FIRST-PHASE INSULIN RESPONSE (FPIR) TO INTRAVENOUS GLUCOSE TOLERANCE TEST (IVGTT), INSULIN SENSITIVITY AND LONG-TERM FOLLOW-UP IN TRANSFUSION-DEPENDENT BETA-THALASSEMIA (TDT) NORMOGLYCEMIC PATIENTS WITH REDUCED INSULIN SECRETION TO ORAL GLUCOSE TOLERANCE TEST: A PILOT STUDY. The function of the endocrine pancreas in transfusion-dependent ?-thalassemia

Main Article Content

Vincenzo De Sanctis

Keywords

Transfusion-dependent β-thalassemia, hypoinsulinemia, iron overload, oral glucose tolerance test, intravenous glucose tolerance test, glucose tolerance abnormalities, insulin resistance, follow-up

Abstract

Summary. Objective: To  study the function of the endocrine pancreas in transfusion-dependent ?-thalassemia (?-TDT) patients with normal oral glucose tolerance test (OGTT) and hypoinsulinemia. Patients and methods: Seven ?-TDT patients  (mean age 22.4 ± 4.2 years) with normal glucose tolerance test (NGT) and poor insulin response (hypoinsulinemia) to OGTT,  not associated with ?-cell autoimmunity, were referred for a second opinion to an Italian Centre, part of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A). In this pilot study,  the first-phase insulin response (FPIR), expressed as the sum of 1 and  3 minutes insulin, of ?-TDT patients to intravenous glucose tolerance test (IVGTT), was tested. Moreover, the long-term natural history was followed prospectively using an annual OGTT, with the aim of detecting any abnormality of glucose metabolism. Results: The FPIR value  was between the 1st and 3rd percentile in two patients and between the 3rd and 10th percentile in  five. After 43 ± 26 months (range 11 - 80 months) of follow-up, 2 patients developed impaired glucose tolerance (IGT), 3 both IGT and impaired fasting glucose (IFG) and two overt diabetes mellitus (DM). Interestingly, the patients who developed DM had, at baseline the lowest value of insulinogenic index (IGI, 0.08 and 0.25), defined as the ratio of the increment of plasma insulin to plasma glucose during the first 30 minutes after OGTT. Moreover, a significant correlation was found between the IGI at baseline and at follow-up in the patients who developed IGT with or without IFG (R= 0.927; P: 0.023). A significant reduction of Matsuda insulin sensitivity index (ISIM) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) was documented in the study cohort at diagnosis of IFG, IGT and DM. There was a significant inverse correlation between ISSI-2 and area under the curve of plasma glucose (AUC-PG). Conclusions: These data demonstrated, for the first time, a progressive deterioration in glucose homeostasis in ?-TDT subjects with NGT and hypoinsulinemia.  Thus, we consider that variations of insulin sensitivity could possibly have an impact on glucose tolerance in adult patients with TDT. Further investigations should focus on factors that might positively influence insulin sensitivity, including nutrition, drugs and physical activity.


 

Downloads

Download data is not yet available.


Abstract 5634
PDF Downloads 276
HTML Downloads 147

References

References

1. De Sanctis V, Soliman AT, Elsedfy H, Pepe A, Kattamis C, El Kholy M, Yassin M. Diabetes and Glucose Metabolism in Thalassemia Major: An Update. Expert Rev Hematol. 2016;9:401-408.

2. Liang Y, Bajoria R, Jiang Y, Su H, Pan H, Xia N, Chatterjee R, Lai Y. Prevalence of diabetes mellitus in Chinese children with thalassaemia major. Trop Med Int Health. 2017;22:716-724.

3. He LN, Chen W, Yang Y, Xie YJ, Xiong ZY, Chen DY, Lu D, Liu NQ, Yang YH, Sun XF. Elevated Prevalence of Abnormal Glucose Metabolism and Other Endocrine Disorders in Patients with ?-Thalassemia Major: A Meta-Analysis. Biomed Res Int. 2019 Apr 18;2019:6573497. doi: 10.1155/2019/6573497.

4. Kattamis C, Ladis V, Tsoussis D, Kaloumenou I, Theodoridis C. Evolution of glucose intolerance and diabetes in transfused patients with thalassemia. Pediatr Endocrinol Rev. 2004;2 (Suppl 2) :267-71.

5. Angelopoulos NG, Zervas A, Livadas S, Adamopoulos I, Giannopoulos D, Goula A, Tolis G. Reduced insulin secretion in normoglycaemic patients with beta-thalassaemia major. Diabet Med. 2006;23:1327-1331.

6. Kattanis C,Theodoridis CH, Kanakis E. Intravenous glucose tolerance and plasma insulin response in children with homozygous ?-thalassemia. Aust Paediatr J.1982;18:186-187.

7. Ikeda T, Fujiyama K, Hoshino T, Takeuchi T, Mashiba H, Tominaga M. Oral and intravenous glucose-induced insulin secretion in hyperthyroid patients. Metabolism. 1990;39:633-637.

8. Cucinotta D, De Luca F, Arrigo T, Di Benedetto A, Sferlazzas C, Gigante A, Rigoli L, Magazzù G. First-phase insulin response to intravenous glucose in cystic fibrosis patients with different degrees of glucose tolerance. J Pediatr Endocrinol. 1994;7:13-17.

