Effects of TCF7L2 rs7903146 variant on metformin response in patients with type 2 diabetes

Abstract

The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C>T within the transcription factor 7 like 2 gene (TCF7L2) is the strongest genetic risk factor associated with T2D to date. In this study we explored the effects of TCF7L2 rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of TCF7L2 rs7903146 was performed by the Sequenom MassARRAY® iPLEX® platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (p = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9-38.3%, p = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1-44.1%, p = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1-12.0%, p = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0-25.6%, p = 0.002) compared to the patients with CC genotype. Our results suggest that TCF7L2 rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.

Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target

“…As for islet function, T/T-allele homozygotes exhibited 3.2 mg/dl higher baseline fasting glucose levels than C/C allele homozygotes. In addition, TCF7L2 rs7903146 reduces the efficiency of glipizide and metformin in pre-diabetic or newly diagnosed T2D subjects ( 60 , 61 ). As previously mentioned, TCF7L2 can promote GLP-1 expression and sensitize pancreatic β-cells to blood glucose, but TCF7L2 rs7903146 causes a decrease in protein levels.…”

A Polygenic Score for Type 2 Diabetes Risk Is Associated With Both the Acute and Sustained Response to Sulfonylureas

“…In particular, TCF7L2, the gene harboring common genetic variants with the largest effect 60 on T2D susceptibility discovered to date, has been associated with drug response to sulfonylureas 61 in those with established T2D (18) and in those at risk of T2D (19). For metformin, TCF7L2 has been associated with glycemic response in the early stages of disease (19,20). Because individual variants only have a modest effect, the field is now embracing the use of polygenic scores of aggregated variants, which offer increasing power and capture a greater proportion of the variance explaining a given trait (21).…”

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

“…Transcription factor 7‐like 2 (TCF7L2) gene is closely related to T2DM and obesity . Patients with a single nucleotide polymorphism (SNP) TT or TC genotype in the TCF7L2 gene are 2 to 1.4 times more likely to have T2DM than CC homozygous patients .…”

“…Transcription factor 7-like 2 (TCF7L2) gene is closely related to T2DM and obesity. [22][23][24] Patients with a single nucleotide polymorphism (SNP) TT or TC genotype in the TCF7L2 gene are 2 to 1.4 times more likely to have T2DM than CC homozygous patients. 25 Studies have shown that TCF7L2 can play a significant role in regulating adipose tissue and pancreas via the WNT signalling pathway.…”