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

Jalal Taneera; Eglal Mahgoub; Reem Qannita; Ayah Alalami; Ola Al Shehadat; Mona Youssef; Ayah Dib; Alaa Al Hajji; Amani Al Hajji; Fatheya Al-Khaja; Hany Dewedar; Mawieh Hamad

doi:10.1055/a-2185-5073

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2024; 56(04): 272-278
DOI: 10.1055/a-2185-5073

Review

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

Jalal Taneera

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Eglal Mahgoub

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Reem Qannita

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Ayah Alalami

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Ola Al Shehadat

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Mona Youssef

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Ayah Dib

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Alaa Al Hajji

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Amani Al Hajji

¹Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

,

Fatheya Al-Khaja

²Dubai Thalassemia Center, Dubai, United Arab Emirates

,

Hany Dewedar

²Dubai Thalassemia Center, Dubai, United Arab Emirates

,

Mawieh Hamad

³University of Sharjah College of Health Sciences, Sharjah, United Arab Emirates

› Author Affiliations

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

Full Text

References

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