Influence of genetic factors in newly diagnosed type 2 diabeticpatients: the TCF7L2 and GENETIC LOAD studies.

Background. Genome wide association studies (GWAS) have played a primary role in demonstrating that genetic variation in a number of loci, as assessed by single nucleotide polymorphisms (SNPs), affects the risk of type 2 diabetes mellitus (T2DM). Among these, rs7903146, an intronic variant of the TCF7L2 (Transcription Factor 7 Like 2) gene, is possibly the strongest known genetic risk factor for T2DM (O.R.=1.37). Each risk variant, however, per se contributes quantitatively little to the overall risk and is often of questionable biological significance in affecting the determinants of glucose regulation. Aim(s). To elucidate the effects of several T2DM risk genetic loci on clinical and pathophysiological (beta-cell function and insulin sensitivity) phenotypes of patients with newly diagnosed T2DM. Methods. We studied 464 patients of Italian ancestry with newly diagnosed, GAD-antibody negative, type 2 diabetes mellitus. Standard clinical phenotyping was carried out by classical methods. Beta-cell function and insulin sensitivity were assessed by mathematical modeling of glucose and C-peptide curves during a 240’ frequently sampled OGTT and by euglycemic insulin clamp, respectively. Beta-cell function is described as the sum of two components: i. first phase of insulin secretion or derivative control (DC), presented as the pulse secretory response to a unit rate of change in glucose concentration; ii. second phase of insulin secretion or proportional control (PC), presented as the insulin secretion rate at glucose concentrations of 5.5, 8.0, 11.0, 15.0 and 20.0 mM, respectively. Insulin sensitivity is presented as the amount of glucose infused which is metabolized in the last 60’ of the euglycemic clamp (M value). The following SNPs (related gene in brackets), already known to be risk loci of T2DM, were genotyped: rs7901695 (TCF7L2), rs7903146 (TCF7L2), rs11196205 (TCF7L2), rs12255372 (TCF7L2), rs679931 (CACNA1E), rs1801282 (PPARG), rs1044498 (ENPP1), rs10946398 (CDKAL1), rs1111875 (HHEX/IDE) rs10010131 (WFS1), rs4430796 (TCF2), rs4402960 (IGF2BP2). Results. TCF7L2. The risk alleles of 3 (rs7901695, rs7903146, rs11196205) out of 4 TCF7L2 SNPs were associated with higher fasting plasma glucose (p<0.01, p<0.03 and p<0.01 respectively). The risk alleles of the first two SNPs (rs7901695, rs7903146) were associated to a decrease in the proportional control of beta-cell function (p<0.02 and p<0.03 respectively). Four TCF7L2 haplotypes were detected, two of which (haplo4, frequency: 0.038; and haplo9, frequency: 0.086) had a strong impact on beta-cell function. Haplo4 was associated with the lowest proportional control of beta-cell function while haplo9 showed the highest. Other genetic variants. None of the 8 remaining SNPs (rs679931, rs1801282, rs1044498, rs10946398, rs1111875, rs10010131, rs4430796, rs4402960) showed any significant independent association with insulin sensitivity or beta-cell function. We computed a genetic risk score of this variants, by summing the number of the T2DM risk alleles present in each patient (excluding TCF7L2). The patients were divided into three groups: 6 or less risk alleles (group A, n=76), 7-9 risk alleles (group B, n=226), 10 or more risk alleles (group C, n=69). The porportional control of beta-cell function was significantly impaired (P=0.05) in group C than in the other two groups, i.e. the higher the number of T2DM risk variants the lower beta cell function. Conclusions. These data show that several genetic variants play a significant role in determining the pathophysiological phenotype of patients with newly diagnosed type 2 diabetes, with most of the influence exerted on beta-cell function. Thus, assessment of T2DM risk genotype may turn to be useful for diagnostic, prognostic and therapeutic purposes in patients with newly diagnosed T2DM.