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Influence of the glycation gap on the diagnosis of type 2 diabetes

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Abstract

Aims

The results of using HbA1C-based criteria for diagnosis of type 2 diabetes and prediabetes have been reported to differ from those obtained using fasting plasma glucose (FPG) or an oral glucose tolerance test (OGTT). We aimed to determine whether these discrepancies might be due to the influence of the glycation gap.

Methods

For 430 patients without previously diagnosed diabetes for whom an OGTT had been requested in normal clinical practice, FPG, fructosamine and HbA1C were measured at the time of the test and again 1 month later. Glycaemia/diabetes status was classified as normoglycaemia, prediabetes or diabetes using both HbA1C-based and FPG/OGTT-based criteria, and their glycation gaps GG were calculated.

Results

The specificity of an HbA1C level of 6.5 % (48 mmol/mol) for diagnosis of FPG/OGTT-defined type 2 diabetes was 99 %, but its sensitivity was less than 37 %. HbA1C-diabetic patients had higher average blood glucose levels than FPG/OGTT-diabetic patients. With either set of criteria, high-GG patients were disproportionately numerous among those classified as diabetic and were disproportionately infrequent among those classified as normoglycaemic, but the effect was greater for the HbA1C criteria.

Conclusions

The differences between HbA1C-based and FPG/OGTT-based diagnoses are largely due to the influence of the glycation gap, which may also influence the early stages of FPG/OGTT-defined diabetes.

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Abbreviations

ADA:

American Diabetes Association

cFA:

Frutosamine corrected for albumin concentration

CI:

Confidence interval

FPG:

Fasting plasma glucose

gg :

Instantaneous glycation gap for each visit

GG:

Glycation gap

GG :

Characteristic glycation gap of each patient

HbA1C :

Glycated haemoglobin

OGTT:

Oral glucose tolerance test

PPG:

Post-challenge plasma glucose

ROC:

Receiver operating characteristic

WHO:

World Health Organization

References

  1. American Diabetes Association (2012) Standards of medical care in diabetes. Diabetes Care 35(Suppl 1):S11–S63

    Google Scholar 

  2. Department of Veterans Affairs/Department of Defense (2010) Management of diabetes mellitus in primary care. http://www.healthquality.va.gov/diabetes_mellitus.asp. Accessed Feb 2014

  3. World Health Organization (2014) Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. http://www.who.int/diabetes/publications/diagnosis_diabetes2011/en/index.html. Accessed Jan 2014

  4. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1997) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183–1197

  5. Genuth S, Alberti KG, Bennett P et al (2003) Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26:3160–3167

    Article  PubMed  Google Scholar 

  6. Sacks DB (2011) HbA1C versus glucose testing: a comparison. Diabetes Care 34:518–523

    Article  PubMed Central  PubMed  Google Scholar 

  7. Inzucchi SE (2012) Diagnosis of diabetes. N Engl J Med 367:542–550

    Article  CAS  PubMed  Google Scholar 

  8. Kramer CK, Araneta MRG, Barrett-Connor E (2010) HbA1C and diabetes diagnosis: the Rancho Bernardo Study. Diabetes Care 33:101–103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Lipska KJ, De Reheneire N, Van Ness PT, Johnson KC, Kanaya A, Koster A, Strotmeyer ES, Goodpaster BH, Harris T, Gill TM, Inzucchi SE (2010) Identifying dysglycaemic states in older adults: implications of the emerging use of haemoglobin HbA1c. J Clin Endocrinol Metab 95:5289–5295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Carson AP, Reynolds K, Fonseca VA, Muntner P (2010) Comparison of HbA1C and fasting glucose criteria to diagnose diabetes among US adults. Diabetes Care 33:95–97

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Kumar PR, Bhansali A, Ravikiran M, Bhansali S, Dutta P, Thakur JS, Sachdeva N, Bhadada SK, Walia R (2010) Utility of glycated haemoglobin in diagnosing type 2 diabetes mellitus: a community-based study. J Clin Endocrinol Metab 95:2832–2835

    Article  CAS  PubMed  Google Scholar 

  12. Olson DE, Rhee MK, Herrick K, Ziemer DC, Twombly JG, Phillips LS (2010) Screening for diabetes and pre-diabetes with proposed HbA1C-based diagnostic criteria. Diabetes Care 33:2184–2189

    Article  PubMed Central  PubMed  Google Scholar 

  13. Pinelli NR, Jantz AS, Martin ET, Jaber LA (2011) Sensitivity and specificity of glycated haemoglobin as a diagnostic test for diabetes and prediabetes in Arabs. J Clin Endocrinol Metab 96:E1680–E1683

    Article  CAS  PubMed  Google Scholar 

  14. Nowicka P, Santoro N, Liu H, Lartaud D, Shaw MM, Goldberg R, Guandalini C, Savoye M, Rose P, Caprio S (2011) Utility of haemoglobin HbA1C for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 34:1306–1311

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. James C, Bullard KM, Rolka DB, Geiss LS, Williams DE, Cowie CC, Albright A, Gregg EW (2011) Implications of alternative definitions of prediabetes for prevalence in US adults. Diabetes Care 34:387–391

    Article  PubMed Central  PubMed  Google Scholar 

  16. Yudkin JS, Forrest RD, Jackson CA, Ryle AJ, Davie SJ, Gould BJ (1990) Unexplained variability of glycated haemoglobin in non-diabetic subjects not related to glycaemia. Diabetologia 33:208–215

