Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
Metabolism. 2011 Sep;60(9):1325-33. doi: 10.1016/j.metabol.2011.02.002. Epub 2011 Apr 12.
The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic β-cell dysfunction. We genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose tolerance test (OGTT) was conducted on all subjects, and a subset (n = 525) additionally underwent a hyperinsulinemic-euglycemic clamp. The 9 chosen single nucleotide polymorphisms cover 100% of the common genetic variation (minor allele frequency ≥0.05) within the TRPM5 locus (D' = 1.0; r² ≥ 0.8). Rs800344, rs800345, and rs2301699 were significantly associated with area under the curve (AUC) glucose during the OGTT in the additive and dominant models after adjustment for sex, age, and body mass index (all Ps ≤ .0025). Furthermore, rs800344 was significantly associated with 2-hour glucose in the dominant model (P = .0009). After stratification for sex, rs2301699 was significantly associated with the ratio of AUC insulin 0 to 30 minutes to AUC glucose 0 to 30 minutes in women (P = .0097), but not in men (P = .3), in the dominant model. Female minor allele carriers of rs2301699 showed significantly lower glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P = .0124), whereas in male subjects, no significant differences were found (P = .3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes; and this may in turn contribute to the development of type 2 diabetes mellitus.
钙敏非选择性阳离子通道 TRPM5 的功能缺失突变可改变葡萄糖诱导的胰岛素分泌和葡萄糖耐量。我们假设 TRPM5 基因的遗传变异可能导致糖尿病前期表型，包括胰岛β细胞功能障碍。我们对 1798 名白人进行了 2 型糖尿病高危人群的基因分型，检测了 9 个 TRPM5 单核苷酸多态性（即 rs2301696、rs800344、rs800345、rs800347、rs800348、rs2074234、rs2301698、rs886277 和 rs2301699），并对代谢特征进行了相关分析。所有受试者均进行口服葡萄糖耐量试验（OGTT），其中一部分（n=525）还进行了高胰岛素正葡萄糖钳夹试验。选择的 9 个单核苷酸多态性涵盖了 TRPM5 基因座内 100%的常见遗传变异（次要等位基因频率≥0.05）（D'=1.0；r²≥0.8）。在调整性别、年龄和体重指数（所有 P≤0.0025）后，rs800344、rs800345 和 rs2301699 与 OGTT 期间的 AUC 葡萄糖呈加性和显性模型显著相关。此外，rs800344 与 2 小时葡萄糖在显性模型中显著相关（P=0.0009）。在按性别分层后，rs2301699 在女性的 AUC 胰岛素 0 到 30 分钟与 AUC 葡萄糖 0 到 30 分钟的比值在显性模型中与性别显著相关（P=0.0097），而在男性中则无显著相关性（P=0.3）。在女性中，携带 rs2301699 次要等位基因的个体在 OGTT 时 30 分钟的胰高血糖素样肽-1 水平显著低于主要等位基因纯合子（P=0.0124），而在男性中则无显著差异（P=0.3）。在我们的德国人群中，常见的 TRPM5 变体可能与糖尿病前期表型相关；这可能进而导致 2 型糖尿病的发生。
