The common Arg972 polymorphism in insulin receptor substrate‐1 causes apoptosis of human pancreatic islets

ABSTRACT Molecular scanning of human IRS‐1 gene revealed a common polymorphism causing Gly →Arg972 change. Diabetic and pre‐diabetic carriers of Arg972 IRS‐1 are characterized by low fasting levels of insulin and C‐peptide. To investigate directly whether the Arg972 IRS‐1 affects human islet cells survival, we took advantage of the unique opportunity to analyze pancreatic islets isolated from three donors heterozygous for the Arg972 and six donors carrying wild‐type IRS‐1. Islets from carriers of Arg972 IRS‐1 showed a two‐fold increase in the number of apoptotic cells as compared with wild‐type. IRS‐1‐associated PI3‐kinase activity was decreased in islets from carriers of Arg972 IRS‐1. Same results were reproduced in RIN rat β‐cell lines stably expressing wild‐type IRS‐1 or Arg972 IRS‐1. Using these cells, we characterized the downstream pathway by which Arg972 IRS‐1 impairs β‐cell survival. RIN‐Arg972 cells exhibited a marked impairment in the sequential activation of PI3‐kinase, Akt, and BAD as compared with RIN‐WT. Impaired BAD phosphorylation resulted in increased binding to Bcl‐XL instead of 14‐3‐3 protein, thus sequestering the Bcl‐XL antiapoptotic protein to promote survival. Both caspase‐9 and caspase‐3 activities were increased in RIN‐Arg972 cells. The results show that the common Arg972 polymorphism in IRS‐1 impairs human β‐cell survival and causes resistance to antiapoptotic effects of insulin by affecting the PI3‐kinase/Akt survival pathway. These findings establish an important role for the insulin signaling in human β‐cell survival and suggest that genetic defects in early steps of insulin signaling may contribute to β‐cell failure.