A retrospective study of glucose homeostasis, insulin secretion, sensitivity/resistance in non- transfusion-dependent β-thalassemia patients (NTD- β Thal): reduced β-cell secretion rather than insulin resistance seems to be the dominant defect for glucose dysregulation (GD)

Vincenzo De Sanctis; Shahina Daar; Ashraf Soliman; Ploutarchos  Tzoulis; Mohamed Yassin; Christos Kattamis

doi:10.23750/abm.v94i6.15001

A retrospective study of glucose homeostasis, insulin secretion, sensitivity/resistance in non- transfusion-dependent β-thalassemia patients (NTD- β Thal): reduced β-cell secretion rather than insulin resistance seems to be the dominant defect for glucose dysregulation (GD)

Authors

Vincenzo De Sanctis Quisisana Hospital, Ferrara https://orcid.org/0000-0002-6131-974X
Shahina Daar Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman
Ashraf Soliman Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar
Ploutarchos Tzoulis Department of Diabetes and Endocrinology, Whittington Hospital, University College London, London, UK
Mohamed Yassin Hematology Section, Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation (HMC), Doha, Qatar
Christos Kattamis Τhalassemia Unit, First Department of Paediatrics, National Kapodistrian University of Athens 11527, Greece

DOI: https://doi.org/10.23750/abm.v94i6.15001

Keywords:

Non–transfusion-dependent thalassemia (NTDT), oral glucose tolerance test (OGTT, insulin secretion, insulin sensitivity/resistance.

Abstract

Aims: Non-transfusion - dependent β-thalassemias (NTD-βThal) can cause iron overload and serious iron-related organ complications as endocrine dysfunction, including glucose dysregulation (GD). Patients and methods: We retrieved data of all NTD- β Thal patients referred consecutively to a single Outpatient Italian Clinic from October 2010 to April 2023. All patients underwent a standard 3-h oral glucose tolerance test (OGTT) for analysis of glucose homeostasis, insulin secretion and sensitivity/resistance (IR), using conventional surrogate indices derived from the OGTT. The collected data in NTD- β Thal patients were compared to 20 healthy subjects. Results: Seventeen of 26 (65.3 %) NTD- β Thal patients (aged: 7.8 -35.1 years) had normal glucose tolerance, 1/26 (3.8 %) had impaired fasting glucose (IFG), 5/26 (19.2 %) impaired glucose tolerance (IGT), 1/26 (3.8%) IFG plus IGT and 2/26 (7.6%) plasma glucose (PG) level ≥155 mg/dL 1-h after glucose load. GD was observed exclusively in young adult patients; none of them had diabetes mellitus (DM). These findings were associated with a low insulinogenic index (IGI) and oral disposition index. HOMA-IR and QUICKI were not significantly different compared to controls. Interestingly, in young adult patients, ISI-Matsuda index was statistically higher compared to the control group, suggesting an increased insulin sensitivity. Conclusions: This study reported a high prevalence of GD in young adults with NTD- β Thal. The documented reduction of IGI rather than the presence of IR, indicates reduced insulin secretory capacity as the pathophysiological basis of dysglycemia that may represent a novel investigational path for future studies on the mechanism(s) responsible for GD in NTD- β Thal patients.

References

Cappellini MD, Motta I. New therapeutic targets in transfusion-dependent and -independent thalassemia. Hematology Am Soc Hematol Educ Program. 2017; 2017(1): 278–83. doi: 10.1182/asheducation-2017.1.278

Shash H. Non-Transfusion-Dependent Thalassemia: A Panoramic Review. Medicina. 2022;58:1496. doi.org/10.3390/medicina58101496.

Taher A, Musallam K, Cappellini MD. (Eds.) Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT), 2nd ed.; Thalassaemia International Federation: Nicosia, Cyprus, 2017.

De Sanctis V, Tangerini A, Testa MR, et al. Final height and endocrine function in thalassemia intermedia.

