Abstract
Glycated hemoglobin A1c (HbA1c) concentration in blood is an index of the glycemic control widely used in diabetology. The aim of the work was to validate two mathematical models of HbA1c formation (assuming irreversible or reversible glycation, respectively) and select a model, which was able to predict changes of HbA1c concentration in response to varying glycemia courses with higher accuracy. The experimental procedure applied consisted of an original combination of: in vivo continuous glucose concentration monitoring, long-term in vitro culturing of the human erythrocytes and mathematical modeling of HbA1c formation in vivo and in vitro with HbA1c values scaled according to the most specific analytical methods. Sixteen experiments were conducted in vitro using blood samples collected from healthy volunteer and stable type 1 diabetic patients whose glycemia was estimated beforehand based on long-term monitoring. The mean absolute difference of the measured and predicted HbA1c concentrations for the in vitro experiments were equal to 0.64 ± 0.29% and 1.42 ± 0.16% (p = 0.0007) for irreversible and for reversible model, respectively, meaning that the irreversible model was able to predict the glycation kinetics with a higher accuracy. This model was also more sensitive to a deviation of the erythrocytes life span.
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References
American Diabetes Association. Tests of glycemia in diabetes. Diabetes Care 25:S97–99, 2002. doi:10.2337/diacare.25.2007.S97
Bastanhagh M. H., A. R. Shirvan, R. Heshmat, A. Khalilifard, A. Keshtkar, B. Larijan. Evaluation of the effi cacy of blood glucose home monitoring devices. Med. Sci. Monit. 13:PI1–6, 2007
Beach K. W. A theoretical model to predict the behavior of glycosylated hemoglobin levels. J. Theor. Biol. 81:547–561, 1979. doi:10.1016/0022-5193(79)90052-3
Bunn H. F., D. N. Haney, K. H. Gabbay, P. M. Gallop. Further identification of the nature and linkage of the carbohydrate in hemoglobin A1c. Biochem. Biophys. Res. Commun. 67:103–109, 1975. doi:10.1016/0006-291X(75)90289-2
College of American Pathologists. The College of American Pathologists fresh sample proficiency testing survey for A1c. http://www.ngsp.org/prog/CAP/CAP07a.pdf, 2007
Consensus Committee. Consensus statement on the worldwide standardization of the hemoglobin A1C measurement: the American Diabetes Association, European Association for the Study of Diabetes, International Federation of Clinical Chemistry and Laboratory Medicine and the International Diabetes Federation. Diabetes Care. 30:2399–2400, 2007. doi:10.2337/dc07-9925
Delpierre G., D. Vertommen, D. Communi, M. H. Rider, E. Van Schaftingen. Identification of fructosamine residues deglycated by fructosamine-3-kinase in human hemoglobin. J. Biol. Chem. 279:27613–27620, 2004. doi:10.1074/jbc.M402091200
Diabetes in Research Children Network (DirecNet) Study Group. Evaluation of factors affecting CGMS calibration. Diabetes Technol. Ther. 8:318–325, 2006. doi:10.1089/dia.2006.8.318
Fogh-Andersen N., P. D’Orazio. Proposal for standardizing direct-reading biosensors for blood glucose. Clin. Chem. 44:655–659, 1998
Graf R., J. Halter, D. Porte Jr. Glycosylated hemoglobin in normal subjects and subjects with maturity-onset diabetes. Evidence for a saturable system in man. Diabetes. 27:834–839, 1978. doi:10.2337/diabetes.27.8.834
Guerci B., M. Floriot, P. Böhme, D. Durain, M. Benichou, S. Jellimann, P. Drouin. Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs. Diabetes Care. 26:582–589, 2003. doi:10.2337/diacare.26.3.582
Higgins P. J., H. F. Bunn. Kinetic analysis of the nonenzymatic glycosylation of hemoglobin. J. Biol. Chem. 256:5204–5208, 1981
