Can we Predict Incipient Diabetes Mellitus in Patients with Transfusion Dependent ß-Thalassemia (ß-TDT) Referred with a History of Prediabetes?

Background: Prediabetes and diabetes mellitus (DM) are complications in adult patients with transfusion-dependent ß-thalassemia (ß-TDT), with their incidence increasing with age. Objective: This retrospective observational study describes the glycemic trajectories and evaluates predictive indices of ß-cell function and insulin sensitivity/resistance in ß-TDT patients with prediabetes, both in a steady state and during 3-h oral glucose tolerance test (OGTT), in order to identify patients at high risk for incipient diabetes. Setting: The study was mainly conducted at the Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara (Italy), in collaboration with thalassemia referring centers across Italy. Patients: The study included 11 ß-TDT (aged 15.11-31.10 years) with prediabetes. Methods: The ADA criteria for the diagnosis of glucose dysregulation were adopted. Investigations included evaluating plasma glucose levels and insulin secretion, analyzing glycemic trajectories and indices of ß-cell function, and insulin sensitivity/resistance assessed in steady state and during OGTT. Results: The duration of progression from prediabetes to DM, expressed in years, showed a positive direct correlation with corrected insulin response (CIR-30 = r: 0.7606, P: 0.0065), insulinogenic index (IGI 0-120 = r: 0.6121, P:0.045), oral disposition index (oDI = r: 0.7119, P:0.013), insulin growth factor-1 (IGF-1= r: 0.6246, P: 0.039) and an inverse linear correlation with serum ferritin (SF = r: -0.7197, P: 0.012). The number of patients with 1-hour post-load PG value ≥ 155 mg/dL ( ≥ 8.6 mmol/L) was at -4 years: 4/9 (44.4%); -3 years: 8/9 (88.8%); - 2 years: 7/10 (70 %) and at -1 year: 11/11 (100%) (PG range:162-217 mg/dL). Conclusions: A progressive increase in 1-hour PG in response to OGTT is associated with progressive ß-cell failure, peripheral resistance to insulin action, and reduced oDI and may be considered a relevant marker for incipient DM in ß-TDT patients with prediabetes.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of ß- cell function and insulin sensitivity in patients with transfusion-dependent ß- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate ß-cell response, and the ability of ß-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent ß-thalassemia (ß-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for ß-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with ß-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

A retrospective study of glucose homeostasis, insulin secretion, sensitivity/resistance in non- transfusion-dependent ß-thalassemia patients (NTD- ß Thal): reduced ß-cell secretion rather than insulin resistance seems to be the dominant defect for glucose dysregulation (GD).

AIMS: Non-transfusion - dependent ß-thalassemias (NTD-ßThal) 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- ß 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- ß Thal patients were compared to 20 healthy subjects. RESULTS: Seventeen of 26 (65.3 %) NTD- ß 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- ß 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- ß Thal patients.

A Multicenter ICET-A Study on Age at Menarche and Menstrual Cycles in Patients with Transfusion-Dependent Thalassemia (TDT) who Started Early Chelation Therapy with Different Chelating Agents.

Introduction: To evaluate the effect of early chelation therapy (≤ 3 years) with a variety of chelating agents on age at menarche and menstrual characteristics in patients with transfusion-dependent thalassemia (TDT). Design: A retrospective multicenter study promoted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A). Setting: Eight of 13 International Thalassemia Centers (61.5%) in the ICET-A Network participated. Patients: Fifty-seven female TDT patients, aged 11 to 26 years, and with early iron chelation therapy, were eligible for the present study. They were enrolled from one center from Iran (33 patients), 3 centers from Bulgaria (9), 1 from Greece (8), one from Oman (4), 1 from Cyprus (2), and 1 from Italy (1). Seven patients were excluded, four still prepubertal (age 12-14 years) and 3 with primary amenorrhea. Therefore 50 patients were finally enrolled. Results: All fifty TDT patients developed spontaneous menarche at a mean age of 14.2 ± 2.24 years (range 9 - 20). A significant positive correlation was observed between age at menarche and serum ferritin levels (r: 0. 41, p=0.005). Regular menstrual cycles were reported from 32 (64%) patients, of whom 28 (83.3%) get menarche at age ≤ 14 years. Complications were more frequent in patients older than 14 years at menarche and in those with secondary amenorrhea. Conclusions: Age at menarche greater than 14 years was a forerunner of menstrual irregularities and associated complications in 36% of patients despite precocious chelation therapy. The poor adherence to treatment, to be demonstrated in future studies, could explain the finding.

The effects of excess weight on glucose homeostasis in young adult females with ß-thalassemia major (ß-TM): a preliminary retrospective study.

