Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE Ser1369Ala Variant in Sulfonylurea Receptor Gene ABCC8 Is Associated With Antidiabetic Efficacy of Gliclazide in Chinese Type 2 Diabetic Patients 1 3 YAN FENG, MD, PHD XUEQI LI, MD he epidemic of type 2 diabetes in the 1 4 GUANGYUN MAO, MD, PHD LIRONG SUN, MD last decade in both developed and 1 5 XIAOWEI REN, MD JINQUI YANG, MD, PHD 1 6 developing countries has made it a OUXUN ING MD EIQING A MD T H X , W M , 1 7 major threat to global public health. At GENFU TANG, MD XIAOBIN WANG, MD, SCD 2 1 least 171 million people worldwide had QIANG LI, MD, PHD XIPING XU, MD, PHD diabetes in 2000, and this figure is likely to more than double by 2030 to reach 366 million (1). The majority of diabetes is OBJECTIVE — The purpose of this study was to investigate whether genetic variants could type 2 diabetes. Most of the recent rise in influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients. diabetes prevalence is probably a result of lifestyle and dietary changes, but there is RESEARCH DESIGN AND METHODS — A total of 1,268 type 2 diabetic patients also clear evidence for genetic predisposi- whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic tion to this complex disease. During the treatment were enrolled from 23 hospitals in China. All of the patients were treated with last decade, molecular genetic studies of gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, fasting insulin, type 2 diabetes have shown significant and A1C were measured at baseline and after 8 weeks of treatment. We used two independent progress (2). Five genome-wide associa- 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 tion studies have been published since association with adjustment for important covariates. February 2007, increasing the number of confirmed type 2 diabetes susceptibility loci from three (PPARG, KCNJ11, and RESULTS — After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was TCF7L2) to 9 (with the addition of 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 CDKAL1, CDKN2A/B, IGF2BP2, HHEX/ significantly associated with decreases in FPG (P ϭ 0.002). We further genotyped Ser1369Ala in IDE, FTO, and SLC30A8) (2). In addition, cohort 2 (n ϭ 607) and confirmed the association identified in cohort 1. In the pooled analysis, studies have lent support for the involve- compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a ment of many other genes, such as ABCC8 7.7% greater decrease in FPG (P Ͻ 0.001), an 11.9% greater decrease in 2-h plasma glucose (P ϭ (3–6). In contrast, few studies have inves- 0.003), and a 3.5% greater decrease in A1C (P ϭ 0.06) after 8 weeks of treatment with gliclazide. tigated whether genetic variants may modulate the response to antidiabetic CONCLUSIONS — In two independent cohorts of Chinese type 2 diabetic patients, we agents in type 2 diabetic patients (7–9). found consistent evidence that the Ser1369Ala variant in the ABCC8 gene can influence the Such information can assist clinicians in antidiabetic efficacy of gliclazide. developing individualized treatment plans that will maximize therapeutic effi- Diabetes Care 31:1939–1944, 2008 cacy and minimize side effects. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Sulfonylurea is a widely used oral hy- From the 1Anhui Biomedical Institute, Anhui Medical University, Hefei, China; the 2Division of Endocri- poglycemic agent. Most type 2 diabetic nology, the Second Hospital, Harbin Medical University, Harbin, China; the 3Division of Endocrinology, patients respond well to this agent, but the First Hospital, Harbin Medical University, Harbin, China; 4Tianjin Medical University Metabolic variable efficacy is seen, and primary fail- 5 Hospital, Tianjin, China; the Division of Endocrinology, Tongren Hospital, Capital Medical University, ure to sulfonylurea treatment is seen in a Beijing, China; the 6Division of Endocrinology, the First Hefei People’s Hospital, Hefei, China; and the 7The Mary Ann and J. Milburn Smith Child Health Research Program, Children’s Memorial Hospital and small portion of patients. Secondary fail- Children’s Memorial Research Center, Chicago, Illinois. ure of sulfonylurea monotherapy devel- Corresponding author: Xiping Xu, [email protected]. ops in ϳ34% of patients at 5 years (10). Received 26 November 2007 and accepted 21 June 2008. To explore the underlying genetic factors Published ahead of print at http://care.diabetesjournals.org on 3 July 2008. DOI: 10.2337/dc07-2248. Y.F. and G.M. contributed equally to this study. that may explain individual variable re- Y.F. is currently affiliated with Bridgeport Hospital, Yale University