Genistein Induces Pancreatic beta-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice

Abstract

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet beta-cell proliferation after 24 h of incubation, with 5 mu M genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17 beta-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated beta-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for beta-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet beta-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic beta-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway. (Endocrinology 151: 3026-3037, 2010)

Description

Keywords

glucagon-like peptide-1, tyrosine kinase inhibitors, dependent, protein-kinase, camp-responsive element, oxidative stress, soy, isoflavones, postmenopausal women, quantitative-analysis, soybean, isoflavones, combination therapy, endocrinology & metabolism

Citation

Zhuo Fu, Wen Zhang, Wei Zhen, Hazel Lum, Jerry Nadler, Josep Bassaganya-Riera, Zhenquan Jia, Yanwen Wang, Hara Misra, and Dongmin Liu. "Genistein Induces Pancreatic β-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice," Endocrinology 2010 151:7, 3026-3037. DOI: http://dx.doi.org/10.1210/en.2009-1294.