تأثير تعدد الشكل الجيني لناقل الكاتيون العضوي الاول على الاستجابة العلاجية للميتفورمين للرجال المصابين بمرض السكري من النوع الثاني في محافظة كربلاء

Influence of Genetic Polymorphism of Organic Cation Transporter-1 on Therapeutic Response of Metformin in Type 2 Diabetes Mellitus Patients of Kerbala Province

Abstract

Background
Diabetes is one of the most serious health problems in the world and the most common metabolic disease in humans, characterized by abnormal glucose and fat metabolism. The pathological abnormalities in type 2 diabetes mellitus (T2DM) are impaired insulin secretion from pancreatic beta-cell and/or impaired insulin action due to insulin resistance. The environmental and genetic factors consider important risk factors for T2DM. Multiple genes that contribute to T2DM susceptibility and in heterogeneity of drug responses which have been successfully identified by genome-wide association studies (GWAS).
Different responses to pharmacological treatment may be explained by the presence of a genetic mutation, These genetic variations are associated with either pharmacological targets or drug metabolism effects. Metformin is the first-line, antidiabetic therapy for the treatment of T2DM over the past few decades, it acts primarily on tissues that targeted by insulin, such as the liver, muscle, and adipose tissues, by suppression of hepatic glucose production, increasing the glucose uptake by the skeletal muscles. Also decreasing the absorption of glucose in the intestinal mucosa, and reducing appetite.
The organic cation transporter (OCT1) is found mainly in human hepatocytes and it is responsible for the uptake of many endogenous and exogenous substances including metformin. Because the uptake of metformin by hepatocytes is necessary to elucidate its pharmacological actions, This makes the OCT 1 very important for the therapeutic action of metformin
Variations in the SLC22A1 gene may lead to changes in the function of the OCT1 protein, resulting in a variety of metformin concentrations, these changes in pharmacokinetics and pharmacodynamics profile of metformin leading to change in the therapeutic response to it.
Aims:
To investigate the presence and distribution of Met420 deletion rs72552763 genetic polymorphism of OCT1 and its association with the pathogenesis of T2DM in diabetic male patients. And to investigate the effect of genetic polymorphism of OCT1 on therapeutic response to metformin male patients with T2DM in Kerbala .
Subjects and Methods:
In this cross-sectional study: a total of 150 healthy men and 200 male patients with T2DM treated with metformin (500 mg / tid) between the ages of 30 and 50 years were enrolled, all patients had already been diagnosed as diabetics with type 2 diabetes. Biochemical tests and genetic studies were performed for all patients and healthy control participants to determine the presence of OCT1 SNP and to analyze its effect on the therapeutic response of metformin.

Results:
The results demonstrated that the alleles frequencies of 420del OCT1 were similar in patients with T2DM and control group, concerning metformin action, patients with reference allele (wild type) and heterozygous allele of 420del OCT1 showed statistically different degrees of significant metabolic response to metformin, whereas the patients with mutant allele showed a less or statistically non-significant response.

Conclusion:
Genetic variation in OCT1 was associated with heterogeneity in response to metformin in male patients with T2DM in Kerbala, but it was not correlating with the incidence of type2 DM.