Defects in the dynamic control of beta cell function and in glucose effectiveness underly the initial decline in intravenous glucose tolerance of obese European children

Background and aims: Europe Europeans are thought to be less vulnerable to obesity induced type 2 diabetes. Detailed study of the main components of the glucose (G)-insulin (I) system were never performed in Europe European obese children. We aimed at assessing the main determinants of G levels in Italian obese children with normal G regulation (NGR). Materials and methods: Sixty-five Italian obese children (age: 10.3±1.8 yrs, mean±SD; BMI: 28.1±3.2 Kg/m²) with NGR underwent a frequently sampled intravenous G tolerance test (IVGTT) [12 g/m² of body surface area] lasting 200’. G/C-peptide curves and I/G curves were analyzed with state-of-art mathematical models to quantify the sensitivity of beta-cell to both the rate of increase of G (DC: dynamic or derivative control; units: [pmol·m -2] per [mM·min-1]) and to G concentration (PC: static or proportional; analyzed as I secretion rate at G=4.0,5.5, 8.0, 11.0 mmol/L; units:pmol·min-1·m-2) and the routes of G utilization [global, i.e. liver+periphery, insulin sensitivity, SI, presented as G utilization rate at G=5 mM and I=420 pM; units: mmol·min-1·m-2; G effectiveness, SG units: ml·min-1·m-2]. Acute I response (AIR) was calculated as the AUC under I concentration between 0’ and 10’ of the IVGTT. Median FPG (4.6 mM) and median G level at 60’ during the IVGTT (1hPG: 5.3 mM) were used to classify children in one of 4 groups: low (below median) FPG and low 1h-PG (LowLow, n=20, FPG:4.4±0.16 mM, 1h-PG: 4.4±0.47 mM), high (above median) FPG and low 1h-PG (HighLow, n=13, FPG: 4.9±0.23 mM, 1h-PG: 4.4±0.58 mM), low FPG and high 1h-PG (HighHigh n=13, FPG: 4.3±0.25 mM, 1h-PG: 7.1±0.10 mM), and high FPG and high 1h-PG (HighHigh, n=19, FPG: 5.0±0.22 mM, 1h-PG: 6.5±0.7 mM). Results: Worsening of G regulation was associated with increasing age (from 9.3±1.7 to 10.5±1.8 yrs, p<0.05) and BMI (from 26.6±2.4 to 28.8±3.2 kg/m², p<0.05). AIR was similar across the 4 groups (4.9± 2.9, 4.6± 1.6, 3.4± 2.1 and 5.2± 5.2 in the LowLow, HighLow, LowHigh and HighHigh group, respectively, p=0.31). Both SI and SG were lower (p<0.05-0.01) in the LowHigh and HighHigh groups (SI: 0.95± 0.27 and 0.96± 0.31; SG: 102± 45 and 99± 23) than in the 2 Low 1h-PG groups (SI: 1.5± 0.4 and 1.3± 0.4; SG 137±33 and 152±50). SI, but not SG, was inversely related to both DC and PC of betacell function (r=-0.44 and -0.43, respectively, p<0.01 for both). PC, but not DC, of beta-cell function, was higher in the LowHigh (p=0.02) and HighHigh (p=0.03) groups than in the LowLow group, but after adjusting for SI these differences disappared. After adjusting for both SG and SI, the DC of beta-cell function was lower by~47% (p<0.01) in the LowHigh and HighHigh groups than in the other two groups. Conclusion: In Europe European (Italian) obese children with NGR: 1. elevated 1h-PG is associated to decline in DC of beta-cell function and in both SI and SG. 2. SI, but not SG, is accompanied by an apparently compensatory increase in PC of beta-cell function, 3. hence, the fall in DC of beta-cell function and the uncompensated decline in SG play primary roles in determining the initial decline in i.v. G tolerance