Glycation Gap Is Associated With Macroproteinuria but Not With Other Complications in Patients With Type 2 Diabetes

Abstract

OBJECTIVEWe investigated whether glycation gap (G-Gap), an index of intracellular glycation of proteins, was associated with diabetes complications.RESEARCH DESIGN AND METHODSWe measured concomitantly HbA1c and fructosamine in 925 patients with type 2 diabetes to calculate the G-Gap, defined as the difference between measured HbA1c, and fructosamine-based predicted HbA1c. Patients were explored for retinopathy, nephropathy, peripheral neuropathy, cardiac autonomic neuropathy (n = 512), and silent myocardial ischemia (n = 506).RESULTSMacroproteinuria was the only complication that was associated with G-Gap (prevalence in the first, second, and third tertile of G-Gap: 2.9, 6.2, and 11.0%, respectively; P < 0.001). The G-Gap was higher in patients with macroproteinuria than in those without (1.06 ± 1.62 vs. 0.03 ± 1.30%; P < 0.0001). Because HbA1c was associated with both G-Gap (HbA1c 7.0 ± 1.4, 7.9 ± 1.4, and 10.1 ± 1.8% in the first, second, and third G-Gap tertile, respectively; P < 0.0001) and macroproteinuria (HbA1c 8.8 ± 2.2% if macroproteinuria, 8.3 ± 2.0% if none; P < 0.05), and because it could have been a confounder, we matched 54 patients with macroproteinuria and 200 patients without for HbA1c. Because macroproteinuria was associated with lower serum albumin and fructosamine levels, which might account for higher G-Gap, we calculated in this subpopulation albumin-indexed fructosamine and G-Gap; macroproteinuria was independently associated with male sex (odds ratio [OR] 3.2 [95% CI 1.5–6.7]; P < 0.01), hypertension (2.9 [1.1–7.5]; P < 0.05), and the third tertile of albumin-indexed G-Gap (2.3 [1.1–4.4]; P < 0.05) in multivariate analysis.CONCLUSIONSIn type 2 diabetic patients, G-Gap was associated with macroproteinuria, independently of HbA1c, albumin levels, and confounding factors, suggesting a specific role of intracellular glycation susceptibility on kidney glomerular changes.

Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6–TMC8 and SIX3–SIX2 loci associated with HbA1c

“…GG, indicating the discordance between HbA 1c and other measures of glycaemic control ( e . g ., GA and fructosamine), has been associated with renal impairment and diabetic nephropathy 19 , 53 – 55 . GG was shown previously to be a heritable trait 56 , 57 .…”

The Hemoglobin Glycation Index Identifies Subpopulations With Harms or Benefits From Intensive Treatment in the ACCORD Trial

“…The glycation gap developed by Cohen et al ( 5 ) is calculated in exactly the same way as HGI except fructosamine replaces directly measured glucose for obtaining a predicted HbA 1c . Several studies have shown that patients with type 2 diabetes with a high glycation gap have greater risk for microvascular or macrovascular complications ( 5 , 10 , 13 , 14 ). HGI and the glycation gap are strongly positively correlated, which suggests they reflect the same biological phenomenon ( 15 ).…”

The Benefit of a Glucose-Sparing PD Therapy on Glycemic Control Measured by Serum Fructosamine in Diabetic Patients in a Randomized, Controlled Trial (IMPENDIA)

“…A study of 503 HD patients reported significant associations between higher fructosamine levels and poorer clinical outcomes and increased mortality [21]. In addition, the glycosylation gap, calculated from the difference between measured HbA1c and fructosamine-based predicted HbA1c, showed a positive association with nephropathy and macroproteinuria in a study of 925 patients with diabetes [22]. The glycosylation gap may be a useful indicator of the severity of complications relating to diabetes.…”