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

FASEB J. 2001 Jan;15(1):22-24. doi: 10.1096/fj.00-0414fje. Epub 2000 Nov 14.

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.

MeSH terms

  • 14-3-3 Proteins
  • Animals
  • Apoptosis* / drug effects
  • Arginine / genetics
  • Arginine / metabolism*
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Heterozygote
  • Humans
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Polymorphism, Genetic / genetics*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Tyrosine 3-Monooxygenase / metabolism
  • bcl-Associated Death Protein
  • bcl-X Protein

Substances

  • 14-3-3 Proteins
  • BAD protein, human
  • BCL2L1 protein, human
  • Bad protein, rat
  • Bcl2l1 protein, rat
  • Carrier Proteins
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Arginine
  • Tyrosine 3-Monooxygenase
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • CASP9 protein, human
  • Casp3 protein, rat
  • Casp9 protein, rat
  • Caspase 3
  • Caspase 9
  • Caspases