β-Thalassemia and Diabetes Mellitus: Current State and Future Directions

Abstract

β-Thalassemia major is a congenital hemoglobin disorder that requires regular blood transfusion. The disease is often associated with iron overload and diabetes mellitus, among other complications. Pancreatic iron overload in β-thalassemia patients disrupts β-cell function and insulin secretion and induces insulin resistance. Several risk factors, including family history of diabetes, sedentary lifestyle, obesity, gender, and advanced age increase the risk of diabetes in β-thalassemia patients. Precautionary measures such as blood glucose monitoring, anti-diabetic medications, and healthy living in β-thalassemia patients notwithstanding, the prevalence of diabetes in β-thalassemia patients continues to rise. This review aims to address the relationship between β-thalassemia and diabetes in an attempt to understand how the pathology and management of β-thalassemia precipitate diabetes mellitus. The possible employment of surrogate biomarkers for early prediction and intervention is discussed. More work is still needed to better understand the molecular mechanism(s) underlying the link between β-thalassemia and diabetes and to identify novel prognostic and therapeutic targets.

Key words

thalassemia - United Arab Emirates - biomarkers - diabetes

Publication History

Received: 21 August 2023

Accepted after revision: 29 September 2023

Article published online:
23 October 2023

• References

• 1 Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010; 5: 1-15
• 2 Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia. Lancet 2022; 399: 2310-2324
• 3 Aydinok Y. Thalassemia. Hematology 2012; 17: s28-s31
• 4 Bajwa H, Basit H. Thalassemia. 2019; StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK545151/
• 5 Taher AT, Saliba AN. Iron overload in thalassemia: different organs at different rates. Hematology Am Soc Hematol Educ Program 2017; 265-271
• 6 Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull WHO 2008; 86: 480-487
• 7 Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev 2012; 26: S3-S6
• 8 Sanchez-Villalobos M, Blanquer M, Moraleda JM. et al. New insights into pathophysiology of ®-thalassemia. Front Med 2022; 9: 880752
• 9 Farid Y, Bowman NS, Lecat P. Biochemistry, hemoglobin synthesis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK536912/
• 10 Ciulla AP, Lehman DC. Success! in clinical laboratory science. Pearson Education; Upper Saddle River, N.J: 2010
• 11 White J, Byrne M, Richards R. et al. Red cell genetic abnormalities in Peninsular Arabs: sickle haemoglobin, G6PD deficiency, and alpha and beta thalassaemia. J Med Genet 1986; 23: 245-251
• 12 White J, Byrne M, Richards R. et al. Thalassaemia genes in peninsular Arabs. Br J Haematol 1985; 60: 269-278
• 13 Baysal E. Molecular basis of β-thalassemia in the United Arab Emirates. Hemoglobin 2011; 35: 581-588
• 14 Aydinok Y, Porter JB, Piga A. et al. Prevalence and distribution of iron overload in patients with transfusion-dependent anemias differs across geographic regions: results from the CORDELIA study. Eur J Haematol 2015; 95: 244-253
• 15 Voskaridou E, Kattamis A, Fragodimitri C. et al. National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality. Ann Hematol 2019; 98: 55-66
• 16 Betts M, Flight PA, Paramore LC. et al. Systematic literature review of the burden of disease and treatment for transfusion-dependent β-thalassemia. Clin Therap 2020; 42: 322-337 e322
• 17 Bonifazi F, Conte R, Baiardi P. et al. Pattern of complications and burden of disease in patients affected by beta thalassemia major. Curr Med Res Opin 2017; 33: 1525-1533
• 18 Azami M, Sharifi A, Norozi S. et al. Prevalence of diabetes, impaired fasting glucose and impaired glucose tolerance in patients with thalassemia major in Iran: a meta-analysis study. Caspian J Intern Med 2017; 8: 1
• 19 Mortazavi P, Darvish-Khezri M, Hessami A. et al. Prevalence and risk factors of diabetes Mellitus in β-thalassemia major patients in the north of Iran: mazandaran β-thalassemia registry-2017 to 2019. Tabari Biomed Student Res J 2021; 3: 12-19
• 20 Olivatto GM, Teixeira CRdS, Sisdelli MG. et al. Characterization of thalassemia major and diabetes mellitus patients at a reference center in Brazil. Hematol Transfusion Cell Therapy 2019; 41: 139-144
• 21 Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 2004; 127: 127-139
