Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c.

Although red blood cell (RBC) life span is a known determinant of percentage hemoglobin A1c (HbA1c), its variation has been considered insufficient to affect clinical decisions in hematologically normal persons. However, an unexplained discordance between HbA1c and other measures of glycemic control can be observed that could be, in part, the result of differences in RBC life span. To explore the hypothesis that variation in RBC life span could alter measured HbA1c sufficiently to explain some of this discordance, we determined RBC life span using a biotin label in 6 people with diabetes and 6 nondiabetic controls. Mean RBC age was calculated from the RBC survival curve for all circulating RBCs and for labeled RBCs at multiple time points as they aged. In addition, HbA1c in magnetically isolated labeled RBCs and in isolated transferrin receptor-positivereticulocytes was used to determine the in vivo synthetic rate of HbA1c. The mean age of circulating RBCs ranged from 39 to 56 days in diabetic subjects and 38 to 60 days in nondiabetic controls. HbA1c synthesis was linear and correlated with mean whole blood HbA1c (R(2) = 0.91). The observed variation in RBC survival was large enough to cause clinically important differences in HbA1c for a given mean blood glucose.

[1]  C. Lindsell,et al.  Evidence for Interindividual Heterogeneity in the Glucose Gradient Across the Human Red Blood Cell Membrane and Its Relationship to Hemoglobin Glycation , 2008, Diabetes.

[2]  C. Lindsell,et al.  A method for the continuous calculation of the age of labeled red blood cells , 2008, American journal of hematology.

[3]  R. Cohen.  A1C: Does One Size Fit All? R.M.C. holds stock in Novartis and Medtronic. , 2007, Diabetes Care.

[4]  A. Rigby,et al.  Variability in the relationship between mean plasma glucose and HbA1c: implications for the assessment of glycemic control. , 2007, Clinical chemistry.

[5]  F. Nuttall.  Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins , 2007, Diabetes Care.

[6]  A. Carruthers,et al.  ATP-dependent sugar transport complexity in human erythrocytes. , 2007, American journal of physiology. Cell physiology.

[7]  H. Erman.  A1C: Does One Size Fit All? , 2007 .

[8]  Clinton H Joiner,et al.  The effect of fetal hemoglobin on the survival characteristics of sickle cells. , 2006, Blood.

[9]  J. Furne,et al.  Use of breath carbon monoxide to measure the influence of prosthetic heart valves on erythrocyte survival. , 2006, The American journal of cardiology.

[10]  V. Sathiyapriya,et al.  Effect of lipid peroxides and antioxidants on glycation of hemoglobin: an in vitro study on human erythrocytes. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[11]  T. Gursel,et al.  THE USEFULNESS OF GLYCOSYLATED HEMOGLOBIN (HbA1C) IN DISCRIMINATING BETWEEN IRON DEFICIENCY AND THALASSEMIA , 2006, Pediatric hematology and oncology.

[12]  F. Nuttall,et al.  The relationship between 24-hour integrated glucose concentrations and % glycohemoglobin. , 2006, The Journal of laboratory and clinical medicine.

[13]  B. Szwergold,et al.  Transglycation—A Potential New Mechanism for Deglycation of Schiff's Bases , 2005, Annals of the New York Academy of Sciences.

[14]  B. Szwergold,et al.  Some Clues as to the Regulation, Expression, Function, and Distribution of Fructosamine‐3‐Kinase and Fructosamine‐3‐Kinase‐Related Protein , 2005, Annals of the New York Academy of Sciences.

[15]  Ian Goodall,et al.  HbA1c standardisation destination--global IFCC Standardisation. How, why, where and when--a tortuous pathway from kit manufacturers, via inter-laboratory lyophilized and whole blood comparisons to designated national comparison schemes. , 2005, The Clinical biochemist. Reviews.

[16]  S. Thierfelder,et al.  Biotin labeling as an alternative nonradioactive approach to determination of red cell survival , 1993, Annals of Hematology.

[17]  W. Graninger,et al.  Glycosylated hemoglobin as a long-term parameter in appraising the severity of hemolytic disease , 1983, Klinische Wochenschrift.

[18]  F. Nuttall,et al.  Stability over time of glycohemoglobin, glucose, and red blood cell survival in hematologically stable people without diabetes. , 2004, Metabolism: clinical and experimental.

[19]  E. Ragazzi,et al.  The complexity of non-enzymatic glycation product sets of human globins , 2004, Diabetologia.

[20]  E. Coban,et al.  Effect of Iron Deficiency Anemia on the Levels of Hemoglobin A1c in Nondiabetic Patients , 2004, Acta Haematologica.

[21]  H. Müller,et al.  Demographic window to aging in the wild: constructing life tables and estimating survival functions from marked individuals of unknown age , 2004, Aging cell.

[22]  R. Cohen,et al.  Is poor glycemic control associated with reduced red blood cell lifespan? , 2004, Diabetes care.

[23]  F. Nuttall,et al.  Relationship between GHb concentration and erythrocyte survival determined from breath carbon monoxide concentration. , 2004, Diabetes care.

[24]  Synthesis of glycosylated haemoglobin in vivo , 1981, Diabetologia.

[25]  A. Verkleij,et al.  Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation. , 2003, Blood.

[26]  R. Cohen,et al.  Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy. , 2003, Diabetes care.

[27]  R. McCarter,et al.  High and low hemoglobin glycation phenotypes in type 1 diabetes: a challenge for interpretation of glycemic control. , 2002, Journal of diabetes and its complications.