School of Medicine, New Haven, Con- sponse to sulfonylurea, we conducted a necticut. hospital-based pharmacogenetic study. © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly Our goal was to examine whether type 2 cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. diabetes candidate gene variants can in- org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby fluence the antidiabetic efficacy of glicla- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. zide, a commonly used sulfonylurea DIABETES CARE, VOLUME 31, NUMBER 10, OCTOBER 2008 1939 Ser1369Ala variant in ABCC8 and gliclazide hypoglycemic agent, in Chinese type 2 di- Data collection and clinical our central laboratory. The insulin secre- abetic patients. laboratory methods tion (HOMA-B) and resistance index of At the first visit (screening), a standard homeostatic model assessment (HOMA- questionnaire was administered to collect IR) were calculated according to fasting RESEARCH DESIGN AND information on medical history and med- glucose and insulin level using the METHODS — We conducted a hospi- ication, diet, exercise, and lifestyle factors HOMA2 calculator (http://www.dtu.ox. tal-based pharmacogenetic study of gli- including smoking and alcohol drinking, ac.uk/homa). clazide in type 2 diabetic patients in household income, educational level, and China between December 2003 and Au- occupation. Height, weight, waist cir- Candidate gene and SNP selection gust 2005. Patients were recruited from cumference, and blood pressure were and genotyping method 23 hospitals located in Harbin of the Hei- measured using a standard protocol. We selected 11 type 2 diabetes candidate Ͼ longjiang province, Beijing, Tianjin, and Overnight ( 10 h) fasting blood samples genes on the basis of the published liter- Hefei and Anqing of the Anhui province were collected to determine FPG, insulin, ature (see Table 2). For each gene, one to following the same study protocol. The A1C, lipid profile, liver and renal func- six nonsynonymous or haplotype-tagging 23 hospitals selected were the major hos- tion, and routine blood cell counts. All SNPs, according to the HapMap data study patients underwent a 75-g oral glu- (http://www.hapmap.org/), were se- pitals in the study regions. These hospi- cose tolerance test (OGTT) unless FPG lected. In our central laboratory, we geno- tals were all government owned but were was Ն13.0 mmol/l, and blood samples typed all 25 selected SNPs for all of the run independently. were collected after2htodetermine subjects in cohort 1, which consisted of Type 2 diabetes was diagnosed ac- plasma glucose. Diabetes education was 661 patients from 12 participating hospi- cording to American Diabetes Association also provided to all potentially eligible tals located in northern China. We further criteria (11). To reduce the clinical heter- subjects during the screening visit. The genotyped one significant nonsynony- ogeneity of type 2 diabetes, this study was education included a brief introduction mous SNP (rs757110) identified in co- limited to Han Chinese subjects with on- on type 2 diabetes, with a particular focus hort 1 for all subjects in cohort 2, which set of type 2 diabetes after the age of 35 on diet and physical exercise. In addition, consisted of 607 patients from the re- years who also met all of the following a handbook with more detailed informa- maining 11 participating hospitals lo- criteria: 1) diabetes diagnosed within the tion was given to the subjects for them to cated in southern China. The reasons for past 5 years and no antidiabetes treatment read. the two-phase genotyping were twofold: within the past 2 months, 2)BMIϽ28 All study patients returned for fol- reduce the genotyping cost and minimize kg/m2, and 3) fasting plasma glucose low-up every 2 weeks. A follow-up ques- the multiple testing problem, which (FPG) between 7.8 and 15.0 mmol/l. We tionnaire was administered to monitor could inflate type I error. excluded patients with any acute or patients’ medications, diet, exercise, and DNA was extracted from leukocytes chronic diabetes complications, unstable side effects of gliclazide. Specifically, the in peripheral blood using standard tech- angina, myocardial infarction or heart research staff documented whether the niques. Genotyping was performed by failure, chronic gastrointestinal disease or subjects complied with the treatment and TaqMan genotyping assays that were de- abnormal liver function, renal insuffi- followed the instruction for diet (with a signed and manufactured by Applied Bio- ciency, or clinical problems potentially grade of very good, fair, and poor) and systems (Foster City, CA).