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Aims: Non-transfusion - dependent β-thalassemias (NTD-βThal) can cause iron overload and serious iron-related organ complications as endocrine dysfunction, including glucose dysregulation (GD)., Patients and Methods: We retrieved data of all NTD- β Thal patients referred consecutively to a single Outpatient Italian Clinic from October 2010 to April 2023. All patients underwent a standard 3-h oral glucose tolerance test (OGTT) for analysis of glucose homeostasis, insulin secretion and sensitivity/resistance (IR), using conventional surrogate indices derived from the OGTT. The collected data in NTD- β Thal patients were compared to 20 healthy subjects., Results: Seventeen of 26 (65.3 %) NTD- β Thal patients (aged: 7.8 -35.1 years) had normal glucose tolerance, 1/26 (3.8 %) had impaired fasting glucose (IFG), 5/26 (19.2 %) impaired glucose tolerance (IGT), 1/26 (3.8%) IFG plus IGT and 2/26 (7.6%) plasma glucose (PG) level ≥155 mg/dL 1-h after glucose load. GD was observed exclusively in young adult patients; none of them had diabetes mellitus (DM). These findings were associated with a low insulinogenic index (IGI) and oral disposition index. HOMA-IR and QUICKI were not significantly different compared to controls. Interestingly, in young adult patients, ISI-Matsuda index was statistically higher compared to the control group, suggesting an increased insulin sensitivity., Conclusions: This study reported a high prevalence of GD in young adults with NTD- β Thal. The documented reduction of IGI rather than the presence of IR, indicates reduced insulin secretory capacity as the pathophysiological basis of dysglycemia that may represent a novel investigational path for future studies on the mechanism(s) responsible for GD in NTD- β Thal patients.

Background and Aim: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic β-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (β-TM), also identified as transfusion-dependent thalassemia (TDT)., Study Design and Patients: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young β-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal β-TM females with AHH on HRT were followed for 8.26 ± 1.49 years., Results: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 β-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up., Conclusion: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.

Background: Iron chelation therapy (ICT) is the gold standard for treating patients with iron overload, though its long-term effects are still under evaluation. According to current recommendations regarding  transfusion-dependent  (TD)  β-thalassemia major (β-TM) patients, their serum ferritin (SF) levels should be maintained below 1,000 ng/mL and ICT should be discontinued when the levels are <500 ng/mL in two successive tests. Alternatively, the dose of chelator could be considerably reduced to maintain a balance between iron input and output of  frequent transfusions., Study Design: Due to the paucity of information on long-term effects of ICT  in β-TM with low SF levels on glucose homeostasis, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) promoted a retrospective and an ongoing prospective observational study with the primary aim to address the long-term effects of ICT on glucose tolerance and metabolism (β-cell function and peripheral insulin sensitivity) in adult β-TM patients with persistent SF level below 800 ng/mL., Patients and Methods: 11 β-TM patients (mean age: 35.5 ± 5.5 years; SF range: 345-777 ng/mL) with normal glucose tolerance test (OGTT) or abnormal glucose tolerance (AGT) for a median of 5.3(1.1-8.3) years., Results: Abnormal glucose tolerance (AGT) was observed in 7 patients (63.6%) at first observation and ) persisted in 6 patients (54.5%) at last observation. None of them developed diabetes mellitus. AGT was reversed in two patients. One patient with NGT developed early glucose intolerance (1-h PG ≥155 and 2-h PG <140 mg/dL). Three out of  5 patients with isolated impaired glucose tolerance presented a variation of  ATG. Stabilization of low indices for β-cell function and insulin sensitivity/resistance was observed. One patient developed hypogonadotrophic hypogonadism. Three out of 6 patients with SF below 500 ng/dL had hypercalciuria., Conclusion: Despite low SF level, the burden of endocrine complications remains a challenge in β-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.

