Transcription factor 7-like 2 gene links increased in vivo insulin synthesis to type 2 diabetes

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.
Highlights • We developed a test to follow insulin synthesis in real-time in vivo and used it in type 2 diabetes high-risk families. • Insulin synthesis was increased in individuals with non-insulin treated type 2 diabetes. • A variant of the TCF7L2 gene linked insulin synthesis with type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) is the main susceptibility gene for type 2 diabetes, predominantly by affecting insulin secretion of pancreatic β cells. However the exact in vivo mechanisms remain poorly understood. We investigated the relationship between the TCF7L2 rs7903146 variant and real-time insulin synthesis measurements in vivo. We found that genetically increased insulin synthesis contributed to development of type 2 diabetes. Our data implies that hyperinsulinemia is a sign not only of resistance to insulin but also of intrinsic β cell dysfunction. Our findings can help in the understanding and treatment of type 2 diabetes. The glucose-sensitive TFC7L2 pathway might be a target for intervention.