To better understand the insulin-independent plasma glucose-lowering action of metformin, we used streptozotocin (STZ)-induced diabetic rats to investigate the possible mechanisms. Oral intake of metformin decreased the plasma glucose of STZ-induced diabetic rats with a parallel increase of plasma ␤-endorphin-like immunoreactivity (BER). Mediation of opioid -receptors in the action of metformin was identified by the blockade of receptors with antagonist in STZ-induced diabetic rats and the failure of action in opioid -receptor knockout diabetic mice. Release of BER from adrenal glands by metformin was characterized, using bilateral adrenalectomy and the release of BER from isolated adrenal medulla of STZ-induced diabetic rats. Repeated treatment with metformin in STZ-induced diabetic rats increased the mRNA and protein levels of GLUT-4 in soleus muscle that was blocked by naloxonazine. Reduction of the mRNA or protein levels of hepatic PEPCK was also impeded in the same group of STZ-induced diabetic rats. In conclusion, our results provide novel mechanisms for the plasma glucose-lowering action of metformin, via an increase of ␤-endorphin secretion from adrenal glands to stimulate opioid -receptor linkage, leading to an increase of GLUT-4 gene expression and an attenuation of hepatic PEPCK gene expression in STZinduced diabetic rats. Diabetes 55:819 -825, 2006

Genistein, an isoflavonoid natural product, is widely used to inhibit protein tyrosine kinase (PTK). In the present study, we investigated the possible influence of genistein on alpha (1)-adrenoceptors (AR) in cultured C2C12 cells. Genistein enhanced the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner. Similar results were also observed in samples treated with daidzein, the inactive congener for PTK inhibition. The effect of genistein on alpha (1)-AR was further characterized using the displacement of [ (3)H]prazosin binding in C2C12 cells. The increase in radioactive glucose uptake by genistein was abolished by RS17053 at a concentration sufficient to block alpha (1A)-AR. The pharmacological inhibition of phospholipase C (PLC) by U73122 resulted in a concentration-dependent reduction of genistein-stimulated glucose uptake in C2C12 cells. This inhibition by U73122 was specific because the inactive congener, U73343, failed to modify the action of genistein. Moreover, genistein can activate alpha (1A)-AR at a concentration (1 micromol/L) lower than that (50 micromol/L) needed to abolish the insulin-stimulated phosphorylation of PTK. The obtained data indicate an activation of alpha (1A)-AR by genistein to increase the glucose uptake into C2C12 cells and this supports the application of genistein as a TK inhibitor.

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