Oral glucose tolerance test remains the gold standard for diagnosis of glucose metabolism disturbances in thalassemia patients

Abstract Introduction: In transfusion-dependent β-thalassemia (TDT), pancreatic iron overload may disturb the function of pancreatic β-cells isles and insulin secretion, leading to hyperglycemia and diabetes mellitus. Annual oral glucose tolerance testing (OGTT) from the age of 10 years is recommended for early detection of disturbances in glucose metabolism (GDs). The utility of the serum markers of HbA1c and fructosamine, routinely used for early detection of hyperglycemia remains controversial for thalassemic patients, as they have different hemoglobin composition and shorter lifetime of erythrocytes than non-thalassemic population. Aims: To evaluate the predictive value of OGTT and the correlation with other markers of glucose metabolism disturbances in β transfusion dependent thalassemic patients. Methods: Based on OGTT results, patients were stratified according to the American Diabetes Association criteria in three groups: (a) normal glucose tolerance (NGT), (b) prediabetes [impaired fasting glucose IFG and/or impaired glucose tolerance (IGT)], and (c) overt diabetes mellitus (thalassemia-related diabetes mellitus, Th-RDM).Demographic and clinical parameters – including age at diagnosis, chelation regimen, and iron load [assessed by serum ferritin, MRI-derived liver iron concentration (LIC), and cardiac T2* values] were recorded. HbA1c and fructosamine levels (normal range: 200-285 μmol/L) were measured and analyzed by standard assays. Results: A total of 46 regularly followed TDT patients (median age: 45.0 years; median age at diagnosis: 0.73 years) were included in the analysis. All were on regular transfusions and receiving iron chelation. Of these, 23 patients (50.0%) had NGT [median age: 43.0 years, interquartile range (IQR): 38.0, 49.0]. Prediabetes was detected in 21 patients (45.7%) [median age: 46.0 years, interquartile range (IQR): 40.0, 50.0]. Two patients (4.3%) were diagnosed with Th-RDM; one of them was pregnant [median age: 48.5 years, interquartile range (IQR): 45.0, 52.0]. The correlation of OGTT with HbA1c and fructosamine was investigated. Neither HbA1c (p=0.993) nor fructosamine (p=0.925) differed significantly between groups [NGT: HbA1c (median: 6.8%, IQR: 6.5, 7.1), fructosamine (median: 246.0 μmol/L, IQR: 229.0, 255.0), IGT: HbA1c (median: 6.75%, IQR: 6.5, 7.15), fructosamine (median: 250.0 μmol/L, IQR: 233.0, 259.0), Th-RDM: HbA1c (median: 6.8%, IQR: 6.6, 7.0), fructosamine (median: 238.5 μmol/L, IQR: 215.0, 262.0)].Thirty-five out of 46 patients were included in a longitudinal analysis based on paired OGTT data collected over a median follow-up of 18 years. An improvement in glucose tolerance was observed (mean decrease in 2-hour glucose: -18.72 mg/L, p=0.017), accompanied by a median reduction in serum ferritin of -713 ng/mL, p=0.0001. Notably, patients with IGT remained stable over time, with no progression to overt diabetes despite not receiving antidiabetic treatment. Among the remaining patients, no significant shifts were observed between the classification groups. (McNemar's test; p=0.774). Conclusions: Our data show that early diagnosis and optimized chelation therapy contribute to the stabilization of glucose homeostasis. The proportion of patients with IGT remained stable over two decades, despite the absence of antidiabetic treatment. HbA1c and fructosamine were not reliable markers for detecting glucose dysregulation in this population. Given the limited compliance with annual OGTT and low patient awareness, further research is needed to identify more practical and sensitive screening tools for glucose intolerance in TDT patients.