TCF7L2 Genetic Variation and the Acute Glycaemic Response to Metformin in Patients With Type 2 Diabetes

TCF7L2 may affect fasting and postprandial hyperglycaemia in carriers of the rs7903146 polymorphism due to its crucial role in hepatic glucose production. Metformin functions by reducing hepatic glucose production while simultaneously increasing peripheral glucose uptake. Thus, the intensity of response under application of metformin may depend on the presence of TCF7L2 gene polymorphism. The aim was to analyze the association between rs7903146 polymorphism of the TCF7L2 gene and acute metformin glycaemic response in patient with newly diagnosed type 2 diabetes (T2D) measured by continuous glucose monitoring (CGM).

Methods:

We genotyped rs7903146 in 77 patients with newly diagnosed T2D. Both gender (39% male) aged 35-72 years, body mass index 33.9±4.3 kg/m2, HbA1c 9.2±1.5 % and treatment naïve to metformin were included. All patients received metformin at an initial dose of 1500 mg per day. Glycemic parameters such as, mean 24-hour glucose level, minimum 24-hour glucose level and 24-hour standard deviation (glycemic variability) were derived from data collected with a CGM system iPro2 after the 5th half-life of drug. Analyses were performed in Statistica for Windows version 10.0 (StatSoft Inc., USA). A p-value of less than 0,05 was considered significant.

Results:

The frequencies of the CC, CT and TT genotypes were 57.1%, 36.4% and 6.5% respectively. Minor allele T frequency was 0.25. Genotype distribution followed Hardy-Weinberg equilibrium. All patients receiving 1500 mg of metformin per day, were divided into two groups based on rs7903146 genotype: CC genotype carriers (n=44) and CT/TT genotype carriers (n=33). The mean 24-hour glucose level and the minimum 24-hour glucose level tended to be higher in CT/TT genotype carriers than in CC genotype carriers: 6.2 [5.9; 6.9] versus 6.0 [5.8; 6.2] mmol/l (p=0.23) and 4.2 [3.7; 4.3] versus 3.8 [3.3; 4.4] mmol/l (p=0.31) respectively, but these were not statistically significant. We observed no differences in the measures of glycemic variability between the two groups: 24-hour standard deviation of CC genotype carriers was 0.9 [0.8;1.1] mmol/l versus 0.8 [0.6; 1.0] mmol/l of CT/TT genotype carriers (p >0,05). Additionally, no significant differences in prescribed dose change were observed among the different genotypes after 3 months of observation (χ2=0,12; p=0,94).

Discussion/Conclusion:

There is a considerable variability in the effect of metformin. The glycaemic response to metformin is consider has been widely associated with a number of gene polymorphisms. Our findings demonstrate that common variant of TCF7L2 rs7903146 does not influence acute glycaemic response to metformin in type 2 diabetic patients. In summary, a more complete investigation of TCF7L2 variants may identify novel polymorphisms which can affect the metformin response.