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., H.M. (2001). The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. THE FASEB JOURNAL, 15(1), 22-24.
|Tipologia:||Articolo su rivista|
|Citazione:||Federici M., H.M. (2001). The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. THE FASEB JOURNAL, 15(1), 22-24.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/09 - Medicina Interna|
Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie
|Revisione (peer review):||Sì, ma tipo non specificato|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2001|
|Titolo:||The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets.|
|Autori:||Federici M., Hribal M.L., Ranalli M., Marselli L., Porzio O., Lauro D., Borboni P., Lauro R., Marchetti P., Melino G., Sesti G.|
|Appare nelle tipologie:||01 - Articolo su rivista|