Potentiating effect of metformin on insulin-induced glucose uptake and glycogen metabolism within Xenopus oocytes

Xenopus laevis oocytes were chosen as the in vitro model for this study with the aim of reconsidering metformin action on the main insulin-responsive glucose pathway, Metformin alone, when present at a therapeutic dose (20 mu mol/l) in the incubation medium, did not alter the basal rate of glucose uptake or of glycogen synthesis as measured by [U-C-14] D-glucose incorporation. The drug had no effect on the main rate-limiting enzyme implicated in this pathway, i.e. glycogen synthase. In contrast, when combined with 2 mu mol/l insulin, metformin led to a specific rise of both free and stored glucose, by 42.4 and 102.3 % respectively. Moreoever, a short-term preincubation of mature oocytes with metformin, but in the absence of glucose, enhanced significantly the amount of synthase a when stimulated by 50 nmol/l insulin (basal 17.4 +/- 5.7 %, metformin 21.3 +/- 4.1 %, insulin 31.2 +/- 4.6 %. metformin together with insulin 62.7 +/- 4.2 %, p<0.005, n=5). Interestingly, the microinjection of this biguanide, at a final concentration of 20 nmol/l, allowed a similar biochemical response, These data clearly suggest that metformin could act primarily at postreceptor steps which are thought to be key sites in controlling the cellular glucose homeostasis.