The common Arg 972 polymorphism in insulin receptor substrate‐1 causes apoptosis of human pancreatic islets
Copyright policy )The common Arg 972 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 →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.
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protein bcl x, arginine, Apoptosis, Phosphatidylinositol 3-Kinases, insulin receptor substrate-1 protein, caspase 3, AKT1 protein, human; Akt1 protein, rat; arginine; BAD protein, human; Bad protein, rat; BCL2L1 protein, human; Bcl2l1 protein, rat; carrier protein; CASP3 protein, human; Casp3 protein, rat; CASP9 protein, human; Casp9 protein, rat; caspase; caspase 3; caspase 9; insulin; insulin receptor substrate 1 protein; insulin receptor substrate-1 protein; mitogen activated protein kinase; oncoprotein; phosphatidylinositol 3 kinase; phosphoprotein; protein 14 3 3; protein BAD; protein bcl 2; protein bcl x; protein kinase B; protein serine threonine kinase; tyrosine 3 monooxygenase; animal; apoptosis; article; biological model; cell line; cell survival; chemistry; cytology; drug effect; enzyme activation; enzymology; genetic polymorphism; genetics; heterozygote; human; metabolism; molecular genetics; pancreas islet; phosphorylation; rat; 1-Phosphatidylinositol 3-Kinase; 14-3-3 Proteins; Animals; Apoptosis; Arginine; bcl-Associated Death Protein; bcl-X Protein; Carrier Proteins; Caspase 3; Caspase 9; Caspases; Cell Line; Cell Survival; Enzyme Activation; Heterozygote; Humans; Insulin; Islets of Langerhans; Mitogen-Activated Protein Kinases; Models, Biological; Molecular Sequence Data; Phosphoproteins; Phosphorylation; Polymorphism, Genetic; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Tyrosine 3-Monooxygenase, Insulin, rat, animal, phosphatidylinositol 3 kinase, caspase 9, mitogen activated protein kinase, Caspase 3, drug effect, insulin receptor substrate 1 protein, article, AKT1 protein, cell line, CASP9 protein, phosphoprotein, Caspase 9, oncoprotein, Caspases, Mitogen-Activated Protein Kinases, insulin, Heterozygote, protein bcl 2, Cell Survival, caspase, enzymology, Molecular Sequence Data, CASP3 protein, chemistry, Arginine, cell survival, Models, Biological, Cell Line, Islets of Langerhans, protein BAD, protein serine threonine kinase, Animals, Humans, human, BAD protein, tyrosine 3 monooxygenase, enzyme activation, BCL2L1 protein, biological model, apoptosi, Enzyme Activation, carrier protein, 14-3-3 Proteins, protein 14 3 3, cytology, Insulin Receptor Substrate Proteins, protein kinase B, Carrier Proteins
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