TCF7L2 and therapeutic response to sulfonylureas in patients with type 2 diabetes

We recruited 189 patients with T2D being treated with SUs and determined the rs7903146 diabetes risk genotype. We used a logistic regression with secondary SU failure defined as an A1C ≥7.0% after 6 months of SU treatment.In univariate regression analyses, TCF7L2 genotype was the only predictor of SU treatment failure. The rs7903146 T allele was significantly more frequent in the group of patients who failed to respond to SU (36%) than in the control group (26%) [P = 0.046; odds ratio (OR): 1.57 (1.01-2.45) in an additive mode of inheritance].Our data suggest that patients with diabetes risk alleles in TCF7L2 have an altered hypoglycaemic response to SUs resulting in earlier secondary failure.The TCF7L2-gene (TCF7L2; Transcription factor 7-like 2) encodes a transcription factor (Tcf-4) that is involved in the regulation of cellular proliferation and differentiation [1]. Variants in the TCF7L2 have initially been shown to be associated with an increased risk for type 2 diabetes (T2D) in a genome-wide analysis of the isolate population of Iceland [2]. The strongest associations with T2D with a clear gene dose effect were reported for the rs7903146 variant [3]. The initial findings have been replicated in independent studies in multiple ethnic populations and were summarized in a large global meta-analysis [4]. The risk alleles actually predicted the progression from impaired glucose tolerance to diabetes prospectively [5] and an increased severity of the disease [6] in adults. Also, TCF7L2 variants conferred a higher risk for early impairment of glucose metabolism emerging as soon as in childhood and adolescence [7]. Some clinical data suggested that the polymorphisms affected the capacity of pancreatic β-cells to secrete insulin rather than aggravating insulin resistance [5,8-13], possibly by impaired β-cell proinsulin-processing [14]. This was further supported by expression data suggesting a putative role of TCF7L2 in β-cell differentiation [12]. Considering the ro