Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes

Context  Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress. Objective  To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes. Design, Setting, and Participants  Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) in Montpellier, France. Main Outcome Measures  Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F₂ (8-iso PGF₂). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A_1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period. Results  Mean (SD) urinary 8-iso PGF₂ excretion rates were higher in the 21 patients with diabetes (482 206] pg/mg of creatinine) compared with controls (275 85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF₂ excretion rates. Relationships between 8-iso PGF₂ excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R² = 0.72 for the model including MAGE and multiple R² = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp. Conclusions  Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A_1c and mean glucose concentrations but also acute glucose swings.