Long-Term Follow-up of β-Transfusion-Dependent Thalassemia (TDT) Normoglycemic Patients with Reduced Insulin Secretion to Oral Glucose Tolerance Test (OGTT): A Pilot Study
of ICET-A Network (International Network of Clinicians for
Endocrinopathies in Thalassemia and Adolescence Medicine), Ferrara,
2 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar and Department of Pediatrics, Division of Endocrinology, Alexandria University Children’s Hospital, Alexandria, Egypt.
3 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman.
4 Department of Diabetes & Endocrinology, Whittington Hospital, University College London, London, UK.
5 Emeritus Director in Pediatrics, Children’s Hospital “Santobono-Pausilipon,” Naples, Italy.
6 First Department of Paediatrics, National Kapodistrian University of Athens, Greece.
Received: November 15, 2020
Accepted: February 11, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021021 DOI 10.4084/MJHID.2021.021
| 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 study the endocrine pancreas' function in transfusion-dependent
β-thalassemia (β-TDT) patients with a normal glucose tolerance test
(NGT) and hypoinsulinemia. In addition, the prospective long–term
follow-up using an annual oral glucose tolerance test (OGTT) to detect
any abnormality of glucose metabolism.
In patients receiving suboptimal iron chelation, pancreatic iron loading starts in early childhood. The pathogenesis of glycemic abnormalities in β-TDT patients is complex and multifactorial, and significantly different from the pathogenesis of glucose metabolism's dysregulation in a normal individual, particularly children and adolescents. Several studies have shown that insulin resistance and insulin deficiency mark both the prediabetic state and diabetes in thalassemia.[3-5] Insulin secretory defects, however, may originate from pancreatic β-cell damage rather than from insulin resistance.
To evaluate the possible role of autoimmunity in the pathogenesis of diabetes, Monge et al. studied a cohort of 53 β-TDT patients, including twelve patients with diabetes (22.6%). To be evaluated about the activation of an autoimmune response, individuals were tested for islet cell antibodies (ICA), glutamic acid decarboxylase (GAD) autoantibodies, insulin autoantibodies (IAA), and serum antinuclear antibodies (ANA). The study demonstrated evidence of immune system activation against pancreatic β-cells in β-TDT patients. The authors suggested that iron deposition may act through oxidative damage as an environmental factor that triggers the autoimmune response.
Overall, these diabetogenic factors have a cumulative effect that seems to be progressive and can lead to glucose intolerance in long-term.
In the light of these observations, we report seven β-TDT patients with normal glucose tolerance test (NGT) and reduced insulin response (hypoinsulinemia), after an oral glucose tolerance test (OGTT), referred for a second opinion, from Italian Centers taking care of patients with hemoglobinopathies. Due to very uncommon observations, their long-term natural history, assessed by an annual OGTT, is reported with the aim of detecting any abnormality of glucose metabolism.
Patients and Methods
The following data were collected from each subject: demographic data, age at first transfusion, the interval between transfusions, type and compliance to iron chelation therapy, anthropometric data [weight, height, body mass index (BMI)], pubertal status, and associated endocrine complications. BMI was calculated as body weight in kilograms divided by height in meters squared.
A subject was considered obese when BMI exceeded 30 Kg/m2, overweight when BMI was 25 - 30 kg/m², of average weight when BMI was 18.5-25 kg/m², and underweight when the BMI was < 18.5 kg/m².
First step: Study of autoimmunity and first-phase insulin release (FPIR) after intravenous glucose tolerance test (IVGTT). The β-cell autoimmunity was assessed in all patients by GAD, ICA, and IAA. The samples were analyzed for ICA by immunofluorescence and for GAD and IAA by specific radioligand binding assays. Waiting for autoimmunity results against pancreatic β-cells, an intravenous glucose tolerance test (IVGTT) was performed between 08.30 and 09.30, after fasting for 8-10 hours. Patients consumed a regular diet for 3 days and avoided smoking before the test.
