NATURAL HISTORY OF GLUCOSE HOMEOSTASIS AND AND Β-CELL FUNCTION FROM CHILDHOOD TO EARLY ADULTHOOD IN TRANSFUSION-DEPENDENT Β-THALASSEMIA: A NINE-YEAR LONGITUDINAL COHORT STUDY

Abstract. Background: Iron overload from chronic transfusion therapy progressively impairs pancreatic β-cell function and insulin action in transfusion-dependent β-thalassemia (β-TDT), but longitudinal data from childhood through early adulthood are scarce. Objectives: To describe, in a single retrospective cohort of patients with β-TDT followed for nine years, (i) the annual evolution of oral glucose tolerance test (OGTT)-derived glycemic values and (ii) insulin resistance and β-cell function indices from late childhood to early adulthood. Methods: Twenty-three patients with TDT (12 males, 11 females) were followed from mean age of 10.2 ± 0.9 years (baseline) to 20.8 ± 0.85 years (nine-year follow-up). All patients received subcutaneous iron chelation with deferoxamine (DFO) monotherapy throughout. A standardized OGTT was done yearly. Plasma glucose and serum insulin were measured at 0, 30, 60, and 120 minutes after glucose load to evaluate the glucose homeostasis and indices of insulin secretion and sensitivity. Results were compared with contemporaneous healthy controls. Pearson and Spearman correlations examined bivariate relationships between glycemic, insulin, and ferritin parameters Results: In the whole cohort, fasting glucose rose from 91.6 ± 11.6 to 94.6 ± 10.7 mg/dL, 30-minute post-load glucose from 137.6 ± 26.8 to 147.6 ± 20.1 mg/dL, and 120-minute post-load glucose from 113.5 ± 23.5 to 147.6 ± 31.4 mg/dL. HOMA1-% β fell from 119.8 ± 72.1 to 62.6 ± 24.9, while HOMA1-IR changed from 101.6 ± 16.9 to 132.4 ± 15.3 and ISSI-2 remained essentially stable (1.82 ± 0.58 to 1.87 ± 0.57). At baseline, fasting glucose correlated positively with HOMA-IR (r: 0.46, P =0.027) and inversely with HOMA-%β (r: −0.69, P =< 0.001) and ISSI-2 (r: −0.72, P= <0.001); 30-minute post-load glucose at baseline predicted 1-hour post-load glucose at nine years (r: 0.6545, P= < 0.001. At 9 years of follow-up, dysglycemia was present in 10/23 patients (43.5%; 3 isolated impaired fasting glucose [IFG], 4 impaired glucose tolerance [IGT], 3 combined IFG plus IGT), with a non-significant male predominance (6/12 vs. 2/11; χ²: 2.56, P =0.10). Notably, HOMA 1-%β and ISSI-2 were statistically lower at baseline and after 9 years of follow-up compared to the healthy controls (P = < 0.0001 and 0.0042, respectively). No significant difference between patients with good (607.4 ± 180.3 μg/L vs. moderate/poor (1998.6 ± 886.3 μg/L) iron chelation therapy with DFO was documented (6/11 vs. 3/12; χ²:0.685, P= 0.40). Conclusions: Deterioration in glucose tolerance over the study period was driven predominantly by a decline of insulin secretory capacity rather than by a progressive increase in insulin resistance (IR). The decline of β-cell secretory capacity was present from childhood and was associated with an early higher elevation of plasma glucose at 30 minutes, after glucose load, compared to controls. OGTT-derived indices of insulin secretion and sensitivity could help tailor screening intensity.