ArticleThe Journal of clinical investigation1999
The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells.
Article in The Journal of clinical investigation, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 2 of them syntheses that pooled it.
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Who cites it
42 citing papers in PubMed, 2 syntheses or guidelines pooled it, 156 citations in OpenAlex.
- Association between insulin receptor substrate 1 Gly972Arg polymorphism and cancer risk.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2013Pooled it
- Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies.Diabetologia · 2003Pooled it
- Insulin enhances glucose-stimulated insulin secretion in healthy humans.Proceedings of the National Academy of Sciences of the United States of America · 2010Trial
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- Diabetes mellitus with severe insulin resistance in a young male patient with a heterozygous pathogenicClinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2024Article
- Article
- Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes.Cell discovery · 2022Article
- Epigenetic modifications in pancreas development, diabetes, and therapeutics.Medicinal research reviews · 2022Review
- The Phosphatase PHLPP2 Plays a Key Role in the Regulation of Pancreatic Beta-Cell Survival.International journal of endocrinology · 2020Article
- Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine.Diabetes/metabolism research and reviews · 2019Review
- The combined role of allelic variants ofDiabetology & metabolic syndrome · 2019Article
- The Role of Polymorphisms in Genes of PI3K/Akt Signaling Pathway on Prostate.Journal of Cancer · 2019Article
- Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation.Cell metabolism · 2017Article
- IRS-1 gene polymorphism and DNA damage in pregnant women with diabetes or mild gestational hyperglycemia.Diabetology & metabolic syndrome · 2015Article
- Joint effect of insulin signaling genes on all-cause mortality.Atherosclerosis · 2014Article
- Arg972 Insulin receptor substrate-1 is associated with decreased serum angiotensin-converting enzyme 2 levels in acute myocardial infarction patients: in vivo and in vitro evidence.Cardiovascular diabetology · 2013Article
- Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data.Molecular diagnosis & therapy · 2012Review
- Article
- The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases.Endocrine reviews · 2012Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
Recent studies have identified several polymorphisms in the human insulin receptor substrate-1 (IRS-1) gene. The most prevalent IRS-1 variant, a Gly-->Arg change at the codon 972, has been reported to be increased in prevalence among patients with type 2 diabetes. Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. Compared with control RIN cells, insulin content was reduced to the same extent in RIN-WT or RIN-Arg(972) at both the protein and mRNA levels. Both glucose- and sulfonylurea-induced insulin secretion was increased in RIN-WT compared with control RIN cells. By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant.
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