Main Article Content
β-thalassemia, Diabetes, Insulin deficiency, Insulin resistance, Treatment
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. Natural history of glucometabolic status before the diagnosis of DM was also reviewed.
Results: On average, the TDT patients with DM were younger compared to TDT patients without diabetes. The mean age at diagnosis of DM in female and male TDT patients was 24.0 ± 7.1 years and 31.9 ± 5.6 years, respectively (P: 0.007). Serum alanine aminotransferase values, basal insulin levels and prevalence of hypogonadism were consistently higher in TDT patients with DM compared to those without diabetes. Decreased insulin secretion and increased insulin resistance was observed in patients with DM. Conclusion: The natural history of glucometabolic status in TDT patients is characterized by a deterioration of glucose tolerance over time. Iron overload and liver dysfuction are the main factors responsible for glucose disturbances (GD) in TDT patients. The therapeutic approach must be individualized and followed by a multidisciplinary team.
2. Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018 1;98:2133-2223.
3. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014; 7 (Suppl. 1):S81–S90.
4. Leslie RD, Palmer J, Schloot NC, Lernmark A. Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment. Diabetologia. 2016;59:13–20.
5. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S15-S33.
6. World Health Organization. Classification of diabetes mellitus. Geneva: World Health Organization; 2019.
7. De Sanctis V, Soliman AT, Daar S, Di Maio S, Elsedfy H, Kattamis C. For Debate: Assessment of HbA1c in Transfusion Dependent Thalassemia Patients. Pediatr Endocrinol Rev. 2020;17:226-34.
8. Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of diabetes
by pathophysiology, natural history, and prognosis. Diabetes. 2017;66:241–55.
9. Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab. 1986;15:411-51.
10. Cacciari E, Milani S, Balsamo A, Spada E, Bona G, Cavallo L, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest. 2006;29:581-93.
11. Emmanuel M, Bokor BR. Tanner Stages. 2020. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021
12. 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.
13. 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.
14. 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.
15. Crofts C, Schofield G, Zinn C, Wheldon M, Kraft J. Identifying hyperinsulinaemia in the absence of impaired glucose tolerance: an examination of the kraft database. Diabetes Res Clin Pract. 2016;118:50-7.
16. De Sanctis V, Soliman A, Tzoulis P, Daar S, Pozzobon GC, Kattamis C. 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. Acta Biomed. 2021;92(4):e2021322.
17. Seltzer HS, Allen EW, Herron AL, Jr., Brennan MT. Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest.1967; 46: 323-35.
18. 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.
19. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–70.
20. 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.
21. Retnakaran R, Shen S, Hanley AJ, Vuksan V, Hamilton JK, Zinman B. Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test. Obesity (Silver Spring).2008;16:1901–7.
22. Alder R, Roesser EB. Introduction to probability and statistics.WH Freeman and Company Eds. Sixth Edition. San Francisco (USA), 1975.
23. 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.
24. De Sanctis V, Soliman A,Tzoulis P, Daar S, Kattamis A, Delaporta P, et al. Early detection of glucose dysregulation (GD) in patients with β-thalassemia major: Review of current diagnostic criteria and the ICET-A survey. Curr Trends Endocrinol. 2021;11:1-11.
25. 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.
26. Barnard M, Tzoulis P, Jones R, Prescott E, Shah F. Diabetes and halassemia. Thal Rep. 2013;3:e18
27. De Sanctis V, Zurlo MG, Senesi E, Boffa C, Cavallo L, Di Gregorio F. Insulin dependent diabetes in thalassaemia. Arch Dis Child. 1988;63:58-62.
28. De Sanctis V, Soliman AT, Elsedfy H, Yaarubi SA, Skordis N, Khater D, et al. The ICET-A Recommendations for the Diagnosis and Management of Disturbances of Glucose Homeostasis in Thalassemia Major Patients. Mediterr J Hematol Infect Dis. 2016;8(1):e2016058.
29.Tzoulis P, Shah F, Jones R, Prescott E, Barnard M. Joint Diabetes Thalassaemia Clinic: An Effective New Model of Care, Hemoglobin.2014; 38:104-10.
30. Loebstein R, Lehotay DC, Luo X, Bartfay W, Tyler B, Sher GD. Diabetic Nephropathy in Hypertransfused Patients With β-Thalassemia: The role of oxidative stress. Diabetes Care Aug 1998;21: 1306-9.
