Plasma F2 isoprostanes: direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes.

OBJECTIVES: Acute hyperglycemia in type 2 diabetes increases the generation of plasma 8-epi-prostaglandin F2 (8-epi-PGF2alpha) isoprostane, a sensitive direct marker of in vivo free radical oxidative damage to membrane phospholipids. RESEARCH DESIGN AND METHODS: A total of 21 patients with type 2 diabetes underwent an oral 75-g glucose tolerance test. Plasma 8-epi-PGF2alpha isoprostane concentrations (by gas chromatography [GC]/mass spectrometry [MS]), intralymphocyte reduced-to-oxidized glutathione ratios, and plasma total antioxidant capacity were measured at baseline and 90 min after glucose loading. RESULTS: Plasma 8-epi-PGF2alpha isoprostane concentrations rose significantly (P=0. 010) from 0.241 +/- 0.1 to 0.326 +/- 0.17 ng/l after 90 min. Intracellular oxidative balance and plasma antioxidant capacity did not change in either group. CONCLUSIONS: Plasma concentrations of 8-epi-PGF2alpha isoprostane increase during acute hyperglycemia in type 2 diabetes, providing direct evidence of free radical-mediated oxidative damage and demonstrating a pathway for an association between acute rather than fasting hyperglycemia and macrovascular risk in type 2 diabetes.

Increased expression of a scavenger receptor (CD36) in monocytes from subjects with Type 2 diabetes.

Uptake of modified low density lipoprotein (LDL) by monocyte-macrophages is mediated by the scavenger receptor CD36, which is upregulated in vitro by high glucose concentrations and oxidatively modified LDL. We hypothesised that monocyte CD36 expression would be higher in Type 2 diabetes, and would increase during acute hyperglycaemia. Sixteen subjects with Type 2 diabetes and 11 controls underwent a 75 g oral glucose load. Monocyte CD36 expression (by laser flow cytometry), plasma LDL diene conjugates, plasma LDL hydroxyoctadecadienoic acid-13 (a peroxisome proliferator activator receptor gamma agonist) were measured at 0, 2 and 4 h. Mean monocyte CD36 expression at baseline was 34% higher in the diabetes group (P=0.01), did not change during acute hyperglycaemia and plasma LDL conjugated diene concentration was the only variable directly related to CD36 expression (F=4.53; P=0.05; r=0.51). Higher baseline CD36 expression in Type 2 diabetes could reflect increased post-transcriptional efficiency of CD36 mRNA in response to chronic hyperglycaemia and could be a proatherogenic mechanism in Type 2 diabetes.

Monocyte matrix metalloproteinase production in Type 2 diabetes and controls--a cross sectional study.

BACKGROUND: Coronary plaque rupture may result from localised over expression of matrix metalloproteinases (MMPs) within the plaque by infiltrating monocyte-macrophages. As MMP expression can be promoted by the modified lipoproteins, oxidative stress and hyperglycaemia that characterises Type 2 diabetes, we hypothesised that peripheral monocytes in these patients, exposed to these factors in vivo, would demonstrate increased MMP production compared to controls. METHODS: We examined peripheral venous monocyte expression of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) in 18 controls and 22 subjects with Type 2 diabetes and no previous cardiovascular complications. RESULTS: No significant difference in MMP-1, 3 or 9 or TIMP-1 production was observed between control and diabetes groups. CONCLUSIONS: Monocyte MMP-1, 3, and 9, and TIMP-1, production are not abnormal in Type 2 diabetes. This data cannot be extrapolated to monocyte-macrophage behaviour in the vessel wall, but it does suggest MMP and TIMP-1 expression prior to monocyte infiltration and transformation are not abnormal in Type 2 diabetes.