An intravenous catheter was placed in the antecubital vein, and an intravenous bolus of 0.5 g glucose/kg body weight (maximum 35 g, as 25% water solution) was injected manually through an indwelling intravenous cannula in the contralateral antecubital vein over 3 - 4 minutes. The end of glucose infusion was defined as time zero. Blood was assessed for insulin radioimmunoassay at baseline (completion of glucose infusion) and after 1, 3, 5, and 10 minutes. The sum of insulin values at 1 and 3 minutes was used as an index of the first phase insulin response (FPIR).[11,12] For FPIR, the 1st percentile is 48 µU/ml, 3rd percentile 56 µU/ml, 5th percentile 64 µU/ml, 10th percentile 81 µU/ml, and 50th percentile 162 µU/ml.
Other laboratory assays and cardiac imaging. The serum alanine aminotransferase (ALT) level was determined by an automated analyzer (normal range 0–40 mU/L). Serum ferritin was measured by immunoassays. The 90th percentile of reported average values is 201-243: ng/mL.
Plasma glucose was measured using an automated glucose oxidase reaction (Glucose Analyser, Ames). Plasma samples were centrifuged at 4°C, separated, and stored at −20°C until assay. Plasma insulin was determined by a commercial solid-phase radioimmunoassay technique (Coat-A-Count insulin kit, Diagnostic Products Corporation, Los Angeles, CA) with intra- and inter-assay coefficients of variance of 3.3% and 2.5%, respectively.
Cardiac T2* was assessed by magnetic resonance imaging (MRI) using a 1.5 T scanner. A conservative cut-off value of heart T2* > 20 ms was considered normal.
Follow-up. After IVGTTs, all patients were followed yearly with an OGTT to detect any potential glucose abnormalities, including quantitative and qualitative defects in insulin secretion, using the following methods and calculation indices;
Plasma glucose, insulin, and islet β-cell function indices from the OGTT. One week following the blood transfusion, a 75-g OGTT was performed in the morning after an overnight fast. Blood samples were collected from the venous catheter at 0, 30, 60, 90, 120, and 180 minutes for plasma glucose and insulin assessment. Participants remained seated for the entire testing period.
Based upon plasma glucose results on OGTT, patients were classified according to the American Diabetes Association (ADA) criteria into the following categories:
- Normoglycemia: FPG < 100 mg/dL and 2-h PG < 140 mg/dL;
- IFG: FPG between 100 and 125 mg/dL;
- IGT: 2-h PG between 140 and 199 mg/dL;
- DM: Fasting plasma glucose (FPG) ≥ 126 mg/dl or 2-hour plasma glucose (2-h PG) ≥ 200 mg/dL.
Different indirect indices were applied for insulin resistance and sensitivity recognition; among them those calculated from fasting glucose and insulin concentration and those derived during the OGTT, including Insulinogenic Index (IGI), plasma glucose (PG), and insulin (INS) area under the curves (AUC- PG 0–120 min and AUC-INS 0–120 min), Homeostasis Model Assessment of Insulin Resistance (HOMA1-IR), Quantitative Insulin sensitivity Check Index (QUICKI), Matsuda insulin sensitivity index (ISIM), and Insulin Secretion-Sensitivity Index-2 (ISSI-2). AUC- PG, and AUC-INS during OGTT were calculated with the trapezoid method.[15-19]
Statistical analysis. Data are presented as means ± standard deviation (SD). Statistical comparison between parameters was made using the paired “t” test. Simple linear regression tested the correlations between variables. For the statistical analysis, a software program was used and validated, according to Alder and Roesser. A p-value < 0.05 was considered statistically significant.