• 22 Mehrvar A, Azarkeivan A, Faranoush M. et al. Endocrinopathies in patients with transfusion-dependent ß-thalassemia. Pediatr Hematol Oncol 2008; 25: 187-194
• 23 Bazi A, Sharifi-Rad J, Rostami D. et al. Diabetes mellitus in thalassaemia major patients: a report from the Southeast of Iran. J Clin Diagnos Res. 2017; 11 BC01
• 24 Ibrahim AS, Abd El-Fatah AH, Abd El-Halim AF. et al. Serum ferritin levels and other associated parameters with diabetes mellitus in adult patients suffering from beta thalassemia major. J Blood Med 2023; 67-81
• 25 De Sanctis V, Soliman A, Tzoulis P. et al. Prevalence of glucose dysregulation (GD) in patients with β-thalassemias in different countries: a preliminary ICET-A survey. Acta Bio Medica: Atenei Parmensis 2021; 92
• 26 Sleiman J, Tarhini A, Bou-Fakhredin R. et al. Non-transfusion-dependent thalassemia: an update on complications and management. Int J Mol Sci 2018; 19: 182
• 27 Lee S-H, Park S-Y, Choi CS. Insulin resistance: from mechanisms to therapeutic strategies. Diabetes Metab J 2022; 46: 15-37
• 28 Hafez M, Youssry I, El-Hamed FA. et al. Abnormal glucose tolerance in β-thalassemia: assessment of risk factors. Hemoglobin 2009; 33: 101-108
• 29 Bas M, Gumruk F, Gonc N. et al. Biochemical markers of glucose metabolism may be used to estimate the degree and progression of iron overload in the liver and pancreas of patients with β-thalassemia major. Ann Hematol 2015; 94: 1099-1104
• 30 Nam E, Han J, Suh J-M. et al. Link of impaired metal ion homeostasis to mitochondrial dysfunction in neurons. Curr Opin Chem Biol 2018; 43: 8-14
• 31 Gerencser AA. Metabolic activation-driven mitochondrial hyperpolarization predicts insulin secretion in human pancreatic beta-cells. Biochim Biophys Acta Bioenerg 2018; 1859: 817-828
• 32 Noetzli LJ, Mittelman SD, Watanabe RM. et al. Pancreatic iron and glucose dysregulation in thalassemia major. Am J Hematol 2012; 87: 155-160
• 33 Cooksey RC, Jouihan HA, Ajioka RS. et al. Oxidative stress, β-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology 2004; 145: 5305-5312
• 34 Altamura S, Marques O, Colucci S. et al. Regulation of iron homeostasis: lessons from mouse models. Mol Aspecet Med 2020; 75: 100872
• 35 Mao X, Chen H, Tang J. et al. Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression. Endocr Connect 2017; 6: 121-128
• 36 Shu T, Lv Z, Xie Y. et al. Hepcidin as a key iron regulator mediates glucotoxicity-induced pancreatic β-cell dysfunction. Endocr Connect 2019; 8: 150-161
• 37 Jouihan HA, Cobine PA, Cooksey RC. et al. Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis. Mol Med 2008; 14: 98-108
• 38 Mukherjee S, Dey SG. Heme bound amylin: spectroscopic characterization, reactivity, and relevance to type 2 diabetes. Inorg Chem 2013; 52: 5226-5235
• 39 Seal M, Mukherjee S, Dey SG. Fe–oxy adducts of heme–Aβ and heme–hIAPP complexes: intermediates in ROS generation. Metallomics 2016; 8: 1266-1272
• 40 Hansen JB, Dos Santos LRB, Liu Y. et al. Glucolipotoxic conditions induce β-cell iron import, cytosolic ROS formation and apoptosis. J Mol Endocrinol 2018; 61: 69-77
• 41 Li D, Jiang C, Mei G. et al. Quercetin alleviates ferroptosis of pancreatic β cells in type 2 diabetes. Nutrients 2020; 12: 2954
• 42 Bogna-Pignatti C, Rugolotto S, De Stefano P. et al. Survival and disease complications in thalassemia major. Ann New York Acad Sci 1998; 850: 227-231
• 43 Chuncharunee S, Teawtrakul N, Siritanaratkul N. et al. Review of disease-related complications and management in adult patients with thalassemia: a multi-center study in Thailand. PLoS One 2019; 14: e0214148
• 44 Belhoul KM, Bakir ML, Kadhim AM. et al. Prevalence of iron overload complications among patients with β-thalassemia major treated at Dubai Thalassemia Centre. Ann Saudi Med 2013; 33: 18-21
• 45 De Sanctis V, Soliman AT, Elsedfy H. et al. Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia. Expert Rev Hematol 2017; 10: 1095-1106
• 46 De Sanctis V, Soliman AT, Daar S. et al. For debate: assessment of HbA1c in transfusion dependent thalassemia patients. Pediatr Endocrinol Rev 2020; 17: 226-234
• 47 Choudhary A, Giardina P, Antal Z. et al. Unreliable oral glucose tolerance test and HbA1C in Beta Thalassaemia Major-A case for continuous glucose monitoring?. Br J Haematol 2013; 162: 132
• 48 De Sanctis V, Soliman AT, Elsedfy H. 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: e2016058
• 49 Pepe A, Pistoia L, Gamberini MR. 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: 2830-2839
