Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
EBioMedicine. 2018 Apr;30:295-302. doi: 10.1016/j.ebiom.2018.03.026. Epub 2018 Mar 30.
Transcription factor 7-like 2 (TCF7L2) is the main susceptibility gene for type 2 diabetes, primarily through impairing the insulin secretion by pancreatic β cells. However, the exact in vivo mechanisms remain poorly understood. We performed a family study and determined if the T risk allele of the rs7903146 in the TCF7L2 gene increases the risk of type 2 diabetes based on real-time stable isotope measurements of insulin synthesis during an Oral Glucose Tolerance Test. In addition, we performed oral minimal model (OMM) analyses to assess insulin sensitivity and β cell function indices. Compared to unaffected relatives, individuals with type 2 diabetes had lower OMM indices and a higher level of insulin synthesis. We found a T allele-dosage effect on insulin synthesis and on glucose tolerance status, therefore insulin synthesis was higher among T-allele carriers with type 2 diabetes than in wild-type individuals. These results suggest that hyperinsulinemia is not only an adaptation to insulin resistance, but also a direct cause of type 2 diabetes.
转录因子 7 样 2（TCF7L2）是 2 型糖尿病的主要易感基因，主要通过损害胰岛β细胞的胰岛素分泌。然而，确切的体内机制仍知之甚少。我们进行了一项家族研究，并通过实时稳定同位素测量口服葡萄糖耐量试验期间的胰岛素合成，确定 TCF7L2 基因 rs7903146 中的 T 风险等位基因是否会增加 2 型糖尿病的风险。此外，我们进行了口服最小模型（OMM）分析，以评估胰岛素敏感性和β细胞功能指数。与未受影响的亲属相比，2 型糖尿病患者的 OMM 指数较低，胰岛素合成水平较高。我们发现胰岛素合成和葡萄糖耐量状态存在 T 等位基因剂量效应，因此 2 型糖尿病患者的 T 等位基因携带者的胰岛素合成高于野生型个体。这些结果表明，高胰岛素血症不仅是对胰岛素抵抗的一种适应，也是 2 型糖尿病的直接原因。