BACKGROUND: With the rising prevalence of obesity worldwide, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent type 2 diabetes (T2D) development. STUDY DESIGN: The present retrospective observational study aimed to evaluate the relationship between BMI and glucose metabolism, insulin secretion and sensitivity indices, derived from glucose tolerance test (OGTT), in ß -TM female patients who were overweight (BMI 25-29.9 kg/m2) and follow its outcome over time. SUBJECTS AND METHODS: Eleven overweight and 11 females with ideal weight and ß -TM, matched for age, were recruited. OGTT was undertaken and different indices for ß-cell function, insulin sensitivity and insulin secretion were calculated. RESULTS: At first evaluation, 7 of 11 overweight ß -TM patients (63.6%) and 3 of 11 normal weight ß-TM patients (27.2%) had glucose dysregulation (GD) during OGTT. Overweight patients with ß-TM had increased HOMA-IR and QUICKI indices associated with decreased Matsuda WBISI index. The mean ± SD duration of follow-up was 4.5 ± 1.2 years. At last observation, 2/11 overweight patients had developed T2D (18.1%). In patients with normal weight, GD increased from 3/11 (27.2%) to 5/11 (45.4%), but none developed T2DM. The difference between SF at first and last observation (1,220 ± 702 vs.1,091 ± 454 ng/mL; P: 0.61) was not significant. CONCLUSION: Overweight seems to be an additional risk factor for the development of GD in ß-TM patients. This is particularly important in clinical practice, due to the lack of appropriate guidelines dedicated to this group of patients.

Mortality and complications in Omani patients with beta-thalassemia major: a long-term follow-up study.

BACKGROUND AND AIM: Beta thalassemia major (ß-TM) is a genetic blood disorder requiring lifelong blood transfusions.  The resulting iron overload damages multiple organs, particularly the heart and endocrine organs. This study aimed to describe and assess the predictors of survival and complications in Omani patients with ß-TM.   Methods: All ß-TM patients registered in the day care of Sultan Qaboos University Hospital were included in this retrospective study.   Results: There were 187 patients with ß-TM with a median follow-up of 24.9 years.  The median ages at diagnosis and the start of chelation were 0.7 and 4.8 years, respectively. The following complications developed at different time points [Median (age in years), Complication Free Probability at 20 years]: Death (20.0 years;85%), hypogonadism (15.9 years;50%), insulin-dependent or non-insulin dependent diabetes (20.0 years;88%), cardiac complications (20.3 years;91%), osteoporosis (20.7 years;96%), hypothyroidism (25.7 years;97%), liver complications (7.3 years;54%). The number of complications predicted death (P = 0.0038). Those born after 1980 had a lower risk of death (P = 0.005), hypogonadism (P = < 0.0001), and cardiac complications (P = 0.004). Higher serum ferritin at the start of chelation was associated with the development of diabetes (P = < 0. 001).   Conclusions: This long-term study shows complications development at different ages, and the number of complications is associated with survival. Later birth cohorts had a lower risk of death, hypogonadism, and cardiac complications. There was a persistent negative impact of delay in the start of iron chelation that is present even after a long follow-up. (www.actabiomedica.it).

Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (ß-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

BACKGROUND AND AIM: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic ß-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (ß-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 ß-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal ß-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 ß-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.

Recent advancements in glucose dysregulation and pharmacological management of osteoporosis in transfusion-dependent thalassemia (TDT): an update of ICET-A (International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine).

PURPOSE OF REVIEW: The aim of this short review is to provide an update on glucose homeostasis, insulin secretion and pharmacological management of osteoporosis in transfusion-dependent thalassemia (TDT). RECENT FINDINGS: A retrospective study, documenting the changes in glucose-insulin homeostasis from early childhood to young adulthood, has advanced our understanding of the evolution of glucose regulation in patients with TDT. Magnetic Resonance Imaging (T2* MRI) is considered to be a reliable tool to measure pancreatic iron overload. Continuous glucose monitoring systems (CGMS) can be used in early diagnosis of glucose dysregulation and in disease management in patients with already diagnosed diabetes. Oral glucose-lowering agents (GLAs) are effective and safe for the treatment of diabetes mellitus (DM) in patients with TDT, achieving adequate glycemic control for a substantial period of time. Current modalities for the management of osteoporosis in adults with TDT include inhibitors of bone remodeling such as bisphosphonates and denosumab as well as stimulators of bone formation (e.g., teriparatide), Considering the unique characteristics of osteoporosis associated with TDT, early diagnosis, treatment initiation and treatment duration are critical issues in the management this special population. CONCLUSIONS: Advances in the care of TDT patients  have led to improved survival and quality of life. Nevertheless, many chronic endocrine complications still remain. Their routine screening and a high index of suspicion are imperative in order to provide timely diagnosis and  treatment.

Assessment of glucose homeostasis in young adult female ß-thalassemia major patients (ß-TM) with acquired hypogonadotropic hypogonadism (AHH) never treated with sex steroids compared to eugonadal ß-TM patients with spontaneous menstrual cycles.