J Pediatr Endocrinol Metab. 1998;11(Suppl 3):965–71.PIMD:10091174.

Baldini M, Marcon A, Cassin R, et al. Beta-thalassaemia intermedia: evaluation of endocrine and bone complications. Biomed Res Int.. 2014;2014:174581. doi:10.1155/2014/174581.

Inati A, Noureldine MA, Mansour A, Abbas HA. Endocrine and bone complications in beta-thalassemia intermedia: current understanding and treatment. Biomed Res Int. 2015;2015:813098.doi:10.1155/2015/ 813098.

Kurtoglu A, Kurtoglu E, Temizkan AK. Effect of iron overload on endocrinopathies in patients with beta-thalassaemia major and intermedia. Endokrynol Polska.2012;63 (4): 260–3. ISSN 0423–104X.

Karimi M, Zarei T, Haghpanah S, et al. Evaluation of Endocrine Complications in Beta-Thalassemia Intermedia Patients: A Cross Sectional Multi-Center Study. Blood. 2018; 132 (Supplement 1): 2343. doi: 10.1182/blood-2018-99-110903.

Luo Y, Bajoria R, Lai Y, et al. Prevalence of abnormal glucose homeostasis in Chinese patients with non-transfusion-dependent thalassemia. Diabetes Metab Syndr Obes. 2019;12:457–68. doi: 10.2147/ DMSO. S194591

Yassin MA, Soliman AT, De Sanctis V, Yassin KS, Abdulla MAJ. Final height and endocrine complications in patients with β-thalassemia intermedia: our experience in non-transfused versus infrequently transfused patients and correlations with liver iron content. Mediterr J Hematol Infect Dis. 2019, 11(1): e2019026. doi.org/10.4084/MJHID.2019.026.

Meloni A, Pistoia L, Gamberini MR, et al. The Link of Pancreatic Iron with Glucose Metabolism and Cardiac Iron in Thalassemia Intermedia: A Large, Multicenter Observational Study. J Clin Med. 2021;10: 5561.doi.org/10.3390/jcm10235561.

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 Biomed. 2021; 92 (3): e2021240 doi: 10.23750/abm.v92i3.11733.

Vogiatzi MG, MacKlin EA, Trachtenberg FL, et al. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. Br J Haematol. 2009;146(5):546–556. doi: 10.1111/j.1365-2141.2009.07793.x.

Ricchi P, Meloni A, Pistoia L, et al. Longitudinal follow-up of patients with thalassaemia intermedia

who started transfusion therapy in adulthood: a cohort study. Br J Haematol. 2020:191:107–14. doi: 10. 1111/bjh.16753.

American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl.1): S14-S31. doi.org/10.2337/dc20-S002.

De Sanctis V, Soliman A, Tzoulis P, Daar S, Pozzobon G, 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. doi: 10.23750/abm.v92i4.11105.

Kasim N, Khare S, Sandouk Z, Chan C. Impaired glucose tolerance and indeterminate glycemia in cystic fibrosis. J Clin Transl Endocrinol. 2021;26:100275. doi:10.1016/j.jcte.2021.100275.

Cai X, Han X, Zhou X, Zhou L, Zhang S, Ji L. Associated Factors with Biochemical Hypoglycemia during an Oral Glucose Tolerance Test in a Chinese Population. J Diabetes Res. 2017;2017:3212814. doi: 10.1155/2017/3212814.

Hanefeld M, Hanefeld M, Koehler C, et al. Insulin secretion and insulin sensitivity pattern is different in isolated impaired glucose tolerance and impaired fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. Diabetes Care.2003;26:868–74. doi:10.2337/ diacare. 26.3.868.

Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care.1999;22(9):1462-70. doi:10.2337/ diacare. 22.9.1462.

Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7): 2402–10. doi: 10.1210/jcem.85.7.6661.

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(7):412-9. doi:10.1007/BF00280883.

