Vincenzo De Sanctis1, Mohammad Faranoush2, Shahina Daar3, Ihab Elhakim4, Ashraf T Soliman5, Forough Saki6, Mehran Karimi7 and Ploutarchos Tzoulis8.
1
Coordinator of ICET-A Network (International Network of Clinicians for
Endocrinopathies in Thalassemia and Adolescent Medicine), Pediatric and
Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
2
Pediatric Growth and Development Research Center, Institute of
Endocrinology, Iran University of Medical Sciences, Tehran, Iran.
3 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman.
4
Emeritus Professor of Pediatric Nephrology, Ain Shams University; Head
of the Department of Pediatrics, BUC (Badr University in Cairo), Cairo,
Egypt.
5 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
6 Shiraz Endocrinology and Metabolism Research Center, Shiraz, Iran.
7 Pediatric Hematology Oncology Department, American Hospital, Dubai, UAE
8 Department of Diabetes and Endocrinology, Whittington Hospital, University College London, London, UK.
.
Correspondence to:
Vincenzo De Sanctis, Coordinator of ICET-A Network (International
Network of Clinicians for Endocrinopathies in Thalassemia and
Adolescent Medicine) and Pediatric and Adolescent Outpatient Clinic,
Quisisana Hospital, Ferrara, Italy. E-mail: vdesanctis@libero.it
Ploutarchos
Tzoulis, Department of Diabetes and Endocrinology, Whittington
Hospital, University College London, London, UK. E-mail: ptzoulis@yahoo.co.uk
Published: January 01, 2026
Received: November 07, 2025
Accepted: December 04, 2025
Mediterr J Hematol Infect Dis 2026, 18(1): e2026011 DOI
10.4084/MJHID.2026.011
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
|
To the editor
In
patients with transfusion-dependent β-thalassemia (β-TDT), several
forms of dysglycemia have been reported at various stages of the
disease. Although diabetes mellitus (DM) in patients with β-TDT shares
many characteristics with type 2 DM (T2DM) and fewer with type 1 DM, it
is a distinct type of diabetes, known as thalassemia-related diabetes
mellitus (Th-RDM), with different outcomes and monitoring. The
estimated prevalence of Th-RDM varies from 9.7% to 29%.[1]
Current
standards of care for β-TDT patients recommend an annual 2-h oral
glucose tolerance test (OGTT) starting at age 10 (or earlier if the
patient has severe iron overload).[2]
Recommendations do not include simultaneous measurement of insulin
response during OGTT, while glycated hemoglobin (HbA1c) is considered
an unreliable biomarker for long-term glucose control in β-TDT.[2]
The
diagnostic criteria for DM of the American Diabetes Association (ADA)
are based on fasting plasma glucose (FPG) ≥ 126 mg/dL or 2-h PG:≥ 200
mg/dL, after glucose load, or random venous plasma glucose (PG)≥ 200
mg/dL associated with clinical symptoms of hyperglycemia or
hyperglycemic crisis, and/or HbA1c≥ 6.5%.[3]
To
the best of our knowledge, no studies have evaluated the diagnostic
accuracy of FPG ≥ 126 mg/dL in patients with β-TDT. Thus, the ICET-A
promoted a multicenter survey to establish: (a) the concordance rate of
criteria used to diagnose diabetes between FPG and 2-hour PG post OGTT,
and (b) to evaluate the optimal cutoff value of FPG to establish
confirmation of DM diagnosis.
Patients and Methods
We
retrospectively selected 71 β-TDT patients with FPG ≥ 126 mg/dL, who
were followed at three Thalassemia centers (Iran, Italy, and Oman) and
underwent annual or biannual 2-h OGTTs over the last 30 years. The main
exclusion criteria included: (a) non-transfusion-dependent thalassemia
(NTDT); b) bone marrow transplanted patients; (c) pregnancy; (d)
patients on treatment with medications influencing glucose metabolism;
(e) patients with incomplete data, and (f) positive history of recent
surgery, or illness, or current use of oral hypoglycemic agents. Data
collected at OGTT screening included: age, gender, anthropometric
measurements [standing height, weight and body mass index (BMI),
according to Center for Disease Control and Prevention],[4]
and patients’ medical data (age at first transfusion, age of
splenectomy, type and dose of chelating drugs, family history of
diabetes, relevant biochemical and hematological parameters). Serum
alanine aminotransferase (ALT) was measured by an automated analyzer
(normal range 0–40 mU/L), and active HCV infection was determined by a
qualitative HCV-RNA assay according to the manufacturer's instructions.
