Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

Abstract

Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.

Figure 1. Diabetes-free survival (Kaplan-Meier curves) in carriers of different TCF7L2 rs7903146 genotypes.

(A) Diabetes-free survival in the MPP (n = 6,913). (B) Diabetes-free survival in the Botnia study (n = 2,651). The blue lines represent carriers of non-risk CC genotype; the red lines represent carriers of the risk CT/TT genotypes. 95% CIs are from logistic regression analyses adjusted for age at entry and time of follow-up, BMI, sex, and family history of diabetes.

Figure 2. Insulin secretion according to different TCF7L2 rs7903146 genotypes or haplotypes.

(A) Insulinogenic index, i.e., incremental (40-minute) insulin response to oral glucose (Malmö cohort; n = 1,038). (B) Disposition index represents the insulinogenic index adjusted for insulin sensitivity by the HOMA index (Malmö cohort; n = 1,038). (C) Change in insulin secretion (disposition index) over time in subjects who converted to T2D (Botnia cohort, n = 120; n = 420 observations). (D) AIR to arginine at basal level (5 mmol/l) and 14 and 28 mmol/l of glucose according to TCF7L2 rs7903146 genotypes in subjects with IGT/T2D (Malmö cohort; n = 130). (E) AIR to arginine at 14 mmol/l of glucose according to TCF7L2 rs7903146 genotypes in subjects with IGT/T2D. (F) AIR to arginine at 28 mmol/l of glucose according to TCF7L2 rs7903146 genotypes in subjects with IGT/T2D. Bars represent mean ± SEM. Blue lines represent non-risk and red lines risk genotype carriers of rs7903146 in TCF7L2.

Figure 3. Metabolic effects of different genotypes in rs7903146 of TCF7L2.

(A) Correlation between the area under the insulin curve during OGTT and IVGTT (Botnia cohort; n = 403). (B) Incretin effect measured as 100% × (AUC_{ins OGTT} – AUC_{ins IVGTT})/AUC_{ins OGTT} in hyperglycemic subjects (fasting plasma glucose > 5.4 mmol/l) (Botnia cohort; n = 235). (C) Correlation between fasting GIP (pg/ml) and glucagon (pg/ml) concentrations (Botnia cohort; n = 78). (D) Whole-body glucose uptake during a euglycemic-hyperinsulinemic clamp. (E) Basal EGP. (F) Change in BMI over time in subjects who converted to T2D. Bars represent mean ± SEM. Blue lines represent non-risk and red lines risk genotype carriers of rs7903146 in TCF7L2.

Figure 4. Expression of TCF7L2 in human pancreatic islets was influenced by T2D and correlates positively with insulin gene expression and negatively with insulin secretion.

(A) The TCF7L2 mRNA levels in human pancreatic islets. (B) The TCF7L2 mRNA levels in different TCF7L2 rs7903146 genotype carriers. (P refers to ANCOVA comparison between CC, CT, and TT genotypes) (C) Correlation between the TCF7L2 mRNA levels and insulin gene expression. (D) Correlation between the TCF7L2 mRNA levels and glucose-stimulated insulin release (stimulation index). Bars represent mean ± SEM.

Figure 5. Colocalization of TCF7L2 expression with insulin in pancreatic islets(A–D).

Double staining of RhodZin (red) (B) and TCF7L2 (green) (C) in human pancreatic islets (yellow) (D).