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

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          Abstract

          OBJECTIVE

          We investigated whether glycation gap (G-Gap), an index of intracellular glycation of proteins, was associated with diabetes complications.

          RESEARCH DESIGN AND METHODS

          We measured concomitantly HbA 1c and fructosamine in 925 patients with type 2 diabetes to calculate the G-Gap, defined as the difference between measured HbA 1c, and fructosamine-based predicted HbA 1c. Patients were explored for retinopathy, nephropathy, peripheral neuropathy, cardiac autonomic neuropathy ( n = 512), and silent myocardial ischemia ( n = 506).

          RESULTS

          Macroproteinuria 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 HbA 1c was associated with both G-Gap (HbA 1c 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 (HbA 1c 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 HbA 1c. 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.

          CONCLUSIONS

          In type 2 diabetic patients, G-Gap was associated with macroproteinuria, independently of HbA 1c, albumin levels, and confounding factors, suggesting a specific role of intracellular glycation susceptibility on kidney glomerular changes.

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          Most cited references 20

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          Defining the relationship between plasma glucose and HbA(1c): analysis of glucose profiles and HbA(1c) in the Diabetes Control and Complications Trial.

          To define the relationship between HbA(1c) and plasma glucose (PG) levels in patients with type 1 diabetes using data from the Diabetes Control and Complications Trial (DCCT). The DCCT was a multicenter, randomized clinical trial designed to compare intensive and conventional therapies and their relative effects on the development and progression of diabetic complications in patients with type 1 diabetes. Quarterly HbA(1c) and corresponding seven-point capillary blood glucose profiles (premeal, postmeal, and bedtime) obtained in the DCCT were analyzed to define the relationship between HbA(1c) and PG. Only data from complete profiles with corresponding HbA(1c) were used (n = 26,056). Of the 1,441 subjects who participated in the study, 2 were excluded due to missing data. Mean plasma glucose (MPG) was estimated by multiplying capillary blood glucose by 1.11. Linear regression analysis weighted by the number of observations per subject was used to correlate MPG and HbA(1c). Linear regression analysis, using MPG and HbA(1c) summarized by patient (n = 1,439), produced a relationship of MPG (mmol/l) = (1.98 . HbA(1c)) - 4.29 or MPG (mg/dl) = (35.6 . HbA(1c)) - 77.3, r = 0.82). Among individual time points, afternoon and evening PG (postlunch, predinner, postdinner, and bedtime) showed higher correlations with HbA(1c) than the morning time points (prebreakfast, postbreakfast, and prelunch). We have defined the relationship between HbA(1c) and PG as assessed in the DCCT. Knowing this relationship can help patients with diabetes and their healthcare providers set day-to-day targets for PG to achieve specific HbA(1c) goals.
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            Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications--the French multicenter study.

             J Pariès,  ,  J Attali (2003)
            The current study sought to examine in a large series of diabetic patients the prevalence of symptoms of autonomic neuropathy and subclinical cardiac autonomic neuropathy (CAN) and their determinants, particularly the influence of diabetes duration, obesity, and microangiopathic complications. Three hundred ninety-six patients, 245 type 1 and 151 type 2, were recruited in 7 French departments of diabetology. CAN was detected by measuring heart rate variability during 3 standardized tests: deep-breathing, Valsalva, and lying-to-standing tests. At least 24.5% of the patients had one or more symptoms suggesting overt autonomic neuropathy. They were older than those free of dysautonomic symptom (P<.001). The deep-breathing test correlated negatively with body mass index (BMI) in type 2 diabetic patients (P<.0001). In the whole population, the deep-breathing and Valsalva tests correlated negatively with diabetes duration (P=.0004 and.019, respectively) and the log urinary albumin/creatinine ratio (P<.002 and.001, respectively). The prevalence of CAN (51%) was higher than the prevalence of other diabetic complications. The rate of moderate and severe CAN (defined by 2 or 3 abnormal CAN function tests) was higher in type 1 than in type 2 diabetic patients (P=.031). It correlated with diabetes duration (P=.026) and was higher in the patients with retinopathy than in those without (P=.035). Among type 2 diabetic patients, the prevalence of CAN was higher in the obese ones (P=.033); in a logistic regression taking age, diabetes duration, and obesity as independent variables, CAN was associated independently with obesity (P=.034). Mild or moderate CAN was found in 33.8% and 13.0% of the 80 patients with diabetes duration less than 18 months. We conclude that CAN is found early in the course of diabetes and should be considered as a prognostic marker of microangiopathic complications. Obesity could be involved in the impairment of CAN function in type 2 diabetics and body weight control could provide an approach to reducing neuropathic complications.
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              Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy.

              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. 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. 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 >or = 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. The glycosylation gap may be a useful clinical research tool for evaluating physiologic sources of variation in diabetic complications beyond glycemic control.
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                July 2013
                12 June 2013
                : 36
                : 7
                : 2070-2076
                Affiliations
                1AP-HP, Jean Verdier Hospital, Paris 13 University, Sorbonne Paris Cité, Department of Endocrinology, Diabetology, and Nutrition, CRNH-IdF, Bondy, France
                2Sorbonne Paris Cité, UMR U557 Inserm /U1125 Inra/Cnam/Université Paris 13, Bobigny, France
                3Shangai Clinical Center for Endocrine and Metabolic Diseases, Shangai, China
                4Paris 13 University, Sorbonne Paris Cité, AP-HP, Jean Verdier Hospital, Biochemistry Laboratory, Bondy, France
                Author notes
                Corresponding author: Paul Valensi, paul.valensi@ 123456jvr.aphp.fr
                Article
                1780
                10.2337/dc12-1780
                3687281
                23378625
                © 2013 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                Page count
                Pages: 7
                Product
                Categories
                Original Research
                Pathophysiology/Complications

                Endocrinology & Diabetes

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