Iron overload (IOL) was assessed by serum ferritin (SF) in μg/L. IOL
was arbitrarily classified as mild (SF:< 800 µg/L),moderate (SF: ≥
800 µg/L and < 1,500 µg/L), high (SF: ≥ 1,500 µg/L and < 3,000
µg/L), and severe (SF: ≥ 3,000 µg/L).
OGTT was performed after a
10-h fast using 75 g dextrose monohydrate, and results were evaluated
according to the current ADA criteria. Plasma glucose (PG)
concentrations were measured by an automated glucose oxidase reaction.
Data on insulin secretion, sensitivity, and resistance were available
for 27 patients followed at a single Center (Ferrara). Serum insulin
concentrations were assessed by a commercial immunoassay technique
(Diagnostic Products Corporation, Los Angeles, CA) at 0', 30', 60', and
120' minutes after OGTT. The following surrogate indices were
calculated: homeostasis model assessment (HOMA-IR), insulinogenic
index (IGI), Matsuda Whole Body Insulin Sensitivity Index (Matsuda
Index), and oral disposition index (oDI). The oral disposition index
(oDI) was determined as the product of the Matsuda index and the IGI
obtained during the OGTT.[5]
Statistical analysis
was conducted using STATA (v12.1, College Station, TX). Numeric
variables are expressed as mean ± standard deviation (SD) and 95%
confidence intervals (CI). The Kolmogorov-Smirnov test was used to
verify the normality of the distributions of the variables. Normally
distributed continuous variables were compared using a one-way analysis
of variance (ANOVA). and non-normally distributed variables were
calculated using the Kruskal-Wallis test. Relationships between
variables were assessed using Pearson's linear correlation for normally
distributed variables and Spearman's Rank Correlation for non-normally
distributed quantitative variables. According to Swinscow, the
correlation coefficient was considered as follows: <0.4 as weak,
from 0.4 to 0.59 as moderate, from 0.6 to 0.79 as strong, and ≥ 0.8 as
very strong.[6] The categorical data were analyzed
using the chi-square (χ2) test. Furthermore, time-dependent receiver
operating characteristic (ROC) curve analyses and respective areas
under the curve. Multiple linear regression analyses were employed to
evaluate the relationship between the dependent variable, 2-h PG after
OGTT, and potential associated risk factors: age, gender, BMI,
pre-transfusion hemoglobin level, oral iron chelating agents, SF,
history of splenectomy, and positive family history for T1 DM and T2
DM. Other variables were not assessed because the major risk factors
for dysglycemia currently reported in the literature include older age,
high BMI, elevated SF levels, chronic liver disease, and history of
splenectomy.[1,2,7] A p-value <0.05 was considered statistically significant.
Ethics.
All patients provided informed consent in accordance with principles of
the Declaration of Helsinki. Patients underwent only routine diagnostic
procedures in accordance with international recommendations for the
diagnosis and management of dysglycemia in β-TDT patients.[2]
The study was approved by the local institutional review boards or was
waived in accordance with the local legislation and institutional
requirements.
Results
The
cohort included 71 β-TDT patients (34 males and 37 females), with a
mean age of 25.6 ± 10.5 years (range: 13– 59.7 years). Of these, 19/71
patients (26.7%) were under 18 years of age. 60/71 patients were of
normal weight (84.5%), 3/71 (4.2%) were underweight, and 8/71 (11.2%)
were overweight or obese.
Genotypic data were available for 49
patients, with the majority (39/49; 79.5%) being homozygous for
β⁰-thalassemia and 10 patients (20.4%) having a compound heterozygous
β⁰/β⁺genotype. The mean annual pre-transfusion Hb level was 9.2 ± 0.38
(range: 8-10.2 g/dL; median: 9.1 g/dL).
A positive family
history for type 1 or 2 DM was reported in 26/66 (39.3%) patients. A
past history of splenectomy was reported in 46/71 (56.3%) patients with
β-TDT. Mean and median ALT in 49/71 patients were 59.8 ± 44.3 and 49
IU/L, respectively. A positive HCV RNA history was reported in 19/49
(38.7%).
For IOL treatment, various iron chelators have been used
over the last 3 decades. Over the years, different combinations have
been developed to allow individualized therapy in β-TDT patients with
poor adhesion to iron chelation therapy, persistent IOL, and/or organ
damage. The most common treatment was the combination of
desferrioxamine (DFO) plus deferiprone (DFP) (25/70 patients; 35.7%),
followed by subcutaneous desferrioxamine (DFO: 14/70; 20.0%). One
adolescent patient refused any iron chelation therapy (Figure 1).
 |
- Figure 1. Distribution of iron chelators used for the treatment of iron overload. Legend: [1] desferrioxamine (DFO); [2] deferiprone (DFP); [3] deferasirox (DFX); [4] DFO+DFP; [5] DFP+DFX, and [6] DFO + DFX.
|
The
mean value of SF was 3,492 ± 3,063 µg/L (95% CI 2,780–4,204). In 9/71
(12.6%) patients, the SF levels were < 800 µg/L, and in 37/71
(52.1%) patients, they were > 2,500 µg/L. A 14-year-old patient with
Th-RDM refused ICT.