Hoelzel W., C. Weykamp, J. O. Jeppsson, K. Miedema, J. R. Barr, I. Goodall, T. Hoshino, W. G. John, U. Kobold, R. Little, A. Mosca, P. Mauri, R. Paroni, F. Susanto, I. Takei, L. Thienpont, M. Umemoto, H. M. Wiedmeyer. IFCC Working Group on HbA1c Standardization. IFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the United States, Japan, and Sweden: a method-comparison study. Clin. Chem. 50:166–174, 2004. doi:10.1373/clinchem.2003.024802
Jeffcoate S. L. Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet. Med. 21:657–665, 2004. doi:10.1046/j.1464-5491.2003.01065.x
Jeppsson J. O., U. Kobold, J. Barr, A. Finke, W. Hoelzel, T. Hoshino, K. Miedema, A. Mosca, P. Mauri, R. Paroni, L. Thienpont, M. Umemoto, C. Weykamp. International Federation of Clinical Chemistry and Laboratory Medicine (IFCC): Approved IFCC reference method for the measurement of HbA1c in human blood. Clin. Chem. Lab. Med. 40:78–89, 2002. doi:10.1515/CCLM.2002.016
YSI Life Sciences, YSI 2300 Stat Plus—Operation Manual. Yellow Springs: YSI Inc., 7 pp, 2003
Mortensen H. B., C. Christophersen. Glucosylation of human haemoglobin A in red blood cells studied in vitro. Kinetics of the formation and dissociation of haemoglobin A1c. Clin. Chim. Acta. 134:317–326, 1983. doi:10.1016/0009-8981(83)90370-4
Mortensen H. B., A. Vølund. Variations in hemoglobin A1c and blood glucose in children with newly diagnosed diabetes mellitus described by a biokinetic model. Diabetes Metab. 10:18–24, 1984
Mortensen H. B., A. Vølund. Application of a biokinetic model for prediction and assessment of glycated haemoglobins in diabetic patients. Scand. J. Clin. Lab. Invest. 48:595–602, 1988. doi:10.3109/00365518809085778
Osterman-Golkar S. M., H. W. Vesper. Assessment of the relationship between glucose and A1c using kinetic modeling. J. Diabetes Complicat. 20:285–294, 2006. doi:10.1016/j.jdiacomp.2005.07.009
Skowroska M., B. Marczewska. The comparative study of glucose determination by selected point-of-care glucose meters on the quality control viewpoint. Diebetologia Praktyczna 6:173–176, 2005
Smith R. J., R. J. Koenig, A. Binnerts, J. S. Soeldner, T. T. Aoki. Regulation of hemoglobin A1c formation in human erythrocytes in vitro. Effects of physiologic factors other than glucose. J. Clin. Invest. 69:1164–1168, 1982. doi:10.1172/JCI110552
Tahara Y., K. Shima. The response of GHb to stepwise plasma glucose change over time in diabetic patients. Diabetes Care. 16:1313–1314, 1993
Tosi F., M. Muggeo, E. Brun, G. Spiazzi, L. Perobelli, E. Zanolin, M. Gori, A. Coppini, P. Moghetti. Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, double-blind, comparative study. Metabolism. 52:862–867, 2003. doi:10.1016/S0026-0495(03)00101-X
Traczyk W. Z., A. Trzebski (eds.). Human Physiology with Elements of the Applied and Clinical Physiology. Warszawa: PZWL, 2004, 210 pp
Vermes I., C. Haanen, H. Steffens-Nakken, C. Reutelingsperger. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J. Immunol. Meth. 184:39–51, 1995. doi:10.1016/0022-1759(95)00072-I
Willekens F. L., B. Roerdinkholder-Stoelwinder, Y. A. Groenen-Döpp, H. J. Bos, G. J. Bosman, A. G. van den Bos, A. J. Verkleij, J. M. Werre. Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation. Blood 101:747–751, 2003. doi:10.1182/blood-2002-02-0500
Zhang Y., S. Neelamegham. “Cell counter, blood.” In: Encyclopedia of Medical Devices and Instrumentation, edited by J. G. Webster. New York: John Wiley & Sons, 2006
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Ładyżyński, P., Wójcicki, J.M., Bąk, M. et al. Validation of Hemoglobin Glycation Models Using Glycemia Monitoring In Vivo and Culturing of Erythrocytes In Vitro . Ann Biomed Eng 36, 1188–1202 (2008). https://doi.org/10.1007/s10439-008-9508-x
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DOI: https://doi.org/10.1007/s10439-008-9508-x