[28]  F. Collard,et al.  Fructosamine 3-kinase is involved in an intracellular deglycation pathway in human erythrocytes. , 2002, The Biochemical journal.

[29]  R. Little,et al.  Biological variation of glycohemoglobin. , 2002, Clinical chemistry.

[30]  T. Spector,et al.  HbA(1c) levels are genetically determined even in type 1 diabetes: evidence from healthy and diabetic twins. , 2001, Diabetes.

[31]  B. Szwergold,et al.  Human fructosamine-3-kinase: purification, sequencing, substrate specificity, and evidence of activity in vivo. , 2001, Diabetes.

[32]  B. Kumpel,et al.  Comparison of flow cytometric assays with isotopic assays of 51chromium‐labeled cells for estimation of red cell clearance or survival in vivo , 2000, Transfusion.

[33]  J. Widness,et al.  Measurement of red cell survival using biotin‐labeled red cells: validation against 51Cr‐labeled red cells , 1999, Transfusion.

[34]  D. Goldstein,et al.  What is hemoglobin A1c? An analysis of glycated hemoglobins by electrospray ionization mass spectrometry. , 1998, Clinical chemistry.

[35]  E. Silberstein,et al.  Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells. , 1998, The Journal of clinical investigation.

[36]  J. Yudkin,et al.  Investigation of the mechanism underlying the variability of glycated haemoglobin in non-diabetic subjects not related to glycaemia. , 1997, Clinica chimica acta; international journal of clinical chemistry.

[37]  T. Sözen,et al.  Investigation of the effect of poorly controlled diabetes mellitus on erythrocyte life. , 1995, Journal of diabetes and its complications.

[38]  R Chirillo,et al.  Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia. , 1995, Blood.

[39]  S. Williams,et al.  Fetal hemoglobin and potassium in isolated transferrin receptor-positive dense sickle reticulocytes. , 1994, Blood.

[40]  P. Low,et al.  Senescence of canine biotinylated erythrocytes: increased autologous immunoglobulin binding occurs on erythrocytes aged in vivo for 104 to 110 days. , 1993, Blood.

[41]  C. Ou,et al.  Rapid analysis of hemoglobin variants by cation-exchange HPLC. , 1993, Clinical chemistry.

[42]  R. Engel,et al.  A simple carbon monoxide breath test to estimate erythrocyte turnover. , 1992, The Journal of laboratory and clinical medicine.

[43]  R. Franco,et al.  Studies with biotinylated RBC: (1) use of flow cytometry to determine posttransfusion survival and (2) isolation using streptavidin conjugated magnetic beads. , 1992, Advances in experimental medicine and biology.

[44]  T Suzuki,et al.  Rheologic properties of senescent erythrocytes: loss of surface area and volume with red blood cell age. , 1992, Blood.

[45]  R. Daniels,et al.  Quantitation of immunoglobulin associated with senescent erythrocytes from the rabbit. , 1991, Blood.

[46]  G. Dale,et al.  Density fractionation of erythrocytes by Percoll/hypaque results in only a slight enrichment for aged cells. , 1990, Biochimica et biophysica acta.

[47]  L. Forman,et al.  In vivo aging of red cell enzymes: Study of biotinylated red blood cells in rabbits , 1990, American journal of hematology.

[48]  G. Gaudernack,et al.  A new method for isolation of reticulocytes: positive selection of human reticulocytes by immunomagnetic separation. , 1990, Blood.

[49]  M. Itakura,et al.  Inorganic phosphate accelerates hemoglobin A1c synthesis. , 1989, Life sciences.

[50]  T. Hoy,et al.  The measurement of the total volume of red cells in man: a non‐radioactive approach using biotin , 1988, British journal of haematology.

[51]  T. Suzuki,et al.  Biotinylated erythrocytes: in vivo survival and in vitro recovery. , 1987, Blood.

[52]  D. Singer,et al.  The clinical information value of the glycosylated hemoglobin assay. , 1984, The New England journal of medicine.

[53]  E. Neumann,et al.  Glycosylated hemoglobins (GHb): an index of red cell survival. , 1982, Blood.

[54]  P. Higgins,et al.  Kinetic analysis of the nonenzymatic glycosylation of hemoglobin. , 1981, The Journal of biological chemistry.

[55]  A. Cerami,et al.  Structure of carbohydrate of hemoglobin AIc. , 1977, The Journal of biological chemistry.

[56]  C. Peterson,et al.  Reversible hematologic sequelae of diabetes mellitus. , 1977, Annals of internal medicine.

[57]  R. Jones,et al.  Red cell age-related changes of hemoglobins AIa+b and AIc in normal and diabetic subjects. , 1976, The Journal of clinical investigation.

[58]  P. Gallop,et al.  The biosynthesis of human hemoglobin A1c. Slow glycosylation of hemoglobin in vivo. , 1976, The Journal of clinical investigation.

[59]  P. Gallop,et al.  Further identification of the nature and linkage of the carbohydrate in hemoglobin A1c. , 1975, Biochemical and biophysical research communications.

[60]  T. Waldmann,et al.  Life span of red blood cell. , 1959, Physiological reviews.

[61]  W. G. Curtis,et al.  The potential life span and ultimate survival of fresh red blood cells in normal healthy recipients as studied by simultaneous Cr51 tagging and differential hemolysis. , 1955, The Journal of clinical investigation.