatment. In the latter study the effect was only seen in the basal state but not in the insulin-stimulated state where FFA flux was largely suppressed. Thus, the metformin effect on peripheral glucose uptake may, at least in part, be mediated by suppression of FFA and lipid oxidation. In contrast, a causal relationship with endogenous glucose production is unlikely, since distinctly greater reductions in circulating FFA levels with acipimox failed to lower glucose production (56,57).

Evidence for other proposed mechanisms of metformin action is less convincing. Increased intestinal utilization of glucose has been suggested by animal studies (58-60). More

TABLE 1 In Vitro Studies—Effect of Metformin on Insulin-Mediated Glucose Metabolism

Effect cell/tissue type

Administration

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Author (Ref)

Glucose transport

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