Ethics. All procedures were in accordance with the 1964 Helsinki declaration and its later amendments. According to the Italian regulations, the local Ethics Committee's approval was not required for the following reasons: no identifiable private information was collected; patients underwent only routine diagnostic and therapeutic procedures according to current guidelines; an anonymized dataset was analyzed. Informed consent was obtained from all patients after a detailed explanation of the study's nature and purpose and the likely risks and benefits of study participation.
1. Clinical and laboratory characteristics of 7 patients with β- TDT at baseline.
Five of seven patients were on desferrioxamine (DFO) monotherapy with an average daily dose of 40 ± 5.34 mg/kg body weight (range: 35-50 mg/kg body weight), given subcutaneously by pump for 7 to 8 hours per night, for 5 to 6 days a week. Two patients were on oral deferiprone (DFO) monotherapy (total dose 75 mg/kg/day, divided into 3 doses). At baseline, their mean serum ferritin levels were 1,562.5 ± 834.7 ng/mL (range: 955-3,015 ng/mL) (Table 1).
The highest mean serum ferritin level ("peak level") registered in the course of previous years was 3,664.2 ± 1,567.5 ng/mL (range: 6,000-2,250 ng/mL). ALT was elevated in 3 patients (patients 2, 5, and 7 with DFO). Cardiac T2* was impaired in one patient (18.8 msec) with a peak ferritin level of 5,400 ng/mL.
Glucose tolerance at baseline. At baseline, all patients had normal glucose values with reduced insulin secretion on OGTT. The peak of plasma glucose and insulin response, after OGTT, was delayed (60'-90' minutes) in 3 patients (Table 2).
2. Oral glucose tolerance test (OGTT) and first-phase insulin response
(FPIR), after IVGTT, at baseline in seven β- TDT patients.
No statistical correlation was observed between age and BMI, AUC-PG, AUC-Ins, and peak of serum ferritin level. Similarly, a non-significant correlation was found between HOMA-IR, QUICKI, and ISSI-2 with AUC-PG and AUC-INS. Conversely, a significant correlation was found between ISIM and AUC-INS (R= 0.7824; P: 0.037) but not with AUC-PG. An inverse correlation was present between HOMA-IR and QUICKI (R= -0.9567; P: 0.0007).
Correlations between serum ferritin levels (peak over previous years ) with HOMA-IR, QUIKI, AUC-PG, and AUC-INS were not significant. An inverse correlation was present between serum ferritin at the time of study vs. ISIM and ISSI-2 (R= -0.962; P: 0.00053 and R= -0.8459; P: 0.016, respectively).
Adverse effects of OGTT. There were no adverse events secondary to OGTT, and none of the subjects experienced hypoglycemia.
FPIR after IVGTT. In two patients, the FPIR value FPIR after IVGTT. In two patients, the FPIR value (expressed as the sum of 1 + 3 min insulin) was between the 1st and 3rd percentile (patients 1 and 6), and in five patients between the 3rd and 10th percentile (Table 2). No correlation was observed between FPIR and age, AUC-PG, AUC-Ins, the peak of serum ferritin level, or serum ferritin at baseline. These results were not associated with β-cell autoimmunity.
Glucose tolerance, insulin and islet β-cell function indices from the OGTT during annual follow-up. During the annual OGTT follow-up, glucose homeostasis's first alteration was documented after 43 ± 26 months (range 13-80). Two patients developed IGT (patients 4 and 7), three IFG associated with IGT (patients 1, 2 and 3), and two overt DM (patients 5 and 6) within 3.3 and 1.1 yrs, respectively (Table 3). All seven patients had abnormal 2-hour plasma glucose (Figure 1). A strong linear correlation was also observed between the FPIR value at baseline and interval (expressed in months) of the appearance of glucose homeostasis abnormalities (R= 0.8753, P: 0.009).
|Table 3. Age at first documentation of glucose homeostasis impairment in 7 β- TDT patients followed yearly with an OGTT.|
|Figure 1. Outcome of 7 β-TDT patients with normal OGTT and hypoinsulinemia followed for 13-80 months.|
The AUC-Ins120/AUC-PG 120 was not statistically different between baseline values vs. last observation (P: 0.16). However, the β-TDT patients who developed DM had the lowest IGI index values at baseline (0.08 and 0.25). Throughout the entire follow-up, five patients developed IGT; there was a significant difference in baseline IGI in these patients compared to those who did not develop IGT (R= 0.927; P: 0.023), independently from IFG presence.