The mean FPG was 141.6 ± 16.5 mg/dL (95%
137.7–145.4). The mean 1-h PG, after glucose load, was 253.4 ± 73.1
(95% 236.3–270.4) and the mean 2-h PG, after glucose load, was 233.8 ±
67.0 mg/dL (95% 218.215–249.385). Among 71 β-TDT patients with FPG ≥
126 mg/dL, 2-h PG ≥ 200 mg/dL was documented in 53 patients (74.6%),
while PG 2-h after OGTT was 140-199 mg/dl in 12 patients (16.9 %) and
< 140 mg/dl in 6 patients (8.5%).
The ROC curve analysis showed
that the optimal cutoff value for FPG ≥ 126 mg/dL to detect 2-h PG ≥
200 mg/dL after OGTT was 133.6 mg/dL, with a sensitivity of 66% and
specificity of 77.8% (Figure 2).
 |
- Figure 2.
Receiver operating characteristic (ROC) curve using the performance of
FPG measurements (≥ 126 mg/dL) as outcomes for 2-h PG ≥ 200 mg/dL,
after OGTT. The best cutoff value was 133.6 mg/dL, with a sensitivity
of 66% and a specificity of 77.8%, yielding an AUC (area under the ROC
curve) of 0.711.
|
Data
on insulin secretion, sensitivity, and resistance were available for 27
patients. The surrogate indices of insulin secretion and
sensitivity/resistance in 17 β-TDT patients with FPG ≥ 126 mg/dL and
2-h PG after OGTT ≥ 200 mg/dL were compared to those in 16 young adult
healthy controls (Table 1). The
increased HOMA-IR index was associated with a significant defect in
β-cell secretion (IGI) and a reduction in oDI, indicating insufficient
compensation for IR and reflecting a decline in pancreatic β-cell
function. In the remaining 10 patients, 6 had FPG ≥ 126 mg/dL and PG
2-h after OGTT between 140 -199 mg/dL, and 4 patients had FPG ≥ 126
mg/dL with PG 2-h after OGTT < 140 mg/dL; comparison with healthy
controls was not performed due to the small numbers.
 |
- Table 1.
Derived indices of insulin sensitivity/resistance, secretion, and
β-cell function in 17 β-TDT patients with FPG ≥ 126 mg/dL and 2-h PG
after OGTT ≥ 200 mg/dL (Group A) versus 16 young adult healthy controls (Group B; from Ref 1).
|
A
linear, significant but weak correlation was found between SF and 2-h
PG after OGTT (r: 0.3909, P: 0.00089). A moderate correlation was
documented between FPG and 2-h PG after OGTT (r: 0.4669; P: 0.000055),
and between 30-min vs. 2-h PG after OGTT (47 patients; r: 0.429, P:
0.0036).
A strong correlation was observed between 1-h PG and
2-h PG after OGTT (48 patients; r = 0.7325, P < 0.00001). Moreover,
the combination of FPG ≥ 126 mg/dL and 1-h PG 253.5 mg/dL (1st
quartile) was associated with 2-h PG > 200 mg/dL in 44/48 (91,6%)
β-TDT patients.
The multivariate linear regression model confirmed
an association between 2-h PG after OGTT and SF level (t-stat: 2.4798;
P: 0.015), but not with the other investigated variables.
