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 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 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 b-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 b-cell survival. RIN-Arg972 cells exhibited a marked impairment in the sequential activation of PI3-kinase, Akt, and BAD as compared with RI N-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 b-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 b-cell survival and suggest that genetic defects in early steps of insulin signaling may contribute to b-cell failure.

Federici, M., Hribal, M.l., Ranalli, M., Marselli, L., Porzio, O., Lauro, D., et al. (2001). The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. THE FASEB JOURNAL, 15(1), 22-24.

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

FEDERICI, MASSIMO;PORZIO, OTTAVIA;LAURO, DAVIDE;BORBONI, PATRIZIA;LAURO, RENATO;MELINO, GENNARO;
2001-01-01

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 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 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 b-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 b-cell survival. RIN-Arg972 cells exhibited a marked impairment in the sequential activation of PI3-kinase, Akt, and BAD as compared with RI N-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 b-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 b-cell survival and suggest that genetic defects in early steps of insulin signaling may contribute to b-cell failure.
2001
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/09 - MEDICINA INTERNA
Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITA' MOTORIE
English
Con Impact Factor ISI
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
Federici, M., Hribal, M.l., Ranalli, M., Marselli, L., Porzio, O., Lauro, D., et al. (2001). The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. THE FASEB JOURNAL, 15(1), 22-24.
Federici, M; Hribal, Ml; Ranalli, M; Marselli, L; Porzio, O; Lauro, D; Borboni, P; Lauro, R; Marchetti, P; Melino, G; Sesti, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/53042
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