Background: Insulin-like growth factor-1 (IGF-1) has been shown to lower blood glucose through stimulating glucose transport to fat and muscle and inhibiting hepatic glucose output. Although previous cross-sectional reports reported an association between low circulating concentrations of IGF-1 and glucose dysregulation (GD), its role is still debated., Aims of Study: The present retrospective study was designed to assess the circulating IGF-1 levels in β-thalassemia major (β -TM) patients with normal oral glucose tolerance test (NGT-OGTT) and (GD) referred for an endocrine evaluation to explore the potential link between low IGF-1 and GD., Study Design and Methods: Our study included 34 young adult patients with β-TM; 12 patients with NGT after OGTT, 7 with impaired glucose tolerance (IGT), 9 with impaired fasting glucose (IFG) plus IGT, and 6 patients with β-TM-related diabetes mellitus (β-TM- DM)., Results: Twenty-two β-TM patients with GD or β-TM- DM and 1 patient with NGT had IGF-1 levels below the 2.5th percentile. Correlation of IGF-1 with fasting plasma glucose, HOMA-IR (homeostatic model assessment for insulin resistance) and OGIS (oral glucose insulin sensitivity) was found. Moreover, a negative correlation was documented between ALT and the Insulinogenic Index (IGI) and a positive correlation between serum ferritin and PG 2-h after OGTT., Conclusion: This study reports for the first time an association between low levels of IGF-1 and GD in β-TM patients. Despite some limitations, our study can serve to generate proposals for more convenient and efficient methods to identify and treat early GD in patients with β-TM, and to conduct more extensive studies. www.actabiomedica.it).

Background: Advances in β- thalassemia major (β-TM) care have transformed a disease which had previously led to an early childhood death into a chronic condition. With increased lifespan, comorbidities associated with the disease have become more common, among them glucose dysregulation (GD) which develops insidiously, aggravating prognosis and patients' quality of life., Objectives: The objectives of this study were to retrospectively review the extent to which β-TM patients, having combined impaired fasting glucose (IFG) and impaired glucose tolerance test (IGT) on oral glucose tolerance test (OGTT), progressed to diabetes and to analyze the potential determinants inducing this progression, or regression to normal glucose tolerance test (NGT)., Research Design and Method: Data of 58 β-TM patients, followed for a mean duration of 7.7 years (range: 1-20 years) with annual or biennial OGTT, were retrieved. Insulin release and insulin sensitivity (IS) were also analyzed., Results: During the follow-up, FPG and 2-h PG levels after OGTT reverted to NGT in 13 patients (22.4%), deteriorated in 13 patients (22.4%) who developed diabetes mellitus, and did not change in the remaining 32 patients (55.2%). A significant correlation was observed between FPG and ALT level (r: 0.3158; P:0.01) and an inverse correlation was found between chronological age and serum ferritin (SF) level (r: -0.321; P:0.014). Finally, SF and ALT, both at the baseline and at the time of last observation, were independent predictors of evolution to diabetes mellitus., Conclusion: The combination IFG/IGT in β-TM patients with severe iron overload constitutes a high-risk state for developing diabetes.

Background: Thalassemia guidelines recommend oral glucose tolerance test (OGTT), starting from the age of 10 years, or earlier in the presence of iron overload., Objective: The aim of this retrospective study was to review and document the changes of glucose-insulin homeostasis from early childhood to young adulthood in β-thalassemia major (β -TM) patients with impaired fasting glucose (IFG) and normal OGTT., Methods: All data of the clinical patients' records of 18 β -TM patients' from September 1983 to September 2021 were included in the study. Annual or biennial OGTT results, for a duration of 15-20 years, were available for all patients., Results: The main findings are: a) IFG in children with β -TM represents a risk factor for the development of glucose dysregulation (GD) at later age; b) fluctuations of glucose homeostasis during follow-up were observed mainly in β-TM patients with IFG at baseline; and c) the primary defect of GD appears to be a low degree insulin resistance (IR), as estimated by HOMA-IR, followed by an insulin secretion defect., Conclusion: These results are noteworthy as they revealed that firstly, the baseline IFG predicts future development of GD, and secondly, that almost half of patients with IFG at the outset had normal glucose handling 15 years later. Understanding the sequence of abnormalities in the progression from normal glucose homeostasis to GD and identifying the risk factors for the glycometabolic defects in thalassemic patients might help in the formulation of interventions.