Conclusions
Pancreatic
IOL in β-TDT patients generally begins after the first decade of life
and increases with age. The incidence of dysglycemia is primarily
driven by chronic IOL from frequent blood transfusions, through
reactive oxygen species (ROS)- mediated impairment of insulin
synthesis, secretion, and apoptosis, contributing to the development of
Th-RDM.[8]
A significant correlation was found
between SF and 2-h PG after OGTT (r: 0.3909, P: 0.00089). In 9/71
(12.6%) patients, the SF levels were <800 µg/L, and in 37/71 (52.1%)
patients,> 2,500 µg/L (95% CI: 2,780–4,204). A high risk of Th-RDM
has been reported in the UK, using a univariate analysis, in β-TDT
patients with persistently elevated SF levels (an average 10-year SF
level >1,500 µg/L) compared to those with lower average SF levels.[9]
In addition to IOL, other risk factors for developing dysglycemia in
β-TDT patients include: severity of genotype and clinical phenotype,
advanced age at onset of chelation therapy, poor compliance with
chelation therapy, chronic liver disease, overweight/obesity, and
history of splenectomy. Additional risk factors include associated
endocrine complications, zinc deficiency, pancreatic fatty replacement,
low insulin-like growth factor-1 (IGF-1), and reduced physical
activity.[1,2,6,8]
The
present study has important implications for clinical practice: the use
of high FPG as a single screening test is not sufficiently
discriminative for diagnosing diabetes in patients with β-TDT. The ROC
analysis showed that the best cutoff value of FPG for detecting 2-h PG
≥ 200 mg/dL after OGTT was 133.6 mg/dL, with a sensitivity of 66% and
specificity of 77.8%. Nonetheless, even with this cutoff, 15/29 β-TDT
patients (51.7%) had 2-h PG < 200 mg/dL.
The reported sensitivity of FPG ≥126 mg/dL to detect 2-h OGTT diagnosed diabetes was 44.7% in Japanese subjects,[10] 70.1% in UK,[11] and 41% in US subjects.[12] Basically, the strength of association between FPG and 2-h PG is highly variable and depends on various factors.[10-12]
Reproducibility and accuracy of PG levels may be influenced by
pre-analytical, analytical, and post-analytical issues. The
pre-analytical phase is the most important and requires standardized
procedures to minimize variability and bias, both in the analytical
methods used and in biological variability.[13,14]
For
the foregoing reasons, clinicians should be prudent when two different
tests are used, and the results of FPG ≥ 126 mg/dL versus 2-h PG
post-glucose load are discordant. In practice, healthcare professionals
might decide to closely follow patients at risk and consider a second
OGTT, as recommended by the ADA.[3] The long-term
follow-up in 10 β-TDT patients with discordance between FPG and 2-PG
levels documented the development of diabetes in 7/10 patients, after
4.5 ± 2.9 years (range: 1-10 years), and an isolated impaired fasting
glucose in 3 patients, after 1, 4, and 7 years.
Several studies
across different ethnic groups have shown that intermediate glucose
values at 1 h post-glucose load predict an increased risk of incident
T2DM.[15] In the present study, the combination of FPG ≥ 126 mg/dL and 1-h PG 253.5 mg/dL (1st
quartile) was strongly associated with 2-h PG:≥ 200 mg/dL. Additional
studies are needed to expand our understanding of the role of elevated
1-h PG in patients with dysglycemia and to evaluate whether shortening
the OGTT from 2-h to 1-h would be more practical, acceptable, and
effective in clinical practice.[15-18]
The major
limitations in this study were evaluated. First, the small number of
patients included in the retrospective survey. Second, there is a need
to obtain further evidence on the diagnostic accuracy of FPG and to
establish the optimal cutoff for maximum diagnostic accuracy, the
concentration in large numbers of patients with β-TDT in different
countries. Third, although a single FPG measurement is acceptable for
epidemiological studies, its day-to-day variability can lead to
misclassification of glucose tolerance.[19] The
day-to-day intraindividual coefficients of variation range from 6.4 to
11.4% for FPG and 14.3 to 16.7% for 2-h PG during OGTT.[13,14]
Finally, our study did not perform direct clamp measurements of insulin
sensitivity and secretion; these were assessed using surrogate indices:
HOMA-IR, IGI, MI (0-120), and oDI.
Despite these limitations,
this study provides, for the first time, valuable insights into the
diagnostic accuracy of elevated FPG for screening dysglycemia in β-TDT
patients. The concordance rate between elevated FPG and 2-h PG was high
at 74.6%, but it also highlighted disagreement between the two values
in 25% of our patients with β-TDT. Substantially, it indicates that the
risk of diabetes increases with the degree of fasting hyperglycemia,
underlining the importance of long-term follow-up in patients with
discordant levels between FPG and 2-h PG post glucose load, and
suggests that 1-h PG, like in the general population,[20] is a
sensitive marker for detecting β-TDT patients at high risk for Th-RDM.
Author contributions
VDS
conceived and designed the retrospective observational study, wrote the
original draft. VDS, MF, and SD are the guarantors of the data
integrity and take full responsibility for its content. VDS and IE
performed formal analysis and data interpretation. SD and PT played a
pivotal role in shaping the final paper version. MF, ATS, FS, and MK
contributed to the intellectual content. All authors have accepted
responsibility for the entire content of this scientific letter and
approved its submission.
Acknowledgements
We thank all the participants in the study. We are also indebted to our colleagues for their help in facilitating this study.
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