دراسة تأثير تعدد الأشكال الجينية في جين (INSR) مستقبل الأنسولين على الاستجابة للعلاج بالأنسولين الخارجي في عينة من مرضى السكري من النوع الأول العراقيين

An Investigation of the Effect of Genetic Polymorphisms in the Insulin Receptor (INSR) Gene on Response to Exogenous Insulin Therapy in a Sample of Iraqi Patients with Type 1 Diabetes

Abstract
Lifelong administration of exogenous insulin remains the cornerstone of treatment for type 1 diabetes mellitus. The efficacy of insulin in achieving optimal glycemic control is largely dependent on its binding affinity to the insulin receptor. Single nucleotide polymorphisms (SNPs) in the insulin receptor (INSR) gene may influence this efficacy by altering receptor function, potentially contributing to insulin resistance in individuals treated with exogenous insulin. This cross-sectional pharmacogenetic study is particularly significant as it introduces innovative approaches within precision medicine and identifies specific genetic loci associated with reduced sensitivity to exogenous insulin. Moreover, it provides valuable insights into the development of chronic hyperglycemia despite strict adherence to exogenous insulin regimens. The findings related to the examined SNPs may facilitate the development of novel genome engineering applications aimed at precise gene modifications or modulation of gene expression.

Aim: This study investigates the impact of two single nucleotide polymorphisms (SNPs), (rs2245649) T>C and (rs2229429) G>A, in the INSR gene on the therapeutic response to exogenous insulin in a cohort of Iraqi individuals with type 1 diabetes mellitus.
Method: The impact of SNPs in the INSR gene (rs2245649) T>C and (rs2229429) G>A have been examined in 99 T1D individuals with poor glycemic control treated with a monotherapy basal-bolus exogenous insulin regimen. Moreover 30 healthy individuals were typed as healthy control, with both groups having a mean age of 12.3 years old. Genotyping was performed using an allele-specific polymerase chain reaction technique and the data was analyzed statistically.

Results: Type 1 diabetic individuals which are homozygous for the mutant alleles of INSR SNPs (rs2245649) T>C and (rs2229429) G>A, exhibited significantly poorer glycemic control compared to those homozygous for the wild-type alleles. The minor allele frequencies of (rs2245649) T>C and (rs2229429) G>A were 26% and 12%, respectively, within the Iraqi sample population. Patients with type 1 diabetes carrying the minor allele of (rs2245649) had a 2.523-fold increased risk of developing insulin resistance (p = 0.04). Furthermore, homozygous mutant carriers of (rs2229429) demonstrated a 10.479-fold higher risk of developing severe hyperglycemia compared to wild-type genotype carriers (p = 0.008). Notably, non-responders to exogenous insulin harboring the (rs2229429) G>A SNP exhibited significantly elevated serum levels of insulin receptors (p<0.001). Similarly, individuals possessing the C allele of (rs2245649) showed higher concentrations of soluble insulin receptors compared to those with the T allele (p = 0.02).
Conclusion: The minor alleles of the investigated SNPs, INSR (rs2245649) T>C and (rs2229429) G>A, were identified in the Iraqi population and found to be significantly associated with severe hyperglycemia and elevated levels of soluble insulin receptor. These findings suggest a potential link between these genetic variants and the development of insulin resistance.