There was no significant change in HOMA-IR and QUICKI during the follow-up. On the other hand, a significant reduction in the ISIM and ISSI-2 was documented in the whole study cohort at IFG-IGT and DM diagnosis. There was a significant inverse correlation between ISSI-2 and AUC-PG (R= -0.9617, P: 0.0005) (Table 4).
|Table 4. Follow-up of
indirect indices of insulin secretion and resistance at baseline and at
the diagnosis of IGT and DM in patients with β- TDT.
No significant BMI changes occurred in patients from the baseline to the end of the follow-up period (20.8 ±1.0 vs. 21.1 ± 1.2 Kg/m2; P: NS). The mean serum ferritin level did not differ at baseline or at the occurrence of IGT/IFG/DM (1,562 ± 901.6 vs. 1,341 ± 653.3 ng/mL; P: NS).
Due to the limited number of β-TDT patients, a comparison of collected parameters between males and females was impossible.
OGTT is widely used in clinical settings to diagnose patients with IGT and DM, based on ADA recommendations. OGTT is a valuable tool in diabetes research and is commonly used for screening, evaluating disease progression, monitoring treatment, and thoroughly studying physiological and patho-physiological conditions. Because of the increased risk of glucose disturbances in β-TDT patients with iron overload, there are recommendations for annual evaluation of glycemic status in children over ten years.
However, OGTT gives only a crude estimate of β-cell secretory function. The initial insult is considered insulin resistance, which, as long as it is compensated by hyperinsulinemia, does not lead to hyperglycemia. Finally, when pancreatic β-cells are unable to secrete an increased amount of insulin, to compensate for insulin resistance, hyperglycemia develops.[3-6]
In this study, patients with β-TDT, despite exhibiting normal glucose tolerance as defined by standard glucose homeostasis criteria, presented with impaired insulin secretion (hypoinsulinemia) during OGTT. The reduced insulin response to OGTT was further confirmed by FPIR values (between the 1st and 3rd percentile in two patients and in five between the 3rd and 10th percentile). The potential role of autoimmunity was excluded by the assessment of islet cell antibodies (ICA), glutamic acid decarboxylase (GAD) autoantibodies, and insulin autoantibodies (IAA).
Although we cannot identify the cause of the low insulin levels found during OGTT at baseline, we can speculate that these patients had a higher insulin sensitivity. However, we cannot exclude, on the basis of long-term follow-up, the decreased β-cell secretory capacity was due to an initial and progressive impairment of pancreatic β-cells toxicity of iron overload, and/or to loss of pancreatic micro-vascularity.[23-25]
A strong linear correlation was observed between the FPIR value at baseline and the time interval of the appearance of glucose abnormalities (R= 0.8753, P: 0.009). In two patients, the FPIR value (expressed as the sum of 1 + 3 min insulin) was between the 1st and 3rd percentile (patients 1 and 6), and in five, between the 3rd and 10th centile. Nevertheless, the insulin response to IVGTT in all patients was higher compared to OGTT. In healthy individuals, the incretin effect accounts for 70% of the insulin response after oral glucose administration. However, we can speculate a possible reduction of the incretin effect in pivotal experiments; to assess the incretin effects the comparison between oral and i.v. glucose stimuli were performed using well-matched glucose concentrations. That was not the case in our subjects.
