Ser1369Ala Variant in Sulfonylurea Receptor Gene ABCC8 Is Associated With Antidiabetic Efficacy of Gliclazide in Chinese Type 2 Diabetic Patients

Abstract

OBJECTIVE -The purpose of this study was to investigate whether genetic variants could influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS-A total of 1,268 type 2 diabetic patients whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic treatment were enrolled from 23 hospitals in China. All of the patients were treated with gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, fasting insulin, and A1C were measured at baseline and after 8 weeks of treatment. We used two independent cohorts to test the associations of 25 single nuclear polymorphisms in 11 candidate genes with the antidiabetic efficacy of gliclazide. A general linear regression model was used to test the association with adjustment for important covariates.RESULTS -After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was reduced from 11.1 mmol/l at baseline to 7.7 mmol/l. In cohort 1, we genotyped all 25 SNPs (n ϭ 661) and found that Ser1369Ala of the ABCC8 gene and rs5210 of the KCNJ11 gene were significantly associated with decreases in FPG (P ϭ 0.002). We further genotyped Ser1369Ala in cohort 2 (n ϭ 607) and confirmed the association identified in cohort 1. In the pooled analysis, compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a 7.7% greater decrease in FPG (P Ͻ 0.001), an 11.9% greater decrease in 2-h plasma glucose (P ϭ 0.003), and a 3.5% greater decrease in A1C (P ϭ 0.06) after 8 weeks of treatment with gliclazide.CONCLUSIONS -In two independent cohorts of Chinese type 2 diabetic patients, we found consistent evidence that the Ser1369Ala variant in the ABCC8 gene can influence the antidiabetic efficacy of gliclazide.

The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis

“…Our results also indicated that the current BMI of patients with TPP was higher than that of patients with pure hyperthyroidism, confirming the results of Soonthornpun et al (2009). Additionally, a Chinese study revealed that non-obese type 2 diabetic patients with the Ala1369 variant have a better hypoglycaemic response to anti-diabetic sulphonylurea drug gliclazide than Ser1369 patients, reinforcing the existence of insulinresponse genetic predisposition for those bearing this variant (Feng et al 2008). In this study, the C-allele of the Ala1369 risk variant was present at a higher frequency in TPP patients than in the population genetics control that consisted of 1092 multi-ethnic subjects from the 1000 Genomes project.…”

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…A recent publication reported genotyped 25 SNPs from 661 Chinese T2DM patients who received 8 weeks of gliclazide therapy. The subjects with GG genotype in SUR exon 33(S1369A, rs757110) had a 7.7% greater decrease in FPG and 11.9% greater decrease in HbA1c after 8 weeks of gliclazide therapy [127].…”

“…It was described that the exon 33 of the ABCC8 (rs757110) and KCNJ11 (rs5210) genes were associated with gliclazide antidiabetic efficacy [127]. SNPs of TCF7L2 had been consistently associated with T2DM in different ethnic descent and also had great impact on the T2DM patients' response to sulfonylureas [128].…”

Role of KCNJ11 Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus

“…Isoleucine is usually interchangeable with leucine and occasionally with valine in proteins. Of 13 studies on DM, 3 showed strong associations between this variant and T2DM 38,41,46 , whereas the remaining studies showed no association with T2DM47 [60][61][62][77][78][79][80][81][82] . In another study, the rs5215 polymorphism was associated with blood pressure among subjects with T2DM 47,93 .…”