BACKGROUND: Acquired ypogonadotropic hypogonadism (AHH) is the most prevalent endocrine complication in thalassemia major (TM). STUDY DESIGN: Considering the detrimental effect of estrogen deficiency on glucose metabolism, the ICET-A Network promoted a retrospective study on the long-term effects of estrogen deficiency on glucose homeostasis in female ß-TM patients with HH without hormonal replacement therapy (HRT). PATIENTS AND METHODS: Seventeen ß-TM patients with AHH (4 had arrested puberty; Tanners' breast stage 2-3), never treated with sex steroids, and 11 eugonadal ß-TM patients with spontaneous menstrual cycles at the time of referral were studied. A standard 3-h OGTT was performed in the morning, after an overnight fast. Six-point plasma glucose and insulin level determinations, indices of insulin secretion and sensitivity, early-phase insulin insulinogenic index (IGI), HOMA-IR and ß-cell function (HOMA-ß), oral disposition index (oDI), glucose and insulin areas under the OGTT curves were evaluated. RESULTS: Abnormal glucose tolerance (AGT) or diabetes was observed in 15 (88.2%) of 17 patients with AHH and 6 (54.5%) of 11 patients with eumenorrhea. The difference between the two groups was statistically significant (P: 0.048). However, the group of eugonadal patients was younger compared to AHH patients (26.5 ± 4.8 years vs. 32.6 ± 6.2 years ; P: 0.010). Advanced age,  severity of iron overload, splenectomy, increased ALT levels and reduced IGF-1 levels were the main clinical and laboratory risk factors for glucose dysregulation observed in ß-TM with AHH compared to eugonadal ß-TM patients with spontaneous menstrual cycles. CONCLUSION: These data further support the indication for an annual assessment of OGTT in patients with ß-TM. We believe that a registry of subjects with hypogonadism is necessary for a better understanding of the long-term consequences of this condition and  refining treatment options.

Unilateral breast enlargement in males during adolescence (10-19 years): Review of current literature and personal experience.

Idiopathic unilateral breast enlargement (UBE) in males is a, commonly overlooked, diagnosis of exclusion that requires careful history, meticulous physical examination, and pertinent laboratory studies to exclude the possible pathologic causes. The aims of the present update are to review the current literature on UBE in subjects during adolescent age (10-19 years) in 18 cases, and to report the personal experience in 13 adolescents referred to our unit during the last four decades. In total, our survey and personal experience include 31 UBE cases, 10 of whom (32.2 %) being idiopathic or familial gynecomastia (GM). In 3/31 (9.6%) UBE was due to breast sarcoma/ carcinoma; one patient (11-years old) had a 5-year history of painless lump in the right breast, which increased gradually in size followed by bloody nipple discharge. In the personal cases of 13 adolescents, a moderate to marked UBE was secondary to: treatment with androgens (2 ß-thalassemic patients with hypogonadism), high estrogen/androgen ratio in 2 Klinefelter syndrome patients, peripheral aromatization of androgens in 1 patient with non-classical 21-hydroxylase deficiency (NC-21-OH-D). One patient had subareolar hematoma due to injury. In 2 patients (15,3%) marked UBE was due to cystic lymphangioma (histologically proved). Furthermore, 5 patients were characterized as idiopathic UBE In clinical practice, the persistence of UBE for long period before diagnosis necessitates attention and further evaluation. Underlying causes should be treated, when possible, while surgery can be offered to patients with persistent or atypical signs and/or symptoms of UBE. For the optimal management of this condition, better collaboration between primary care physician and specialists is mandatory.

Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and ß-cell secretion in eleven ß-thalassemia major patients with mild iron overload.

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)  ß-thalassemia major (ß-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 ß-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 (ß-cell function and peripheral insulin sensitivity) in adult ß-TM patients with persistent SF level below 800 ng/mL. PATIENTS AND METHODS: 11 ß-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 ß-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 ß-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.

Thalassaemia-A global view.

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context.

Glucose Homeostasis and Assessment of ß-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with ß-Thalassemia Major with Serum Ferritin below 1,000 ng/dL: Results from a Single ICET-A Centre.

