Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, People's Republic of China.
J Clin Endocrinol Metab. 2013 Jul;98(7):E1272-7. doi: 10.1210/jc.2013-1137. Epub 2013 May 2.
The purpose of this study was to investigate the association of two novel β3-adrenergic receptor (ADRB3) gene polymorphisms (Ser165Pro and Ser257Pro) with type 2 diabetes (T2DM) in the Chinese population.
A total of 650 patients with T2DM and 1337 health volunteers were enrolled to conduct the association study. Two candidate polymorphisms were recreated by site-directed mutagenesis and tested for their effect on ADRB3 expression and function in stable transfected human embryonic kidney 293 and Chinese hamster ovary-K1 cells. Real-time PCR, Western blot, confocal microscopy, and cAMP assay were used to determine mRNA, protein expression, trafficking, and ADRB3 function, respectively.
We found that both polymorphisms were significantly associated with T2DM (odds ratio = 2.060 and 95% confidence interval = 1.303-3.258 for Ser165Pro and odds ratio = 7.588, 95% confidence interval = 1.639-35.138 for Ser257Pro). Patients with T2DM with the Ser165Pro C allele had higher hemoglobin A1c, fasting plasma glucose and postprandial plasma glucose values than those in TT genotypes. We also found that patients with T2DM with the Ser257Pro C allele had lower fasting serum insulin, postprandial serum insulin, and homeostasis model assessment for insulin resistance levels than TT genotype carriers. Further in vitro study indicated that cell lines stably expressing Ser165Pro and Ser257Pro mutants of the ADRB3 gene showed impaired cAMP accumulation activity. However, both polymorphisms had no effect on ADRB3 expression and trafficking.
Ser165Pro and Ser257Pro polymorphisms affected ADRB3 function and were significantly associated with susceptibility to and development of T2DM.
本研究旨在探讨两种新型β3-肾上腺素能受体（ADRB3）基因多态性（Ser165Pro 和 Ser257Pro）与中国人群 2 型糖尿病（T2DM）的相关性。
共纳入 650 例 T2DM 患者和 1337 名健康志愿者进行关联研究。通过定点诱变重建两个候选多态性，并在稳定转染的人胚肾 293 和中国仓鼠卵巢-K1 细胞中检测其对 ADRB3 表达和功能的影响。实时 PCR、Western blot、共聚焦显微镜和 cAMP 测定分别用于测定 mRNA、蛋白表达、转运和 ADRB3 功能。
我们发现这两种多态性与 T2DM 显著相关（Ser165Pro 的多态性比值比=2.060，95%置信区间=1.303-3.258；Ser257Pro 的多态性比值比=7.588，95%置信区间=1.639-35.138）。携带 Ser165Pro C 等位基因的 T2DM 患者的糖化血红蛋白、空腹血糖和餐后血糖值均高于 TT 基因型。我们还发现，携带 Ser257Pro C 等位基因的 T2DM 患者的空腹血清胰岛素、餐后血清胰岛素和稳态模型评估的胰岛素抵抗水平均低于 TT 基因型携带者。进一步的体外研究表明，稳定表达 ADRB3 基因 Ser165Pro 和 Ser257Pro 突变体的细胞系 cAMP 积累活性受损。然而，这两种多态性均对 ADRB3 表达和转运没有影响。
Ser165Pro 和 Ser257Pro 多态性影响 ADRB3 功能，与 T2DM 的易感性和发展显著相关。
