Genistein induces pancreatic beta-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes in mice.
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 mum genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17beta-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.
Fu
Zhuo
Z
Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
Zhang
Wen
W
Zhen
Wei
W
Lum
Hazel
H
Nadler
Jerry
J
Bassaganya-Riera
Josep
J
Jia
Zhenquan
Z
Wang
Yanwen
Y
Misra
Hara
H
Liu
Dongmin
D
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D019833:Genistein / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000172:deficiency*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000975:Antioxidants; D007328:Insulin; D019833:Genistein; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3