Płaczkowska S, Pawlik-Sobecka L, Kokot I, Piwowar A. Estimation of reference intervals of insulin resistance (HOMA), insulin sensitivity (Matsuda), and insulin secretion sensitivity indices (ISSI-2) in Polish young people. Ann Agric Environ Med. 2020;27:248–54. doi: 10.26444/aaem/109225.

Utzschneider KM, Prigeon RL, Faulenbach MV, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009;32(2):335-41.doi: 10. 2337/dc08-1478.

Retnakaran R, Qi Y, Goran MI, Hamilton JK. Evaluation of proposed oral disposition index measures in relation to the actual disposition index. Diabet Med. 2009; 26(12): 1198–203. doi.org/10.1111/ j.1464-5491.2009.02841.x.

De Sanctis V, Soliman AT, Tzoulis P, 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(1): e2021051. doi.org/10.4084/ MJHID. 2021.051,

De Sanctis V, Gamberini MR, Borgatti L, Atti G, Vullo C, Bagni B. Alpha and beta cell evaluation in patients with thalassaemia intermedia and iron overload. Postgrad Med J. 1985;61(721):963–7. doi: 10.1136/ pgmj.61.721.963.

Fulwood R, Johnson CL, Bryner JD. Hematological and nutritional biochemistry reference data for persons 6 months–74 years of age: United States, 1976–1980. National Center for Health Statistics, Vital Health Stat Series. 1982;11:1–173.

Alder R, Roesser EB. Introduction to probability and statistics. WH Freeman and Company Eds. Sixth Edition. San Francisco (USA), 1975.PMID:1674139.

De Sanctis V, Soliman AT, Daar S, Tzoulis P, Fiscina B, Kattamis C, International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A). Retrospective observational studies: Lights and shadows for medical writers. Acta Biomed. 2022;93(5):e2022319. doi.org /10.23750/abm.v93i5.13179.

Eyth E, Basit H, Swift CJ. Glucose Tolerance Test. StatPearls [Internet]. Treasure Island (FL):2023. PIMD30422510.

Hovorka R, Jones RH. How to measure insulin secretion. Diabetes Metab Rev.1994;10:91–117. doi:10.1002/dmr.56101100204.

Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539–53.doi:10.1002/(SICI)1096-9136(199807)15:7<539:AID-DIA668>3.0.CO;2-S.

Fiorentino TV, Marini MA, Andreozzi F, Arturi F, Succurro E, Perticone M, et al. One-Hour Postload Hyperglycemia Is a Stronger Predictor of Type 2 Diabetes Than Impaired Fasting Glucose. J Clin Endocrinol Metab. 2015;100:3744–51. doi.org/10.1210/jc.2015-2573.

De Sanctis V, Gamberini MR, Borgatti L, Atti G, Vullo C, Bagni B. Alpha and beta cell evaluation in patients with thalassaemia intermedia and iron overload. Postgrad Med J. 1985; 61(721): 963–7. doi: 10.1136 /pgmj. 61.721.963.

Hücking K , Watanabe RM, Stefanovski D, Bergman RN. OGTT- derived measures of insulin sensitivity are confounded by factors other than insulin sensitivity itself. Obesity (Silver Spring). 2008;16(8):1938–45. doi: 10.1038/oby.2008.336.

Soliman AT, De Sanctis V, Yassin M, Soliman N. Iron deficiency anemia and glucose metabolism. Acta Biomed. 2017;88(1):112-118. doi: 10.23750/abm.v88i1.6049.

Wankanit S, Chuansumrit A, Poomthavorn P, Khlairit P, Pongratanakul S, Mahachoklertwattana P. Acute Effects of Blood Transfusion on Insulin Sensitivity and Pancreatic β-Cell Function in Children with β-Thalassemia/ Hemoglobin E Disease. J Clin Res Pediatr Endocrinol 2018;10(1):1-7. doi: 10.4274/jcrpe.4774.