Genetic variants of the glucose transporter gene SLC2A2 modify the glycemic response to metformin monotherapy in newly diagnosed type 2 diabetes

Introduction:

Pharmacogenetics might explain the observed lack of overall improvement in glycemic control despite the ongoing development of new glucose-lowering drugs. Our aim was to investigate the modifying effect of a genetic variant of the SLC2A2 gene on the glycemic response to metformin, in newly diagnosed type 2 diabetes.

Methods:

The current study was performed within the prospective German Diabetes Study. A total of 509 participants (mean age: 53 ± 10 years; 65% men) with newly diagnosed type 2 diabetes in the previous 12 months underwent detailed demographic and metabolic phenotyping. Participants provided self-reported characteristics from the time of diagnosis. Genotyping of the SLC2A2 gene was performed through allelic discrimination (rs8192675) using real-time PCR.

Results:

At diabetes diagnosis, homo- and heterozygotes for the polymorphic C allele more frequently presented with diabetes symptoms and a tendency for higher glycaemia, compared to homozygotes for the common T allele. In the year following diabetes diagnosis, homo- and heterozygotes for the C allele on metformin monotherapy showed a 42 mg/dl (p= 0.01) greater reduction in fasting glucose levels than homozygotes for the T allele (p for interaction = 0.02), as well as a 21% (p= 0.04) higher increase in C-peptide stimulation (p for interaction = 0.16). These genotypic differences were not observed among participants on metformin combination therapy and participants not receiving medical treatment. Furthermore, there were no evident genotype-treatment interactions regarding changes in insulin sensitivity and obesity.

Conclusion:

The SLC2A2 gene may facilitate personalized medicine, identifying a subgroup of diabetes patients who respond particularly well to metformin monotherapy early-on in disease.