Molecular mechanisms of anti-diabetic effects of soy isoflavones

Dietary soy isoflavones have been shown to favorably alter the metabolic phenotypes associated with type 2 diabetes. However, the direct target tissues and the underlying molecular mechanisms by which soy isoflavones exert antidiabetic effects remain to be elucidated. Since peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue mediates the insulin sensitizing effect of pharmacological drugs, we hypothesized that soy isoflavones may exert antidiabetic effects through a mechanism that involves PPARγ activation in adipose tissue. In these studies, we investigated whether daidzein and genistein, major isoflavones, would increase insulin sensitivity at three different stages of adipocyte development such as adipocyte differentiation, mature adipocytes and insulin-resistant adipocytes. In addition, the involvement of PPARγ in isoflavone\u27s effects was determined. During adipocyte differentiation, daidzein increased insulin-stimulated glucose uptake accompanied by increased GLUT4 and IRS-1 mRNA levels. In addition, daidzein upregulated PPARγ-mediated transcriptional activity and restored the PPARγ antagonist-induced inhibition of adipocyte differentiation. In contrast, genistein was ineffective in insulin-stimulated glucose uptake in differentiating adipocytes, while it enhanced levels of GLUT4 and IRS-1 mRNA. In mature adipocytes, insulin-stimulated glucose uptake was significantly enhanced by chronic treatment of daidzein but not by genistein. Daidzein treatment also increased GLUT1 and GLUT4 mRNA and protein expression as well as translocation of glucose transporters to plasma membrane in response to insulin. The upregulation of insulin-stimulated glucose uptake and GLUT4 protein expression by daidzein was completely blocked by PPARγ antagonist pretreatment. In TNFα-induced insulin resistant adipocytes, insulin-stimulated glucose uptake was also increased by daidzein. Daidzein blocked the reduction of GLUT4 and CAP mRNA levels by TNFα. In the presence of TNFα, daidzein treatment not only restored the suppression of PPARγ activity and gene expression but also inhibited NFκB activity. Furthermore, inhibitory effects of daidzein on NFκB activity were partially but significantly blocked by PPARγ antagonist pretreatment. Taken together these results provide evidence that isoflavones enhance insulin-stimulated glucose uptake through PPARγ activation. The increase of insulin-stimulated glucose uptake in adipocytes and involvement of PPARγ activation by daidzein may be one of the potential mechanisms for the anti-diabetic effects of soy isoflavones