Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University Xiang-Ya School of Medicine, Changsha, Hunan, China.
Br J Clin Pharmacol. 2009 Jul;68(1):14-22. doi: 10.1111/j.1365-2125.2009.03431.x.
The aim of this study was to explore the impact of UCP2 and ADRB3 genetic polymorphisms on the therapeutic efficacy of rosiglitazone in Chinese Type 2 diabetes (T2DM) patients.
A total of 199 T2DM patients and 155 healthy volunteers were enrolled to identify UCP2 -866 G/A genotypes, and 273 T2DM patients and 166 controls were genotyped for Trp64Arg of ADRB3 by polymerase chain reaction-restriction fragment length polymorphism assay. Nine patients with GG genotype and 27 with GA+AA genotype of UCP2 -866 G/A, 11 with Trp64Trp genotype and 25 with Trp64Arg genotype of ADRB3 received oral rosiglitazone as a single-agent therapy (4 mg day(-1)) for 12 weeks. Serum fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin (HbA(1c)), fasting serum insulin, postprandial serum insulin (PINS), triglycerol (TG), cholesterol, homeostasis model assessment for insulin resistance, leptin and adiponectin in all T2DM patients were determined before and after rosiglitazone treatment.
There were no differences in allele frequency of either ADRB3 Trp64Arg or UCP2 -866 G/A between T2DM patients and control subjects. The A allele carriers of UCP2 in the T2DM patients had significantly lower PINS (61.5 +/- 34.3 vs. 41.6 +/- 28.7 mU l(-1), P < 0.01) (37.57, 59.16 vs. 34.82, 49.39) and low-density lipoprotein (LDL)-cholesterol compared with GG genotypes (3.4 +/- 1.1 vs. 2.7 +/- 1.1 mmol l(-1), P < 0.05) (2.64, 3.52 vs. 2.66, 3.15). After rosiglitazone treatment for 12 consecutive weeks, we found that A allele carriers of UCP2 in the T2DM patients had smaller attenuated PINS (-3.82 +/- 13.2 vs.-42.1 +/- 30.7 mU l(-1), P < 0.01) (9.45, 51.31 vs. 0.48, 11.88) and greater attenuated HbA(1c) (-1.85 +/- 1.62 vs.-0.61 +/- 0.80, P < 0.05) (0.14, 1.37 vs. 1.10, 2.38) compared with GG genotypes, and ADRB3 Trp64Arg had greater attenuated serum TG (-3.88 +/- 2.77 vs.-0.24 +/- 1.16 mmol l(-1), P < 0.05) (-0.19, 2.74 vs. 1.19, 1.45) and smaller attenuated LDL-cholesterol (1.08 +/- 1.36 vs.-0.36 +/- 0.99, P < 0.01) (-1.26, 0.78 vs.-1.26, 0.79) as well as reduced enhanced adiponectin (1.57 +/- 1.10 vs. 3.15 +/- 2.12 mmol l(-1), P < 0.05) (1.68, 4.08 vs.-9.18, 11.40) compared with ADRB3 Trp64Trp.
UCP2 -866 G/A and ADRB3 Trp64Arg polymorphisms are associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese T2DM patients.
本研究旨在探讨 UCP2 和 ADRB3 基因多态性对中国 2 型糖尿病（T2DM）患者罗格列酮治疗疗效的影响。
共纳入 199 例 T2DM 患者和 155 例健康志愿者，以鉴定 UCP2-866 G/A 基因型；另外 273 例 T2DM 患者和 166 例对照者，通过聚合酶链反应-限制性片段长度多态性分析鉴定 ADRB3 Trp64Arg。9 例 UCP2-866 G/A 基因型为 GG 者和 27 例 GA+AA 者、11 例 ADRB3 Trp64Trp 基因型者和 25 例 Trp64Arg 基因型者接受罗格列酮（4mg/天）单药治疗 12 周。所有 T2DM 患者治疗前后分别测定空腹血糖、餐后血糖、糖化血红蛋白（HbA1c）、空腹血清胰岛素、餐后血清胰岛素（PINS）、三酰甘油（TG）、胆固醇、胰岛素抵抗指数、瘦素和脂联素。
T2DM 患者和对照者的 ADRB3 Trp64Arg 或 UCP2-866 G/A 等位基因频率无差异。UCP2 基因 A 等位基因携带者的 T2DM 患者 PINS（61.5±34.3 比 41.6±28.7 mU/L，P＜0.01）（37.57，59.16 比 34.82，49.39）和低密度脂蛋白（LDL）-胆固醇均低于 GG 基因型（3.4±1.1 比 2.7±1.1 mmol/L，P＜0.05）（2.64，3.52 比 2.66，3.15）。连续罗格列酮治疗 12 周后，我们发现 UCP2 基因 A 等位基因携带者的 T2DM 患者的 PINS 下降幅度更小（-3.82±13.2 比-42.1±30.7 mU/L，P＜0.01）（9.45，51.31 比 0.48，11.88）和 HbA1c 下降幅度更大（-1.85±1.62 比-0.61±0.80，P＜0.05）（0.14，1.37 比 1.10，2.38），与 GG 基因型相比，ADRB3 Trp64Arg 者的血清 TG 下降幅度更大（-3.88±2.77 比-0.24±1.16 mmol/L，P＜0.05）（-0.19，2.74 比 1.19，1.45）和 LDL 胆固醇下降幅度更小（1.08±1.36 比-0.36±0.99，P＜0.01）（1.26，0.78 比-1.26，0.79），脂联素的增加幅度更小（1.57±1.10 比 3.15±2.12 mmol/L，P＜0.05）（1.68，4.08 比-9.18，11.40）。
UCP2-866 G/A 和 ADRB3 Trp64Arg 多态性与中国 T2DM 患者罗格列酮多剂量治疗疗效相关。
