Casa Sollievo della Sofferenza-Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
J Clin Endocrinol Metab. 2013 Jun;98(6):E1143-7. doi: 10.1210/jc.2012-4282. Epub 2013 Apr 30.
Reduced insulin signaling in insulin secreting β-cells causes defective insulin secretion and hyperglycemia in mice.
We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH).
Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607).
Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R(2) = 0.80, P < .001).
Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces β-cell function and impairs glucose homeostasis.
胰岛素分泌细胞中胰岛素信号的减弱会导致小鼠胰岛素分泌缺陷和高血糖。
我们研究了影响胰岛素信号的功能多态性（即 ENPP1 K121Q，rs1044498；IRS1 G972R，rs1801278；和 TRIB3 Q84R，rs2295490）是否对胰岛素分泌和异常葡萄糖稳态（AGH）有共同作用。
通过 1）口服葡萄糖耐量试验（OGTT）中的处置指数（DI）评估胰岛素分泌，在 829 个人中进行；2）在葡萄糖（n = 92）或格列本脲（n = 89）刺激后，从非糖尿病供体的胰岛中评估胰岛素分泌刺激指数（SI）。在意大利和美国 2 型糖尿病遗传学（GENIUS T2D）联盟的病例对照研究中评估 AGH（包括空腹血糖受损和/或糖耐量受损或 2 型糖尿病；T2D）（n = 6607）。
通过累加个体加权风险等位基因效应获得的基因型风险评分与以下因素相关：1）DI（P =.005）；2）葡萄糖和格列本脲 SI（P =.046 和 P =.009）；或 3）AGH（比值比 1.08，95%置信区间 1.03-1.13；P =.001）。我们观察到遗传效应与 AGH 发病年龄之间存在反比关系，这表明 AGH-基因型风险评分比值比与诊断年龄截止值之间存在线性相关（R(2) = 0.80，P <.001）。
影响胰岛素信号的功能多态性对体内和体外胰岛素分泌以及早发 AGH 有共同作用。我们的数据进一步证明，异常的胰岛素信号会降低β细胞功能并损害葡萄糖稳态。
