Discordance between HbA1c and fructosamine -: Evidence for a glycosylation gap and its relation to diabetic nephropathy

OBJECTIVE - Discordances between HbA(1c) and other measures of glycemic control are common in clinical practice and remain unexplained. We developed a measure of discordance between HbA(1c) 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 HbA(1c) and FA on the same sample in 153 people were used to calculate GG, defined as the difference between measure HbA(1c) and HbA(1c) predicted from FA based on the population regression of HbA(1c) 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 HbA(1c). 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 greater than or equal to 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 HbA(1c) 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.