    Article  CAS  PubMed  Google Scholar 

  17. McCarter RJ, Hempe JM, Gomez R, Chalew SA (2004) Biological variation in HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes. Diabetes Care 27:1259–1264

    Article  CAS  PubMed  Google Scholar 

  18. Cohen RM, Holmes YR, Chenier TC, Joiner CH (2003) Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy. Diabetes Care 26:163–167

    Article  CAS  PubMed  Google Scholar 

  19. Rodriguez-Segade S, Rodriguez J, Cabezas-Agricola JM, Casanueva FF, Camiña F (2011) Progression of nephropathy in type 2 diabetes: the glycation gap is a significant predictor after adjustment for glycohaemoglobin (HbA1c). Clin Chem 57:272–278

    Article  Google Scholar 

  20. Rodriguez-Segade S, Rodriguez J, García-Lopez JM, Casanueva FF, Camiña F (2012) Estimation of the glycation gap in diabetic patients with stable glycaemic control. Diabetes Care 35:2447–2450

    Article  PubMed Central  PubMed  Google Scholar 

  21. Nayak AU, Holland MR, Macdonald DR, Nevill A, Singh BM (2011) Evidence for consistency of the glycation gap in diabetes. Diabetes Care 34:1712–1716

    Article  PubMed Central  PubMed  Google Scholar 

  22. Cohen RM, LeCaire TJ, Lindsell CJ, Smith EP, D’Alessio DJ (2008) Relationship of prospective GHb to glycated serum proteins in incident diabetic retinopathy: implications of the glycation gap for mechanism of risk prediction. Diabetes Care 31:151–153

    Article  CAS  PubMed  Google Scholar 

  23. Nayak AU, Nevill AM, Bassett P, Singh BM (2013) Association of glycation gap with mortality and vascular complications in diabetes. Diabetes Care 36:3247–3253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Selvin E, Rawlings AM, Grams M et al (2014) Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol 2(4):279–288

    Article  PubMed Central  PubMed  Google Scholar 

  25. Herman WH, Cohen RM (2010) Haemoglobin A1c: teaching a new dog old tricks. Ann Intern Med 152(12):815–817

    Article  PubMed  Google Scholar 

  26. Cosson E, Chiheb S, Cussac-Pillegand C et al (2013) Haemoglobin glycation may partly explain the discordance between HbA1c measurement and oral glucose tolerance test to diagnose dysglycaemia in overweight/obese subjects. Diabetes Metab 39:118–125

    Article  CAS  PubMed  Google Scholar 

  27. American Diabetes Association (2013) Diagnosis and classification of diabetes mellitus (Position Statement). Diabetes Care 36(Suppl 1):S67–S74

    Article  PubMed Central  Google Scholar 

  28. Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr JR, Goodall I et al (2004) IFCC reference system for measurement of haemoglobin HbA1C in human blood and the National Standardization Schemes in the United States, Japan, and Sweden: a method-comparison study. Clin Chem 50:166–174

    Article  CAS  PubMed  Google Scholar 

  29. Samsa GP (1996) Sampling distributions of ppos and pneg. J Clin Epidemiol 49:917–919

    Article  CAS  PubMed  Google Scholar 

  30. Cosson E, Banu I, Cussac-Pillegand C et al (2013) Glycation gap is associated with macroproteinuria but not with other complications in patients with type 2 diabetes. Diabetes Care 36:2070–2076

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Herman WH, Cohen RM (2012) Racial and ethnic differences in the relationship between HbA1C and blood glucose: implications for the diagnosis of diabetes. J Clin Endocrinol Metab 97:1067–1072

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported partially by grants from the Secretariat General for Research and Development of the Xunta de Galicia (Refs. PGIDIT06BTF20302PR and 10SCA203008PR), Spain and from Menarini Diagnostics and Siemens Healthcare Diagnostics.

Conflict of interest

Santiago Rodriguez-Segade, Javier Rodríguez, José M. García-López, Felipe F. Casanueva, Ian C. Coleman, Carmen Alonso de la Peña and Félix Camiña declare that they have no conflict of interest.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain

    Santiago Rodriguez-Segade, Javier Rodriguez & Félix Camiña

  2. Clinical Biochemistry Laboratory, University Hospital Clinical Complex, University of Santiago de Compostela, Travesía de la Choupana s/n, 15706, Santiago de Compostela, Spain

    Santiago Rodriguez-Segade, Javier Rodriguez, Ian C. Coleman & Carmen Alonso de la Peña

  3. University Hospital Division of Endocrinology, University of Santiago de Compostela, Santiago de Compostela, Spain

    José M. García-López & Felipe F. Casanueva

  4. The Physiopathology of Obesity and Nutrition Biomedical Research Network Consortium, Santiago de Compostela, Spain

    Felipe F. Casanueva

Authors
  1. Santiago Rodriguez-Segade
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  2. Javier Rodriguez
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  3. José M. García-López
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  4. Felipe F. Casanueva
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  6. Carmen Alonso de la Peña
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  7. Félix Camiña
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Correspondence to Santiago Rodriguez-Segade.

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Rodriguez-Segade, S., Rodriguez, J., García-López, J.M. et al. Influence of the glycation gap on the diagnosis of type 2 diabetes. Acta Diabetol 52, 453–459 (2015). https://doi.org/10.1007/s00592-014-0666-z

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  • DOI: https://doi.org/10.1007/s00592-014-0666-z

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