From the baseline, all patients were followed yearly with an OGTT. After a total period of 43 ± 26 months (range:11-80) of follow-up, two patients developed IGT, three both IFG and IGT, and two developed DM. Nevertheless, no statistical difference was found between the AUC-Ins120/ AUC-PG120, considered an index of total insulin secretion during the OGTT. This observation suggests that a decrease in insulin sensitivity would be a factor involved in the deterioration of glucose tolerance when the insulin secretion is compromised. In patients with β-TDT, IR may be due to: (a) a direct effect of iron overload to pancreatic β-cells and/or (b) hepatic dysfunction leading to reduced hepatic clearance of insulin resulting in impaired glucose homeostasis.[26-27] Moreover, IR can be related to the variation of qualitative and quantitative nutritional intake and low physical activity.
Several techniques have been used in humans to assess IR. Methods for quantifying β-cell sensitivity to glucose (hyperglycemic clamp technique) and tissue sensitivity to insulin (euglycemic insulin clamp technique) are generally recognized as the gold standard reference for assessing IR. However, these methods are laborious, expensive, and inconvenient to patients or study subjects and are not routinely available to every physician. Since OGTT is cheap and straightforward, many mathematical models’ formulas have been developed using OGTT parameters. We calculated the most widely used surrogate indices: IGI, HOMA-IR, QUICKI, ISIM, and ISSI-2, calculated from fasting glucose and insulin concentration, and those derived OGTT evaluation.[28-30]
In brief, IGI is calculated as the ratio of plasma insulin's increment to glucose concentration 30 min after an OGTT. The loss of this early insulin release is a feature of the prediabetic condition. HOMA and QUICKI are mathematically related and provide essentially identical information. Both primarily reflect hepatic insulin resistance rather than peripheral insulin resistance.
ISIM combines two terms that account for insulin sensitivity of the hepatic as well as the peripheral tissues. One part of the equation consists of a hyperbolic conversion of the product of fasting plasma glucose and insulin as a measure of hepatic sensitivity. The second accounts for whole-body insulin sensitivity, described by the inverse product of the mean glucose and insulin concentration after the glucose load. ISSI-2 is defined as the ratio of the area under the insulin curve to the area under the glucose curve, multiplied by the Matsuda index; it constitutes a surrogate measure of insulin secretion relative to insulin sensitivity and emphasizes the pivotal role of impaired insulin secretion in the development of dysregulation of glucose homeostasis. Substantially, it refers to the relationship between insulin sensitivity and insulin secretion.[15-19]
Our results confirm that the ISSI-2 index may be valuable parameters to identify β -TDT patients at the highest risk for developing glucose dysregulation.
Interestingly, the β -TDT patients who developed DM had, at baseline, the lowest values of the IGI index (0.08 and 0.25). Moreover, a significant correlation was found between IGI at baseline in those patients who developed IGT compared to those who did not, regardless of IFG (R= 0.927; P: 0.023416). No significant changes in HOMA-IR and QUICKI were observed during follow-up. Conversely, a significant reduction of ISIM and ISSI-2 was documented in the whole study cohort at the diagnosis of IFG-IGT and DM, with a significant inverse correlation between ISSI-2 and AUC-PG. Therefore, ISIM and ISSI-2, which include post-load glucose and insulin concentrations, provided a more accurate estimate of whole-body insulin sensitivity than HOMA-IR or QUICKI, derived from fasting measurements only, thus constituting a more sensitive tool for detecting alterations of glucose sensitivity/resistance in β-TDT patients.
Our study has several limitations: a) the small number of patients enrolled in the study, but this seems inevitable as the profile of glucose dysregulation in TDT is reported for the first time and is very rare; b) the use of surrogate indices for assessing insulin sensitivity, and c) the evaluation of iron overload assessed with serum ferritin not associated to the evaluation of pancreatic iron stores by magnetic resonance imaging (MRI). However, the major strength is the long-term follow-up study of an uncommon group of β-TDT patients with NGT and hypoinsulinemia who developed, after 43 ± 26 months, a glucose dysregulation.
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