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

Main Article Content

Vincenzo De Sanctis
Shahina Daar
Ashraf T Soliman
Ploutarchos Tzoulis
Mehran Karimi
Christos Kattamis

Keywords

β-thalassemia major, oral glucose tolerance test, impaired fasting glucose, glucose dysregulation, insulin resistance, insulin secretion defect, long-term follow-up

Abstract

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

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References

1. Kwiatkowski JL. Current recommendations for chelation for transfusion-dependent thalassemia. Ann N Y Acad Sci 2016;1368:107-14.

2. De Sanctis V, Soliman A, Tzoulis P, Daar S, Fiscina B, Kattamis C. The Pancreatic changes affecting glucose homeostasis in transfusion dependent β- thalassemia (TDT): a short review. Acta Biomed 2021; 92(3):e2021232.

3. Wood JC. Estimating tissue iron burden: current status and future prospects. Br J Haematol 2015;170:15-28.

4. Au WY, Lam WW, Chu W, Tam S, Wong WK, Liang R,et al. A T2* magnetic resonance imaging study of pancreatic iron overload in thalassemia major. Haematologica 2008;93:116-9.

5. Papakonstantinou O, Ladis V, Kostaridou S, Maris T, Berdousi H, Kattamis C, et al. The pancreas in β-thalassemia major: MR imaging features and correlation with iron stores and glucose disturbunces. Eur Radiol 2007;17:1535-43.

6. Huang J, Shen J, Yang Q, Cheng Z, Chen X, Yu T, et al. Quantification of pancreatic iron overload and fat infiltration and their correlation with glucose disturbance in pediatric thalassemia major patients. Quant Imaging Med Surg 2021;11:665-75.

7. Berdoukas V, Nord A, Carson S, Puliyel M, Hofstra T, Wood J, et al. Tissue iron evaluation in chronically transfused children shows significant levels of iron loading at a very young age. Am J Hematol. 2013;88:E283-5.

8. Noetzli LJ, Mittelman SD, Watanabe RM, Coates TD, Wood JC. Pancreatic iron and glucose dysregulation in thalassemia major. Am J Hematol. 2012;87:155-60.

9. Hankins JS, McCarville MB, Loeffler RB, Smeltzer MP, Onciu M, Hoffer FA, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood 2009;113:4853-5.

10. He LN, Chen W, Yang Y, Xie YJ, Xiong ZY, Chen DY, et al. Elevated Prevalence of Abnormal Glucose Metabolism and Other Endocrine Disorders in Patients with β-Thalassemia Major: A Meta-Analysis. Biomed Res Int 2019;2019:6573497.

11. World Health Organization. Classification of diabetes mellitus. Geneva: World Health Organization; 2019.

12. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021;44 (Suppl 1):S15-S33.

13. De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, et al. Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab 2013;17:8-18.

14. De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Soliman NA, Elalaily R, et al. Endocrine profile of β-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center. Indian J Endocrinol Metab. 2016;20:451-9.

15. De Sanctis V, Soliman AT, Tzoulis P, Daar S, Di Maio S, Fiscina B, et al. 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. Mediterr J Hematol Infect Dis. 2021;13:e2021051.

16. De Sanctis V, Soliman AT, Fiscina B, Elsedfy H, Elalaily R, Yassin M, et al. Endocrine check-up in adolescents and indications for referral: A guide for health care providers. Indian J Endocrinol Metab. 2014;18(Suppl 1):S26-38.

17. August GP, Caprio S, Fennoy I, Freemark M, Kaufman FR, Lustig RH, et al. Prevention and treatment of pediatric obesity: An endocrine society clinical practice guideline based on expert opinion. J Clin Endocrinol Metab 2008;93:4576-99.

18. Positano V, Pepe A, Santarelli MF, Scattini B, De Marchi D, Ramazzotti A, et al. Standardized T2* map of normal human heart in vivo to correct T2* segmental artefacts. NMR Biomed 2007;20:578-90.

19. Maggio A, Capra M, Pepe A, Mancuso L, Cracolici E, Vitabile S, et al. A critical review of non-invasive procedures for the evaluation of body iron burden in thalassemia major patients. Ped Endocrinol Rev 2008;6 (Suppl 1):193-203.

20. Casale M, Meloni A, Filosa A, Cuccia L, Caruso V, Palazzi G, et al. Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study. Circ Cardiovasc Imaging 2015;8(8):e003230.

21. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9.

22.. Kernan WN, Inzucchi SE, Viscoli CM, et al. Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. Stroke 2003; 34: 1431–6.

23. Bahar A, Kashi Z, Sohrab M, Kosaryan M, Janbabai G. Relationship between beta-globin gene carrier state and insulin resistance. J Diabetes Metab Disord 2012;11(1):22.

24. Phillips DI, Clark PM, Hales CN, Osmond C. Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion. Diabet Med 1994;11:286–92.

25. Utzschneider K, Prigeon R, Faulenbach M V, Tong J, Carr DB, Boyko EJ, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care 2009;32:335-41.

26. Alder R, Roesser EB. Introduction to probability and statistics. WH Freeman and Company Eds. Sixth Edition. San Francisco (USA),1975.

27. Bansal N. Prediabetes diagnosis and treatment: A review. World J Diabetes 2015;6:296-303.

28. De Sanctis V, Daar S, Soliman AT, Tzoulis P, Karimi M, Di Maio S, et al. When and How to Screen for Glucose Dysregulation (GD) in Patients with β-Thalassemia Major (β-TM): A Review of Recent Advances. Ped Endocrinol Rev 2021 (Submitted for publication).

29. Soliman AT, el Banna N, alSalmi I, Asfour M. Insulin and glucagon responses to provocation with glucose and arginine in prepubertal children with thalassemia major before and after long-term blood transfusion. J Trop Pediatr. 1996;42:291-6.

30. Farmaki K, Angelopoulos N, Anagnostopoulos G, Gotsis E, Rombopoulos G, Tolis G. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major. Br J Haematol 2006;134:438-44.

31. Osei K, Rhinesmith S, Gaillard T, Schuster D. Beneficial metabolic effects of chronic glipizide in obese African Americans with impaired glucose tolerance: implication for primary prevention of type 2 diabetes. Metabolism 2004; 53: 414–22.

32. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 2006;55:1430-5.

33. Pepe A, Pistoia L, Gamberini MR, Cuccia L, Peluso A, Messina G, et al. The Close Link of Pancreatic Iron With Glucose Metabolism and With Cardiac Complications in Thalassemia Major: A Large, Multicenter Observational Study. Diabetes Care 2020; 43: 2830-9.

34. De Sanctis V, Soliman AT, Candini G, Kattamis C, Raiola G, Elsedfy H. Liver Iron Concentration and Liver Impairment in Relation to Serum IGF-1 Levels in Thalassaemia Major Patients: A Retrospective Study. Mediterr J Hematol Infect Dis 2015;7(1):e2015016.