31. Tzoulis P.Review of endocrine complications in adult patients with β-thalassaemia major. Thal Rep. 2014; 4:4871.
32. De Sanctis V, Incorvaia C, Soliman AT, Candini G, Pepe A, Kattamis C, et al. Does Insulin Like Growth Factor-1 (IGF-1) Deficiency Have a "Protective" Role in the Development of Diabetic Retinopathy in Thalassamia Major Patients? Mediterr J Hematol Infect Dis. 2015;7:e2015038.
33. United Kingdom Thalassaemia Society. Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK. 2nd Edition 2008. Available at: http://www.ukts.org/pdf.html.
34. Soliman A, De Sanctis V, Yassin M, Elalaily R, Eldarsy NE. Continuous glucose monitoring system and new era of early diagnosis of diabetes in high risk groups. Indian J Endocrinol Metab. 2014;18:274-82.
35. El-Samahy MH, Tantawy AA, Adly AA, Abdelmaksoud AA, Ismail EA, Salah NY. Evaluation of continuous glucose monitoring system for detection of alterations in glucose homeostasis in pediatric patients with β-thalassemia major. Pediatr Diabetes. 2019;20:65-72.
36. Knutson MD. Non-transferrin-bound iron transporters. Free Radic Biol Med. 2019;133:101-11.
37. Brissot P, Ropert M, Le Lan C, Loréal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta. 2012;1820:403-10.
38. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. 2000;23:185-92.
39. Craven CM, Alexander J, Eldridge M, Kushner JP, Bernstein S, Kaplan J. Tissue distribution
and clearance kinetics of non-transferrin- bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proc Natl Acad Sci USA.1987; 84:3457-61.
40. Iancu TC, Shiloh H, Raja KB, Simpson RJ, Peters TJ, Perl DP, et al. The hypotransferrinaemic
mouse: ultrastructural and laser microprobe analysis observations. J Pathol. 1995;177:83-94.
41. Gatter KC, Brown G, Trowbridge IS, Woolston RE, Mason DY. Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol. 1983;36:539-45.
42. Nam H, Wang CY, Zhang L, Zhang W, Hojyo S, Fukada T, et al. ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders. Haematologica. 2013;98:1049-57.
43. Fukada T, Kambe T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics. 2011;3: 662-74.
44. Taylor KM, Morgan HE, Johnson A, Nicholson RI. Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett. 2005;579(2):427-32.
45. Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates nontransferrin- bound iron uptake into cells. Proc Natl Acad Sci USA. 2006;103:13612-7.
46. Merkel PA, Simonson DC, Amiel SA, Plewe G, Sherwin RS, Pearson HA, et al. Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion. N Engl J Med.1988; 318 : 809-14.
47. Pappas S, Donohue SM, Denver AE, Mohamed-Ali V, Goubet S, Yudkin JS. Glucose intolerance in thalassemia major is related to insulin resistance and hepatic dysfunction. Metabolism. 1996;45:652-7.
48. Desbois AC, Cacoub P. Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review. World J Gastroenterol. 2017;23:1697-711.
49. Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver Int. 2008;28:355-62.
50. De Sanctis V, Atti G, Lucci M, Capra L, Vullo C, Bagni B, et al. Valutazione della funzionalità alfa e beta pancreatica nella beta-talassemia maior [Evaluation of alpha and beta pancreatic function in beta-thalassemia major]. Radiol Med.1980;66:861-3. Italian.
51. 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.
52. Sung CC, Liao MT, Lu KC, Wu CC. Role of vitamin D in insulin resistance. J Biomed Biotechnol. 2012;2012:634195.
53. Jahng JWS, Alsaadi RM, Palanivel R, Song E, Hipolito VEB, Sung HK, et at. Iron overload inhibits late stage autophagic flux leading to insulin resistance. EMBO Rep. 2019;20:e47911.
54. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140:900–17.
55. Elsammak M, Refai W, Elsawaf A, Abdel-Fattah I, Abd Elatti E, Ghazal A. Elevated serum tumor necrosis factor alpha and ferritin may contribute to the insulin resistance found in HCV positive Egyptian patients. Curr Med Res Opin. 2005;21:527-34.