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A semi-mechanistic model of the relationship between average glucose and HbA1c in healthy and diabetic subjects

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Abstract

HbA1c is the most commonly used biomarker for the adequacy of glycemic management in diabetic patients and a surrogate endpoint for anti-diabetic drug approval. In spite of an empirical description for the relationship between average glucose (AG) and HbA1c concentrations, obtained from the A1c-derived average glucose (ADAG) study by Nathan et al., a model for the non-steady-state relationship is still lacking. Using data from the ADAG study, we here develop such models that utilize literature information on (patho)physiological processes and assay characteristics. The model incorporates the red blood cell (RBC) aging description, and uses prior values of the glycosylation rate constant (KG), mean RBC life-span (LS) and mean RBC precursor LS obtained from the literature. Different hypothesis were tested to explain the observed non-proportional relationship between AG and HbA1c. Both an inverse dependence of LS on AG and a non-specificity of the National Glycohemoglobin Standardization Program assay used could well describe the data. Both explanations have mechanistic support and could be incorporated, alone or in combination, in models allowing prediction of the time-course of HbA1c changes associated with changes in AG from, for example dietary or therapeutic interventions, and vice versa, to infer changes in AG from observed changes in HbA1c. The selection between the alternative mechanistic models require gathering of new information.

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References

  1. Svendsen PA, Lauritzen T, Soegaard U, Nerup J (1982) Glycosylated haemoglobin and steady-state mean blood glucose concentration in Type 1 (insulin-dependent) diabetes. Diabetologia 23(5):403–405

    PubMed  CAS  Google Scholar 

  2. Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan DM, Peterson CM (2004) Tests of glycemia in diabetes. Diabetes Care 27(Suppl 1):S91–S93

    PubMed  Google Scholar 

  3. Nathan DM, Turgeon H, Regan S (2007) Relationship between glycated haemoglobin levels and mean glucose levels over time. Diabetologia 50(11):2239–2244

    Article  PubMed  CAS  Google Scholar 

  4. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ (2008) Translating the A1C assay into estimated average glucose values. Diabetes Care 31(8):1473–1478

    Article  PubMed  CAS  Google Scholar 

  5. Nathan DM, Singer DE, Hurxthal K, Goodson JD (1984) The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 310(6):341–346

    Article  PubMed  CAS  Google Scholar 

  6. International Expert Committee (2009) International Expert Committee Report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32(7):1327–1334

    Google Scholar 

  7. Jeffcoate SL (2004) Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med 21(7):657–665

    Article  PubMed  CAS  Google Scholar 

  8. Weykamp C, John WG, Mosca A (2009) A review of the challenge in measuring hemoglobin A1c. J Diabetes Sci Technol 3(3):439–445

    PubMed  Google Scholar 

  9. Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr JR, Goodall I, Hoshino T, John WG, Kobold U, Little R, Mosca A, Mauri P, Paroni R, Susanto F, Takei I, Thienpont L, Umemoto M, Wiedmeyer HM (2004) 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(1):166–174

    Article  PubMed  CAS  Google Scholar 

  10. Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hoshino T, Miedema K, Mosca A, Mauri P, Paroni R, Thienpont L, Umemoto M, Weykamp C (2002) Approved IFCC reference method for the measurement of HbA1c in human blood. Clin Chem Lab Med 40(1):78–89

    Article  PubMed  CAS  Google Scholar 

  11. Sacks DB (2005) Global harmonization of hemoglobin A1c. Clin Chem 51(4):681–683

    Article  PubMed  CAS  Google Scholar 

  12. IFCC working group (2011) IFCC standardization of HbA1c. http://www.ngsp.org/ifccrs.asp. Accessed Nov 2012

  13. Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ, Ciraolo PJ, Palascak MB, Joiner CH (2008) Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood 112(10):4284–4291

    Article  PubMed  CAS  Google Scholar 

  14. Peterson CM, Jones RL, Dupuis A, Levine BS, Bernstein R, O’Shea M (1979) Feasibility of improved blood glucose control in patients with insulin-dependent diabetes mellitus. Diabetes Care 2(4):329–335

    Article  PubMed  CAS  Google Scholar 

  15. Hempe JM, Gomez R, McCarter RJ Jr, Chalew SA (2002) High and low hemoglobin glycation phenotypes in type 1 diabetes: a challenge for interpretation of glycemic control. J Diabetes Complicat 16(5):313–320