Aims: The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indices of insulin sensitivity and resistance, during a 3-hour oral glucose tolerance test (OGTT), in ß-thalassemia major patients (ß-TM) with serum ferritin (SF) below 1,000 ng/mL. Patients and methods: The retrospective cohort study evaluated the medical records of 24 ß-TM patients from 2010 to 2022. At the year of study the mean age of patients was 31.0 ± 4.1 (20-37.11) years; 13 (54.1%) were females. The most commonly used iron chelator was deferoxamine (DFO: 75%), followed by deferiprone (DFP:12.5%) and deferasirox (DFX: 12.5%). Insulin sensitivity and resistance indices were derived from OGTT. A liver iron concentration (LIC) < 3 mg/g d.w. and a global heart T2* value > 20 ms were considered as conservative cut-off values for insignificant iron overload (IOL). Results: The mean SF levels in the whole study cohort population at the age of evaluation was 549.6 ± 232.3 ng/mL. Based on the SF levels, two groups were identified: Group A (N = 14) < 500 ng/mL and Group B (N=10) 500-1,000 ng/mL. Normal glucose tolerance (NGT) during OGTT was observed in 4 patients of Group A (28.5 %) and in 5 patients of Group B (50%) (P: 0.29). The remaining 15/24 patients (62.5%) had glucose dysregulation (GD). The mean age at starting iron chelation therapy (ICT) and the mean SF peak in Group A versus Group B were significantly higher in group A. The GD was associated with significantly attenuated IGI (first phase of insulin response) and impaired oral disposition index (oDI). Hypogonadotropic hypogonadism (HH) was the most common associated endocrine complication in both groups of patients. Conclusions: This study showed that efficient iron chelation monotherapy in patients with ß-TM and SF < 1,000 ng/ml did not entirely prevent glucose metabolism disorders, abnormalities of insulin secretion and sensitivity, and development of acquired hypogonadism.

Development of a Thalassemia International Prognostic Scoring System (TIPSS).

A prognostic scoring system that can differentiate ß-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ß-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ß Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with ß-thalassemia that could help management and research decisions.

Insulin-Like Growth Factor -1 (IGF-1) and Glucose Dysregulation in Young Adult Patients with ß-Thalassemia Major: Causality or Potential Link?

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 ß-thalassemia major (ß -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 ß-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 ß-TM-related diabetes mellitus (ß-TM- DM). RESULTS: Twenty-two ß-TM patients with GD or ß-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 ß-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 ß-TM, and to conduct more extensive studies. www.actabiomedica.it).

Oral glucose tolerance test: Ηow to maximize its diagnostic value in children and adolescents.

BACKGROUND: Recently, the validity of the oral glucose tolerance test (OGTT) as a gold-standard test for the diagnosis of glucose dysregulation (GD) has been questioned due to the pre-analytical, analytical, and post-analytical variables which can potentially affect its reproducibility and accuracy. AIMS: In this short update, the many  variables that affect the reproducibility and accuracy of the OGTT are described and discussed aiming to enhance its diagnostic value  in  clinical practice. SEARCH STRATEGY: A systematic search was implemented in June 2022, using Scopus, PubMed, Embase and Google Scholar focusing on OGTT relevant  papers published in the last 10 years. Moreover,  the reference lists of these  articles were checked for additional pertinent studies. The research and selection of articles was also supported by the long-term authors' experience in the use of OGTT for the diagnosis of GD in children and adolescents. CONCLUSION: The complexity of diagnosing GD presupposes that clinicians have specific knowledge and experience to perform rigorous assessment of glucose metabolism. It is worth mentioning that during OGTT, subjects with glucose levels  close to the cut-off values proposed  by WHO (World Health Organization)/ADA (American Diabetes Association) require careful evaluation in order to avoid misclassification and unnecessary interventions. For this reason, ADA recommends a second test to confirm the diagnosis of diabetes.

Retrospective observational studies: Lights and shadows for medical writers.

A retrospective study (by definition non-interventional) is a purely observational review and/or reassessment of database records with the aim of analyzing previous events of interest. The ethical and scientific standards for conducting biomedical research with humans have been established in international guidelines. Nevertheless, the reporting of ethical considerations in human research is not yet agreed upon globally, although some progress has been made in recent years. If a study has been granted exemption from ethics approval, this should be indicated in the manuscript (including the reasons for the exemption) and, if formal review by an ethics committee is not available, a statement should be included indicating that the research was conducted according to the principles of the Declaration of Helsinki. Editors play an important role in adherence to these ethical requirements for all submitted and published research papers in their journals. This short review paper focuses on the main lights and shadows of ethical aspects for conducting retrospective observational studies in humans and implications for medical writers.

Evolution of Combined Impaired Fasting Glucose and Impaired Glucose Tolerance in ß-Thalassemia Major: Results in 58 Patients with a Mean 7.7- year Follow-Up.

BACKGROUND: Advances in ß- thalassemia major (ß-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 ß-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 ß-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 ß-TM patients with severe iron overload constitutes a high-risk state for developing diabetes.

The evolution of glucose-insulin homeostasis in children with ß-thalassemia major (ß -TM): A twenty-year retrospective ICET- A observational analysis from early childhood to young adulthood.

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 ß-thalassemia major (ß -TM) patients with impaired fasting glucose (IFG) and normal OGTT. METHODS: All data of the clinical patients' records of 18 ß -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 ß -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 ß-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.