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The common Arg 972 polymorphism in insulin receptor substrate‐1 causes apoptosis of human pancreatic islets
Author(s) -
Federici Massimo,
L. Hribal Marta,
Ranalli Marco,
Marselli Lorella,
Porzio Ottavia,
Lauro Davide,
Borboni Patrizia,
Lauro Renato,
Marchetti Piero,
Melino Gerry,
Sesti Giorgio
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0414fje
Subject(s) - protein kinase b , islet , apoptosis , pancreatic islets , medicine , endocrinology , insulin , insulin receptor , biology , kinase , insulin resistance , cell culture , irs1 , phosphorylation , signal transduction , microbiology and biotechnology , biochemistry , genetics
ABSTRACT Molecular scanning of human IRS‐1 gene revealed a common polymorphism causing Gly →Arg 972 change. Diabetic and pre‐diabetic carriers of Arg 972 IRS‐1 are characterized by low fasting levels of insulin and C‐peptide. To investigate directly whether the Arg 972 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 Arg 972 and six donors carrying wild‐type IRS‐1. Islets from carriers of Arg 972 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 Arg 972 IRS‐1. Same results were reproduced in RIN rat β‐cell lines stably expressing wild‐type IRS‐1 or Arg 972 IRS‐1. Using these cells, we characterized the downstream pathway by which Arg 972 IRS‐1 impairs β‐cell survival. RIN‐Arg 972 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‐X L instead of 14‐3‐3 protein, thus sequestering the Bcl‐X L antiapoptotic protein to promote survival. Both caspase‐9 and caspase‐3 activities were increased in RIN‐Arg 972 cells. The results show that the common Arg 972 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.