Background: Insulin receptor substrate (IRS) molecules are key mediators in insulin signaling. Several polymorphisms in the IRS genes have been identified, but only the Gly to Arg 972 substitution of IRS-1, seems to have a pathogenic role in the development of type 2 diabetes. Many polymorphisms described in IRS1 gene, especially Gly972Arg substitution are shown to be associated with insulin resistance in type 2 diabetes. Subjects and methods :This prospective case control study was done during the period from November 2014 to May 2015. All patients were collected from Diabetes and Endocrinology diseases Department and were screened for eligibility in this study. Subjects were divided in two groups: first group consists of 100 patients with Type 2 diabetes, second group consists of 120 non diabetic control group. First group was further subdivided to 66 insulin resistant subgroup and 34 insulin sensitive subgroup (HOMA homeostatic model assessment was done). Restriction Fragment Polymorphism (RFLP) performed using specific primers for scanning SNPs Gly 972 Arg (rs1801278 SNP) . Results: Taking GG genotype and G allele as a reference, GA, GA+AA genotypes and A allele showed significantly higher frequency in T2DM when compared to control group, with higher risk to develop T2DM within healthy control. Taking GG as a reference, rs1801278GA+AA genotype and A allele showed significantly higher proportion in insulin resistant (IR) when compared to insulin sensitive (IS), with higher risk to develop IR within T2DM cases. Logistic regression analysis showed higher FBG, FPI, HOMAIR, GA+AA genotypes were associated with higher risk to develop IR in univariable analysis. Conclusions: IRS1 genetic factor may be a significant genetic determinant for insulin resistance in T2DM patients during severe/acute phase hyperglycemia