Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes

Sandra Mammarella, Ferdinando Romano, Annalisa Di Valerio, Beatrice Creati, Diana L. Esposito, Raffaele Palmirotta, Fabio Capani, Paola Vitullo, Giustino Volpe, Pasquale Battista, Fulvio Della Loggia, Renato Mariani-Costantini, Alessandro Cama

Research output: Contribution to journalArticle

Abstract

The insulin receptor substrate-2 (IRS-2) is a major insulin signalling molecule. IRS-2 inactivation in mice induces a form of diabetes characterized by peripheral insulin resistance and reduced beta cell mass. We tested the hypothesis that a common non-conservative amino acid substitution of IRS-2 (G1057D) might interact with overweight in the pathogenesis of type 2 diabetes. The variant was genotyped in 193 Italian patients with type 2 diabetes and 206 control subjects. In the absence of overweight, the risk of type 2 diabetes decreased according to the dosage of the D1057 allele (odds ratio for GD genotype 0.46 [95% CI 0.25-0.86]; DD genotype 0.18 [0.04-0.68]; P for trend = 0.0012). Conversely, the interaction between overweight and genotype increased the risk of type 2 diabetes according to the dosage of the D1057 allele (odds ratio for GD genotype 2.50 [1.11-5.65]; DD genotype 5.74 [1.11-29.78]; P for trend = 0.0047). Among controls, fasting C-peptide levels, after adjustment for plasma glucose, were inversely related to the dosage of the D1057 allele (P = 0.020). This finding suggested that carriers of the D1057 allele may have higher insulin sensitivity and supported the protective effect of this allele. Conversely, among overweight patients there was a parallel increase in fasting plasma glucose (P for trend = 0.037) and fasting C-peptide according to the dosage of the D1057 allele, suggesting that higher insulin resistance and relative beta cell failure contributed to the increased risk of type 2 diabetes in overweight carriers of this allele. These data provide evidence for a strong association between type 2 diabetes and the G1057D common genetic variant of IRS-2, which appears to be protective against type 2 diabetes in a codominant fashion. Overweight appears to modify the effect of this polymorphism toward a higher risk of type 2 diabetes. Carriers of this polymorphism may represent an elective target for prevention of type 2 diabetes through preventing or treating excessive weight.

Original languageEnglish
Pages (from-to)2517-2521
Number of pages5
JournalHuman Molecular Genetics
Volume9
Issue number17
Publication statusPublished - Oct 12 2000

ASJC Scopus subject areas

  • Genetics

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    Mammarella, S., Romano, F., Di Valerio, A., Creati, B., Esposito, D. L., Palmirotta, R., Capani, F., Vitullo, P., Volpe, G., Battista, P., Loggia, F. D., Mariani-Costantini, R., & Cama, A. (2000). Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. Human Molecular Genetics, 9(17), 2517-2521.