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.

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Department of Internal Medicine

Jainandunsing, S., Koole, H.R. (H. Rita), van Miert, J.N.I. (Joram N.I.), Rietveld, T., Wattimena, J., Sijbrands, E., & de Rooij, F. (2018). Transcription factor 7-like 2 gene links increased in vivo insulin synthesis to type 2 diabetes. EBioMedicine, 30, 295–302. doi:10.1016/j.ebiom.2018.03.026