Background and aims: Type 2 diabetes (T2DM) is a complex disease, in which both genetic and environmental factors contribute to injure β-cell function (BCF) and insulin sensitivity (IS). Aim of the study was to evaluate the changes over the time of BCF and IS in subjects of the VNDS cohort. Methods: 88 subjects (M/F=65/23; mean±SD: age at diagnosis 55.1±8.7 years, HbA1c 6.7±1.0%), belonging to the VNDS cohort, were longitudinally evaluated, at diagnosis of diabetes and 10 years later, for metabolic phenotypes: insulin sensitivity (SI), by the euglycemic hyperinsulinemic clamp, and β-cell function (BCF) by derivative (DC) and proportional control (PC) through state-of-art modelling of glucose/C-peptide curves during 5h-OGTT. All subjects were genotyped for 19 tag-SNPs covering 95% of common variability of the following genes: TCF7L2, GCKR and FTO. Paired t-test was applied to means comparison, whereas regressions were adjusted for age and HbA1c at diagnosis, change in both HbA1c and BMI during 10 years. Results: Over the time, both DC (690.5±72.6 vs 383.1±46.9 pmol·m-2 BSA; p<0.001) and PC (61.8±3.7 vs 51.2±6.2 pmol·min-1·m-2BSA·mmol/l; p=0.008) significantly worsened, while IS did not show significant changes (746.4±31.8 vs 714.0±41.3 umol/min/m2BSA; p=0.085) as well as BMI (29.0±5.6 vs 29.5±5.7 kg/m2, p=0.161). In regression analysis, the minor alleles of three TCF7L2 tag-SNPs, rs7903146 (G), rs12255372 (A) and rs7901695 (A) were significantly associated with reduction of DC (p<0.020) and both the minor alleles of GCKR, rs1049817 (A) and rs6547626 (G) were associated with a defective PC (p<0.032). Finally, the major allele of rs11114831 (G) and the minor allele of rs1477092 (A) within FTO gene were associated with a lower IS (p<0.025), but no with changes in BMI (p>0.05). Conclusions: In the subjects of the VNDS cohort, the genetic architecture is confirmed to influence both BCF and IS, over the time. The identification of these genetic loci might be useful for risk stratification in clinical practice to identify subjects from diagnosis worthy of early lifestyle preventive interventions and targeted treatments.