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      Phytonutrient genistein is a survival factor for pancreatic β-cells via GPR30-mediated mechanism

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          Abstract

          We previously discovered that phytonutrient genistein rapidly activates cAMP signaling in β-cells and improving islet mass in diabetic mice. However, the mechanism underlying these actions of genistein is still unclear. Here, we show that pharmacological or molecular inhibition of Gαs blocked genistein-stimulated adenylate cyclase activity in plasma membrane and intracellular cAMP production in INS1 cells and islets. Further, genistein stimulation of cAMP generation was abolished in islets exposed to a specific GPR30 inhibitor G15 or islets from GPR30 deficient ( GPR30−/−) mice. In vivo, dietary provision of genistein (0.5 g/kg diet) significantly mitigated streptozotocin-induced hyperglycemia in male WT mice, which was associated with improved blood insulin levels and pancreatic islet mass and survival, whereas these effects were absent in Gpr30−/− mice. Genistein treatment promoted survival of INS1 cells and human islets chronically exposed to palmitate and high glucose. At molecular level, genistein activated CREB phosphorylation and subsequently induced Bcl-2 expression, and knockdown of CREB diminished the protective effect of genistein on β-cells induced by lipoglucotoxicity. Finally, deletion of GPR30 in β-cells or islets ablated genistein-induced CREB phosphorylation and its cytoprotective effect. These findings demonstrate that genistein is a survival factor for β-cells via GPR30-initiated, Gαs-mediated activation of CREB.

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          Author and article information

          Journal
          9010081
          21515
          J Nutr Biochem
          J. Nutr. Biochem.
          The Journal of nutritional biochemistry
          0955-2863
          1873-4847
          15 May 2018
          12 May 2018
          August 2018
          01 August 2019
          : 58
          : 59-70
          Affiliations
          [a ]Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA
          [b ]Department of Human Sciences, College of Agriculture, Human, and Natural Sciences, Tennessee State University, Nashville, TN
          [c ]Department of Biology, University of North Carolina at Greensboro, Greensboro, NC
          [d ]Department of Animal and Poultry Sciences, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA
          [e ]Department of Biochemistry, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA
          Author notes
          [* ] Corresponding author: Dongmin Liu, Department of Human Nutrition, Foods and Exercise, Virginia Tech, 1981 Kraft Drive, Corporate Research Center, Blacksburg, VA 24061, Tel: 540-231-3402; Fax: 540-231-3916; doliu@ 123456vt.edu
          Article
          PMC6095734 PMC6095734 6095734 nihpa967478
          10.1016/j.jnutbio.2018.04.018
          6095734
          29885598
          8587ffa2-e2e1-4de2-bb23-988daf228908
          History
          Categories
          Article

          genistein,cAMP,CREB,apoptosis,GPR30,mice,islets
          genistein, cAMP, CREB, apoptosis, GPR30, mice, islets

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