Discordance Between HbA1c and Fructosamine

Evidence for a glycosylation gap and its relation to diabetic nephropathy

  1. Robert M. Cohen, MD14,
  2. Yancey R. Holmes, MD1,
  3. Thomas C. Chenier, PHD2 and
  4. Clinton H. Joiner, MD, PHD35
  1. 1Division of Endocrinology, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio
  2. 2Institute for Health Care Policy and Research, University of Cincinnati Medical Center, Cincinnati, Ohio
  3. 3Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, Ohio
  4. 4Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio
  5. 5Sickle Cell Center, Children’s Hospital Research Foundation, Cincinnati, Ohio


    OBJECTIVE—Discordances between HbA1c and other measures of glycemic control are common in clinical practice and remain unexplained. We developed a measure of discordance between HbA1c and fructosamine (FA) (glycosylated serum proteins) to conduct a systematic evaluation. We termed this the glycosylation gap (GG) and sought to determine its relationship to diabetic nephropathy.

    RESEARCH DESIGN AND METHODS—Measurements of HbA1c and FA on the same sample in 153 people were used to calculate GG, defined as the difference between measured HbA1c and HbA1c predicted from FA based on the population regression of HbA1c on FA.

    RESULTS—GG had a broad distribution (range, −3.2% to 5.5%); 40% of samples had values indicating major differences in prediction of complications risk by the measured versus predicted HbA1c. GG was highly correlated (r = 0.81) between measurements repeated in 65 patients 23 ± 2 weeks apart, indicating that the discordances are reliable and not explained by differences in turnover of underlying proteins. In 40 patients with type 1 diabetes of ≥15 years’ duration, an increase in GG by 1% was associated with a 2.9-fold greater frequency of increasing nephropathy stage (P = 0.0014). GG was −0.8 ± 0.2% in subjects with no nephropathy, −0.3 ± 0.2% with microalbuminuria/hypertension, and 0.7 ± 0.3% in subjects with proteinuria or renal dysfunction (P < 0.05). GG correlated better with nephropathy than did either HbA1c or FA alone in this population.

    CONCLUSIONS—The glycosylation gap may be a useful clinical research tool for evaluating physiologic sources of variation in diabetic complications beyond glycemic control.


    • Address correspondence and reprint requests to Robert M. Cohen, MD, Division of Endocrinology/Metabolism, P.O. box 670547, Vontz Center for Molecular Studies, 3125 Eden Ave., University of Cincinnati Medical Center, Cincinnati, OH 45267-0547. E-mail: robert.cohen{at}uc.edu.

      Received for publication 16 November 2001 and accepted in revised form 27 September 2002.

      A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    | Table of Contents