• 50 Petznick A. Insulin management of type 2 diabetes mellitus. Am Fam Physician 2011; 84: 183-190
• 51 Bromage DI, Yellon DM. The pleiotropic effects of metformin: time for prospective studies. Cardiovasc Diabetol 2015; 14: 1-4
• 52 Dhouib N, Turki Z, Mellouli F. et al. Efficacy of metformin in the treatment of diabetes mellitus complicating thalassemia major. Tunis Med 2010; 88: 136
• 53 Ladis V, Theodorides C, Palamidou F. et al. Glucose disturbances and regulation with glibenclamide in thalassemia. J Pediatr Endocrinol Metab 1998; 11: 871-878
• 54 Mangiagli A, Campisi S, De Sanctis V. et al. Effects of acarbose in beta-thalassaemia major patients with normal glucose tolerance and hyperinsulinism. Pediatr Endocrinol Rev 2004; 2: 272-275
• 55 De Sanctis V, Soliman AT, Elsedfy H. et al. Diabetes and glucose metabolism in thalassemia major: an update. Expert Rev Hematol 2016; 9: 401-408
• 56 Georgakouli K, Stamperna A, Deli CK. et al. The effects of postprandial resistance exercise on blood glucose and lipids in prediabetic, beta-thalassemia major patients. Sports 2020; 8: 57
• 57 Gamberini MR, De Sanctis V, Gilli G. Hypogonadism, diabetes mellitus, hypothyroidism, hypoparathyroidism: incidence and prevalence related to iron overload and chelation therapy in patients with thalassaemia major followed from 1980 to 2007 in the Ferrara Centre. Pediatr Endocrinol Rev 2008; 6: 158-169
• 58 Farmaki K, Angelopoulos N, Anagnostopoulos G. et al. Effect of enhanced iron chelation therapy on glucose metabolism in patients with β-thalassaemia major. Br J Haematol 2006; 134: 438-444
• 59 Telfer PT, Warburton F, Christou S. et al. Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone. Haematologica 2009; 94: 1777
• 60 Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol 2007; 138: 291-304
• 61 Rund D, Rachmilewitz E. Pathophysiology of α-and β-thalassemia: therapeutic implications. Seminars Hematol 2001; 343-349
• 62 Tzoulis P, Shah F, Jones R. et al. Joint diabetes thalassaemia clinic: an effective new model of care. Hemoglobin 2014; 38: 104-110
• 63 Tzoulis P. Review of endocrine complications in adult patients with β-thalassaemia major. Thalassemia Rep 2014; 4: 4871
• 64 El-Samahy MH, Tantawy AA, Adly AA. et al. 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
• 65 Soliman A, DeSanctis V, Yassin M. et al. Continuous glucose monitoring system and new era of early diagnosis of diabetes in high risk groups. Indian J Endocrinol Metab 2014; 18: 274
• 66 Roberts G, Watts A. Encyclopedia of biophysics. Springer; 2019
• 67 Tessari P, Cecchet D, Cosma A. et al. Insulin resistance of amino acid and protein metabolism in type 2 diabetes. Clin Nutr 2011; 30: 267-272
• 68 Michaliszyn SF, Sjaarda LA, Mihalik SJ. et al. Metabolomic profiling of amino acids and β-cell function relative to insulin sensitivity in youth. J Clin Endocrinol Metab 2012; 97: E2119-E2124
• 69 Würtz P, Soininen P, Kangas AJ. et al. Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Diabetes care 2013; 36: 648-655
• 70 Zhu C, Liang Q-l HuP. et al. Phospholipidomic identification of potential plasma biomarkers associated with type 2 diabetes mellitus and diabetic nephropathy. Talanta 2011; 85: 1711-1720
• 71 Long J, Yang Z, Wang L. et al. Metabolite biomarkers of type 2 diabetes mellitus and pre-diabetes: A systematic review and meta-analysis. BMC Endocr Disord 2020; 20: 1-17
• 72 Nowak C, Sundström J, Gustafsson S. et al. Protein biomarkers for insulin resistance and type 2 diabetes risk in two large community cohorts. Diabetes 2016; 65: 276-284
• 73 Iliodromiti S, Sassarini J, Kelsey TW. et al. Accuracy of circulating adiponectin for predicting gestational diabetes: a systematic review and meta-analysis. Diabetologia 2016; 59: 692-699
• 74 Adela R, Banerjee SK. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res 2015; 490842
• 75 Al-Fadhel SZ, Al-Ghuraibawi NHA, Mohammed Ali DM. et al. Serum cytokine dependent hematopoietic cell linker (CLNK) as a predictor for the duration of illness in type 2 diabetes mellitus. J Diabetes Metab Disord 2020; 19: 959-966
• 76 Yang Q, Graham TE, Mody N. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005; 436: 356-362
• 77 Hamad M, Mohammed AK, Hachim MY. et al. Heme oxygenase-1 (HMOX-1) and inhibitor of differentiation proteins (ID1, ID3) are key response mechanisms against iron-overload in pancreatic β-cells. Mol Cell Endocrinol 2021; 538: 111462