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Increased Insulin Resistance in Obese Children Who Have Both 972 IRS-1 and 1057 IRS-2 Polymorphisms

From the Department of Pediatric Endocrinology, Hôpital Saint-Vincent de Paul, Université Paris V, Paris, France

In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 ± 0.2 in cohort 1, 2.7 ± 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 ± 0.2 and 3.5 ± 0.3, respectively). However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25–35% decrease in sensitivity (2.3 ± 0.2 and 2.0 ± 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1^+/- IRS-2^+/- heterozygous knockout mice. Our results stress the need for combined genotype analysis when candidate genes are functionally involved in the same pathway.

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				P. Bougneres Genetics of Obesity and Type 2 Diabetes: Tracking Pathogenic Traits During the Predisease Period Diabetes, December 1, 2002; 51(90003): S295 - 303. [Abstract] [Full Text] [PDF]