Background and aims: We asked the question whether the metabolic phenotype at baseline and/or a number of type 2 diabetes mellitus (T2DM) risk genes may predict the evolution of glucose control (GC) within the first 18 months after diagnosis of the disease. Materials and methods: 593 GAD-antibodies negative patients with newly diagnosed T2DM (age: 59±0.4 yrs; BMI: 30.0±0.2 kg/m2) were studied with: 1. Prolonged (5-hours) frequently sampled OGTT to assess beta cell function(BCF) by state of art mathematical modelling of glucose and C-peptide; 2. Standard euglycemic insulin clamp to assess insulin sensitivity (SI); 3. Genotyping the common T2DM risk variants of the following genes: ADAMTS9, CDKAL1, FTO, G6PC2, GCK, GCKR, GNPDA2, HHEX, HNF1B, IGF2BP2, IRS1, JAZF1, KCNJ11, MTNR1B, NOTCH2, PPARG, SCL30A8, TCFL2, THADA,TMEM18, TSPAN and WFS1. GC evolution was defined as the difference between HbA1c at diagnosis (7.0±0.1%) and HbA1c at 18 months (6.5±0.1%). Results: 141 patients were lost to follow-up, thereby leaving 452 patients for evaluation. In all multivariate regression models, basal HbA1c (standardizedbeta [stBETA]: 0.92, p<0.0001) was the strongest positive predictor of favourable GC evolution (i.e. the higher HbA1c at diagnosis, the greater its fall within 18 months). No role for T2DM risk gene variants, either as a single SNP or as a genetic score derived from all SNPs, could be detected. BCF(stBETA: 0.26) and eGFR (stBETA: 0.08), but not age nor BMI nor SI nor pharmacological therapy, were positive independent predictors of favourable GC evolution (p<0.001 e p<0.01, respectively). Conclusion: Thus, better BCF at diagnosis, but not SI nor the T2DM genotype assessed in this study, is an independent predictor and a putative determinantof more desirable short-term (18 months) GC evolution.
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