    Article  PubMed  Google Scholar 

  16. Osterman-Golkar SM, Vesper HW (2006) Assessment of the relationship between glucose and A1c using kinetic modeling. J Diabetes Complicat 20(5):285–294

    Article  PubMed  Google Scholar 

  17. Gisleskog PO, Karlsson MO, Beal SL (2002) Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn 29(5–6):473–505

    Article  PubMed  Google Scholar 

  18. Willekens FL, Roerdinkholder-Stoelwinder B, Groenen-Dopp YA, Bos HJ, Bosman GJ, van den Bos AG, Verkleij AJ, Werre JM (2003) Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation. Blood 101(2):747–751

    Article  PubMed  CAS  Google Scholar 

  19. Leitch JM, Carruthers A (2007) ATP-dependent sugar transport complexity in human erythrocytes. Am J Physiol Cell Physiol 292(2):C974–C986

    Article  PubMed  CAS  Google Scholar 

  20. Uehlinger DE, Gotch FA, Sheiner LB (1992) A pharmacodynamic model of erythropoietin therapy for uremic anemia. Clin Pharmacol Ther 51(1):76–89

    Article  PubMed  CAS  Google Scholar 

  21. Hamren B, Bjork E, Sunzel M, Karlsson M (2008) Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment. Clin Pharmacol Ther 84(2):228–235

    Article  PubMed  CAS  Google Scholar 

  22. de Winter W, DeJongh J, Post T, Ploeger B, Urquhart R, Moules I, Eckland D, Danhof M (2006) A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying type 2 diabetes mellitus. J Pharmacokinet Pharmacodyn 33(3):313–343

    Article  PubMed  Google Scholar 

  23. Lledó-García R, Kalicki RM, Uehlinger DE, Karlsson MO (2012) Modeling of red blood cell life-spans in hematologically normal populations. J Pharmacokinet Pharmacodyn 39(5):453–462

    Article  PubMed  Google Scholar 

  24. Virtue MA, Furne JK, Nuttall FQ, Levitt MD (2004) Relationship between GHb concentration and erythrocyte survival determined from breath carbon monoxide concentration. Diabetes Care 27(4):931–935

    Article  PubMed  CAS  Google Scholar 

  25. Ribbing J, Hamren B, Svensson MK, Karlsson MO (2010) A model for glucose, insulin, and beta-cell dynamics in subjects with insulin resistance and patients with type 2 diabetes. J Clin Pharmacol 50(8):861–872

    Article  PubMed  CAS  Google Scholar 

  26. Nuttall FQ, Gannon MC, Swaim WR, Adams MJ (2004) Stability over time of glycohemoglobin, glucose, and red blood cell survival in hematologically stable people without diabetes. Metabolism 53(11):1399–1404

    Article  PubMed  CAS  Google Scholar 

  27. Beach KW (1979) A theoretical model to predict the behavior of glycosylated hemoglobin levels. J Theor Biol 81(3):547–561

    Article  PubMed  CAS  Google Scholar 

  28. Higgins P, Bunn F (1981) Kinetic analysis of the nonenzymatic glycosylation of hemoglobin. J Biol Chem 256(10):5204–5208

    PubMed  CAS  Google Scholar 

  29. Mortensen HB, Volund A, Christophersen C (1984) Glucosylation of human haemoglobin A. Dynamic variation in HbA1c described by a biokinetic model. Clin Chim Acta 136(1):75–81

    Article  PubMed  CAS  Google Scholar 

  30. Ladyzynski P, Wojcicki JM, Bak M, Sabalinska S, Kawiak J, Foltynski P, Krzymien J, Karnafel W (2008) Validation of hemoglobin glycation models using glycemia monitoring in vivo and culturing of erythrocytes in vitro. Ann Biomed Eng 36(7):1188–1202

    Article  PubMed  Google Scholar 

  31. Jonsson EN, Karlsson MO (1999) Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58(1):51–64

    Article  PubMed  CAS  Google Scholar 

  32. Karlsson, MO, Holford, NH (2008) Tutorial on visual predictive checks http://www.page-meeting.org/?abstract=1434. PAGE, Marseille. Accessed Nov 2012

  33. Nuttall FQ (1998) Comparison of percent total GHb with percent HbA1c in people with and without known diabetes. Diabetes Care 21(9):1475–1480

    Article  PubMed  CAS  Google Scholar 

  34. Strocchi A, Schwartz S, Ellefson M, Engel RR, Medina A, Levitt MD (1992) A simple carbon monoxide breath test to estimate erythrocyte turnover. J Lab Clin Med 120(3):392–399