9. Srikanta S, Ganda OP, Gleason RE, Jackson RA, Soeldner JS, Eisenbarth GS. Pre-type I diabetes. Linear loss of beta cell response to intravenous glucose. Diabetes. 1984;33:717-720,

10. Bardet S, Joseph MG, Maugendre D, Matthieu E, Chaillous L, Semana G, Limal JM, Allannic H, Charbonnel B, Sai P. Predictive value of age-related acute insulin response to glucose in subjects at risk for type 1 diabetes: results of a 6-year follow-up study from west-France. Diabete Metab.1993;19:372-380.

11. American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl. 1): S14-S31.

12. 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;118:50–57.

13. Bingley PJ, Colman P, Eisenbarth GS, et al. Standardization of IVGTT to predict IDDM. Diabetes Care 1992;15:1313–1316.

14. Vardi P, Crisa L, Jackson RA. Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin-dependent) diabetic patients. Diabetologia.1991;34:93–102.

15. 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: 412–419.

16.Chen H, Sullivan G, Quon MJ. Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model. Diabetes. 2005;541914-1925.

17. Matsuda M, De Fronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care.1999; 22:1462–1470.

18. P?aczkowska 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;27:248-254.

19. 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: 1198–203.

20. 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.

21.De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Kattamis C, Soliman NA, Elalaily R. Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy. Mediterr J Hematol Infect Dis. 2016 Apr 12;8(1):e2016022. doi: 10.4084/MJHID.2016.022.

22. Alder R, Roesser EB. Introduction to probability and statistics.WH Freeman and Company Eds. Sixth Edition.San Francisco (USA), 1975 PMCid:PMC1674139.

23. American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl. 1): S14-S31.

24. Petersmann A, Müller-Wieland D, Müller UA, Landgraf R, Nauck M, Freckmann G, Heinemann L, Schleicher E. Definition, Classification and Diagnosis of Diabetes Mellitus. Exp Clin Endocrinol Diabetes. 2019;127:S1-S7.

25. Ferrannini E, Mari A. Beta cell function and its relation to insulin action in humans: a critical appraisal.
Diabetologia. 2004; 47: 943-956.

26. De Sanctis V, Soliman AT, Elsedfy H, Yaarubi SA, Skordis N, Khater D, El Kholy M, Stoeva I, Fiscina B, Angastiniotis M, Daar S, Kattamis C. The ICET-A Recommendations for the Diagnosis and Management of Disturbances of Glucose Homeostasis in Thalassemia Major Patients. Mediterr J Hematol Infect Dis 2016 28;8(1):e2016058.

27. Iancu TC. Biological and ultrastructural aspects of iron overload: an overview. Pediatr Pathol. 1990;10:281-296.

28. Iancu TC. Ultrastructural pathology of iron overload. Baillieres Clin Haematol. 1989;2:475-495.

29. Simpson RJ, Deenmamode J, McKie AT, Raja KB, Salisbury JR, Iancu TC, Peters TJ. Time-course of iron overload and biochemical, histopathological and ultrastructural evidence of pancreatic damage in hypotransferrinaemic mice. Clin Sci (Lond). 1997;93:453-462.

30. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma Insulin Response to Oral and Intravenous Glucose
Administration. J Endocrinol Metab. 1964; 24:1076–1082.

31. Grodsky GM. A new phase of insulin secretion. How will it contribute to our understanding of beta-cell function? Diabetes.1989; 38:673–678.

32. Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. The Journal of clinical endocrinology and metabolism. 1973; 37:826–828.

33. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet. 1987; 2:1300–1304.

34. Creutzfeldt W, Ebert R.The enteroinsular axis. In: Van Liang W (ed) The exocrine pancreas: biology, pathobiology, and diseases. Raven Press, New York,1986 pp. 333–346

35. Suvarna J, Ingle H, Deshmukh CT. Insulin resistance and beta cell function in chronically transfused patients of thalassemia major. Indian Pediatr, 2006;43:393-400.

36.Abdul-Ghani MA, DeFronzo RA. Pathogenesis of Insulin Resistance in Skeletal Muscle J Biomed Biotechnol.2010;2010:476279. doi:10.1155/2010/476279.

37. Santos JL, Yevenes I, Cataldo LR, Morales M, Galgani J, Arancibia C, Vega J, Olmos P, Flores M, Valderas JP, Pollak F. Development and assessment of the disposition index based on the oral glucose
tolerance test in subjects with different glycaemic status. J Physiol Biochem. 2016;72:121-131.

38. Singh B, Saxena A. Surrogate markers of insulin resistance: a review. World J Diabetes. 2010;1:36–47.

39. Gutch M, Sukriti K, Razi SM, Gupta KK, Gupta A. Assessment of insulin sensitivity/resistance. Indian J Endocrinol Metab. 2015;19:160–164.

40. Hoffman RP. Indices of insulin action calculated from fasting glucose and insulin reflect hepatic, not peripheral, insulin sensitivity in African-American and Caucasian adolescents. Pediatr Diabetes. 2008;9:57–61.

41. 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;16:1901–1907.