COMMON AMINO-ACID SUBSTITUTIONS IN INSULIN-RECEPTOR SUBSTRATE-4 ARE NOT ASSOCIATED WITH TYPE-II DIABETES-MELLITUS OR INSULIN-RESISTANCE

The family of insulin receptor substrates (IRS1-4) is defined by prote ins with an overall similar structure. IRS-1 and IRS-2 have been shown to have key roles in cellular transmission of the action of insulin, insulin-like growth factor-1 and various cytokines. We have previously identified amino acid polymorphisms in the human IRS-1 and IRS-2 prot eins. Given the documented importance of IRS-1 and -2 in insulin signa lling and the implications of distribution of these genes for the path ogenesis of insulin resistance and diabetes, we decided that the most recently identified member of the IRS family, IRS-4, was a relevant ca ndidate to examine for genetic variability which might be associated w ith subsets of diabetes or insulin resistance. The gene encoding IRS-4 was analysed by the single strand conformation polymorphism technique in 83 Danish Caucasians with Type II (non-insulin-dependent) diabetes mellitus. Five amino acid polymorphisms were identified: Leu34Phe, Ar g411Gly, Gly584Cys, His879Asp and Lys883Thr. In an association study o f 324 patients with Type II diabetes and 267 control subjects with nor mal glucose tolerance the polymorphism at codon 34 was found with alle lic frequencies of 3.9 and 2.3%, respectively, the variant at codon 41 1 with allelic frequencies of 3.9 and 5.6%, respectively, and the vari ant at codon 879 with frequencies of 19.2 and 18.0%, respectively. Eac h carrier of the codon 34 polymorphism was also a carrier of the codon 411 and codon 879 variants and similarly, carriers of the variant at codon 411 were also carriers of the polymorphism at codon 879. The var iants at codon 584 and 883 were each found in only one Type II diabeti c patient. The allelic frequencies of the variants at codon 411 and 87 9 were also determined in 380 young healthy subjects (4.6 and 18.1%, r espectively). The insulin sensitivity index as estimated by Bergman's minimal model of the young healthy subjects carrying either polymorphi sm was indistinguishable from the carriers of wild-type IRS-4. Moreove r, none of the men were heterozygous for the IRS-4 polymorphisms indic ating that the gene is located on the X-chromosome. In conclusion, ami no acid polymorphisms in human IRS-4 are common in Caucasians but are not associated with Type II diabetes or with insulin resistance in you ng healthy subjects.