    PubMed  CAS  Google Scholar 

  35. Wilson DM, Kollman (2008) Relationship of A1C to glucose concentrations in children with type 1 diabetes: assessments by high-frequency glucose determinations by sensors. Diabetes Care 31(3):381–385

    PubMed  CAS  Google Scholar 

  36. Peterson CM, Jones RL, Koenig RJ, Melvin ET, Lehrman ML (1977) Reversible hematologic sequelae of diabetes mellitus. Ann Intern Med 86(4):425–429

    Article  PubMed  CAS  Google Scholar 

  37. Kamada T, McMillan DE, Yamashita T, Otsuji S (1992) Lowered membrane fluidity of younger erythrocytes in diabetes. Diabetes Res Clin Pract 16(1):1–6

    Article  PubMed  CAS  Google Scholar 

  38. Rattan V, Shen Y, Sultana C, Kumar D, Kalra VK (1997) Diabetic RBC-induced oxidant stress leads to transendothelial migration of monocyte-like HL-60 cells. Am J Physiol 273(2 Pt 1):E369–E375

    PubMed  CAS  Google Scholar 

  39. Bunn HF, Haney DN, Kamin S, Gabbay KH, Gallop PM (1976) The biosynthesis of human hemoglobin A1c. Slow glycosylation of hemoglobin in vivo. J Clin Invest 57(6):1652–1659

    Article  PubMed  CAS  Google Scholar 

  40. Khera PK, Joiner CH, Carruthers A, Lindsell CJ, Smith EP, Franco RS, Holmes YR, Cohen RM (2008) Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation. Diabetes 57(9):2445–2452

    Article  PubMed  CAS  Google Scholar 

  41. Mortensen HB, Christophersen C (1983) 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(3):317–326

    Article  PubMed  CAS  Google Scholar 

  42. Mortensen HB, Christophersen C (1993) The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. J Med N Engl 329(14):977–986

    Article  Google Scholar 

  43. Panteghini M, John WG (2007) Implementation of haemoglobin A1c results traceable to the IFCC reference system: the way forward. Clin Chem Lab Med 45(8):942–944

    Article  PubMed  CAS  Google Scholar 

  44. Weykamp C, John WG, Mosca A, Hoshino T, Little R, Jeppsson JO, Goodall I, Miedema K, Myers G, Reinauer H, Sacks DB, Slingerland R, Siebelder C (2008) The IFCC Reference Measurement System for HbA1c: a 6-year progress report. Clin Chem 54(2):240–248

    Article  PubMed  CAS  Google Scholar 

  45. International Federation of Clinical Chemistry and Laboratory Medicine, IFCC Scientific Division, Mosca A, Goodall I, Hoshino T, Jeppsson JO, John WG, Little RR, Miedema K, Myers GL, Reinauer H, Sacks DB, Weykamp CW (2007) Global standardization of glycated hemoglobin measurement: the position of the IFCC Working Group. Clin Chem Lab Med 45(8):1077–1080

    Google Scholar 

  46. Woo S, Krzyzanski W, Duliege AM, Stead RB, Jusko WJ (2008) Population pharmacokinetics and pharmacodynamics of peptidic erythropoiesis receptor agonist (ERA) in healthy volunteers. J Clin Pharmacol 48(1):43–52

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The dataset from Nuttall et al. was kindly shared by Prof. Frank Nuttall. Rocio Lledo-Garcia was supported by a grant from F. Hoffmann-La Roche Ltd. at Basel, Switzerland. The helpful suggestions from Nicolas Frey, F. Hoffmann-La Roche Ltd on the manuscript are gratefully acknowledged.

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Author notes

  1. Rocío Lledó-García

    Present address: Department of Modeling and Simulation, GED, 208 Bath Road, Slough, SL1 3WE, UK

Authors and Affiliations

  1. Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE 751 24, Uppsala, Sweden

    Rocío Lledó-García & Mats O. Karlsson

  2. F. Hoffmann-La Roche Ltd., Pharma Research and Early Development (pRED), Translational Research Sciences (TRS), 4070, Basel, Switzerland

    Norman A. Mazer

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  1. Rocío Lledó-García
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Correspondence to Rocío Lledó-García.

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Lledó-García, R., Mazer, N.A. & Karlsson, M.O. A semi-mechanistic model of the relationship between average glucose and HbA1c in healthy and diabetic subjects. J Pharmacokinet Pharmacodyn 40, 129–142 (2013). https://doi.org/10.1007/s10928-012-9289-6

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