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

Background: Prediabetes and diabetes mellitus (DM) are complications in adult patients with transfusion-dependent β-thalassemia (β-TDT), with their incidence increasing with age.

Objective: This retrospective observational study describes the glycemic trajectories and evaluates predictive indices of β-cell function and insulin sensitivity/resistance in β-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.

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

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.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of β- cell function and insulin sensitivity in patients with transfusion-dependent β- 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 β-cell response, and the ability of β-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 β-thalassemia (β-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.

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.

The effects of excess weight on glucose homeostasis in young adult females with β-thalassemia major (β-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 β -TM female patients who were overweight (BMI 25-29.9 kg/m2) and follow its outcome over time.

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 (β-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

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.

Assessment of glucose homeostasis in young adult female β-thalassemia major patients (β-TM) with acquired hypogonadotropic hypogonadism (AHH) never treated with sex steroids compared to eugonadal β-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 β-TM patients with HH without hormonal replacement therapy (HRT).

Patients And Methods: Seventeen β-TM patients with AHH (4 had arrested puberty; Tanners' breast stage 2-3), never treated with sex steroids, and 11 eugonadal β-TM patients with spontaneous menstrual cycles at the time of referral were studied.

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.

Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and β-cell secretion in eleven β-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)  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.

Glucose Homeostasis and Assessment of β-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with β-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 β-thalassemia major patients (β-TM) with serum ferritin (SF) below 1,000 ng/mL.

Patients And Methods: The retrospective cohort study evaluated the medical records of 24 β-TM patients from 2010 to 2022. At the year of study the mean age of patients was 31.

Insulin-Like Growth Factor -1 (IGF-1) and Glucose Dysregulation in Young Adult Patients with β-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 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.

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.

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.

The evolution of glucose-insulin homeostasis in children with β-thalassemia major (β -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 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.

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

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).

The The use of oral glucose-lowering agents (GLAs) in β-thalassemia patients with diabetes: Preliminary data from a retrospective study of ICET-A Network.

Objective: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations.

Study Design And Method: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network.

Heterozygosity of the Complex Corfu δ0β+ Thalassemic Allele (HBD Deletion and HBB:c.92+5G>A) Revisited.

The Corfu δβ thalassemic allele is a unique thalassemic allele consisting of the simultaneous presence in cis of a deletion of the δ-globin (Hemoglobin Subunit Delta, ) and a single nucleotide variant in the β-globin gene (Hemoglobin Subunit Beta, ). The allele has, so far, been described in individuals of Greek origin. The objectives of the study are to ascertain the prevalence of the Corfu δβ allele in comparison to other β-thalassemia variants encountered in Greece using our in-house data repository of 2558 β-thalassemia heterozygotes, and to evaluate the hematological phenotype of Corfu δβ heterozygotes in comparison to heterozygotes with the most common β- and deletion α- thalassemia variants in Greece.

Screening for glucose dysregulation in β-thalassemia major (β-TM): An update of current evidences and personal experience.

Glucose dysregulation (GD) in patients with β-thalassemia major (β-TM) usually develops gradually. Prediabetes consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), the latter detected by a standardized oral glucose tolerance test (OGTT). Diagnosis of prediabetes is essential for an early identification of high-risk individuals who will benefit from intensive iron chelation therapy and lifestyle modification.

Hypomenorrhea in Adolescents and Youths: Normal Variant or Menstrual Disorder? Revision of Literature and Personal Experience.

Menstrual health affects a large number of women throughout reproductive life since adolescence. Knowledge of the duration and variation of the menstrual cycle is necessary for patient education and to identify deviations from normal  to guide clinical evaluation. The average duration of menstrual flow is between 4 to 6 days, with anormal range from 2 up to 8 days ; the mean blood loss per menstrual cycle is 25- 30 mL.

The clinical characteristics, biochemical parameters and insulin response to oral glucose tolerance test (OGTT) in 25 transfusion dependent β-thalassemia (TDT) patients recently diagnosed with diabetes mellitus (DM).

Background: Patients with transfusion dependent β-thalassemia (TDT) are at high risk for developing, over the time, a form of diabetes distinct from type 1 and type 2 diabetes, but with similarities to both.

Aims Of Study: The aim of this study is to describe the clinical and laboratory data, and the insulin secretion and sensitivity, in TDT patients , recently diagnosed with diabetes mellitus (DM).

Materials And Methods: The medical records of 25 TDT patients with DM, diagnosed by standardized oral glucose tolerance test (OGTT) and insulin secretion, were analysed; data were compared to TDT patients without diabetes and to a group of healthy subjects.

The Myxedema coma in children and adolescents: A rare endocrine emergency - Personal experience and review of literature.

Decompensated hypothyroidism, formerly known as myxedema coma, represents the most extreme clinical expression of severe primary or secondary hypothyroidism in which patients exhibit multiple organ abnormalities and progressive mental deterioration. The exact incidence of myxedema coma in adults is not known, but some authors have estimated that is approximately 0.22 per 100.

Glucose Metabolism and Insulin Response to Oral Glucose Tolerance Test (OGTT) in Prepubertal Patients with Transfusion-Dependent β-thalassemia (TDT): A Long-Term Retrospective Analysis.

Background: Glucose dysregulation (GD), including prediabetes and diabetes mellitus (DM), is a common complication of transfusion-dependent β-thalassemia (TDT) patients. The prevalence increases with age and magnitude of iron overload, affecting a significant proportion of patients. According to the international guidelines, the development of GD is frequently asymptomatic.

A study of isolated hyperglycemia (blood glucose ≥155 mg/dL) at 1-hour of oral glucose tolerance test (OGTT) in patients with β-transfusion dependent thalassemia (β-TDT) followed for 12 years.

Objective: Subjects with normal glucose tolerance (NGT) but 1-hour post-load plasma glucose (1-h OGTT) ≥ 155 mg/dl (8.6 mmol/L; H-NGT) have an increased risk for developing Type 2 diabetes mellitus (T2DM), determining a new risk factor category with deeper metabolic impairment. The aim of this study was to evaluate the H-NGT as a diagnostic predictor of future dysglycemia in β-transfusion dependent thalassemia (β-TDT).

The different patterns of insulin response during Oral Glucose Tolerance Test (OGTT) in transfused young patients with β-Thalassemia.

Background And Aim: Dysregulation of glucose metabolism is a common complication of transfusions in Transfusion Dependent Thalassemia (TDT) patients. For early diagnosis of glucose disturbances, screening is recommended. The age of starting and the type of screening vary; the more common methods are assessment of RPG, FPG, 2h PG and 2 hours OGTT.

The Pancreatic changes affecting glucose homeostasis in transfusion dependent β- thalassemia (TDT): a short review.

Background: The natural history of the glycometabolic state in transfusion-dependent β-thalassemia (TDT) patients is characterized by a deterioration of glucose tolerance over time.

Aims: This review depicts our current knowledges on the complex and multifacet pathophysiologic mechanisms implicated in the development of alteration of glucose homeostasis in patients with TDT.

Search Strategy: A systematic search was done on December 2020 including Web of Science (ISI), Scopus,  PubMed, Embase, and Scholar for papers published in the last 20 years.