linoleic-acid and Diabetic-Angiopathies

Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease. Evidence suggests that inflammatory responses in the vasculature can be elicited by small oxidized lipids that are components of oxidized low-density lipoprotein or products of the lipoxygenase and cyclooxygenase pathways of arachidonic and linoleic acid metabolism. This review evaluates these inflammatory and proatherogenic pathways in the pathogenesis of diabetic vascular disease.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Chemotaxis; Coronary Restenosis; Cyclooxygenase 2; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Gene Expression Regulation; Humans; Hydroxyeicosatetraenoic Acids; Inflammation Mediators; Insulin Resistance; Linoleic Acid; Lipoxygenase; Membrane Proteins; Mice; Models, Biological; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Signal Transduction

Topics: Adolescent; Arteriosclerosis; Blood Pressure; Child; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diet, Sodium-Restricted; Dietary Fats; Energy Intake; Female; Humans; Hypertension; Linoleic Acid; Linoleic Acids; Lipoproteins; Male; Sodium

Haptoglobin serves as an antioxidant by virtue of its ability to prevent hemoglobin-driven oxidative tissue damage. It was recently demonstrated that an allelic polymorphism in the haptoglobin gene is predictive of the risk for numerous microvascular and macrovascular diabetic complications. Because these complications are attributed in large part to an increase in oxidative stress, a study was conducted to determine whether the different protein products of the 2 haptoglobin alleles differed in the antioxidant protection they provided. A statistically significant difference was found in the antioxidant capacity of purified haptoglobin protein produced from the 2 different alleles, consistent with the hypothesis that differences in genetically determined antioxidant status may explain differential susceptibility to diabetic vascular complications. These differences may be amplified in the vessel wall because of differences in the sieving capacity of the haptoglobin types. Therefore, an attempt was made to identify the minimal haptoglobin sequences necessary to inhibit oxidation by hemoglobin in vitro, and 2 independent haptoglobin peptides that function in this fashion as efficiently as native haptoglobin were identified. Identification of the biochemical basis for differences among haptoglobin types may lead to the rational development of new pharmacologic agents, such as the mini-haptoglobin described here, to avert the development of diabetic vascular complications.

Topics: Alleles; Antioxidants; Binding Sites; Diabetic Angiopathies; Enzyme-Linked Immunosorbent Assay; Genetic Predisposition to Disease; Haptoglobins; Hemoglobins; Humans; Linoleic Acid; Lipid Peroxidation; Lipoproteins, LDL; Oxidation-Reduction; Recombinant Proteins; Structure-Activity Relationship

An excess of Oxidative Stress can occur either through an increase in the generation of free radicals and their metabolites (which overwhelm the protective capacity of the normal defence mechanisms of the body) or through a decrease in the protective ability of the body to withstand normal Oxidative Stress or both. Excessive Oxidative Stress plays an important role in the pathogenesis of diabetes and its chronic complications like retinopathy and nephropathy. Through various mechanisms, it plays a prominent role in the progression and acceleration of atherosclerosis. Free radicals being highly unstable due to their high reactivity are very difficult to measure accurately. Recourse is therefore taken to measure the compounds that are formed due to the activity of these free radicals. These compounds are relatively more stable and therefore can be measured as diene congugate and lipid peroxides. Another valuable measurement is to measure the levels of reduced glutathione in serum. Measurements of these products can be an excellent parameter to judge the metabolic control of diabetes.

Topics: Adult; Aged; Antioxidants; Arteriosclerosis; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Evaluation Studies as Topic; Female; Free Radicals; Glutathione; Humans; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Male; Middle Aged; Myocardial Ischemia; Oxidative Stress

In non-insulin-dependent diabetes mellitus (NIDDM) patients, microalbuminuria predicts early mortality, predominantly from cardiovascular disease. Increased free radical activity and abnormalities in hemostasis have been implicated in the development of vascular disease. Therefore, we measured markers of free radical activity (nonperoxide-conjugated diene isomer of linoleic acid [PL-9,11-LA'] and lipid peroxides expressed as malondialdehyde [MDA]) along with the hemostatic variables: fibrinogen, von Willebrand factor (vWf), plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA), and plasmin activity (B beta 15-42) in 24 NIDDM patients (12 patients with microalbuminuria and 12 without microalbuminuria) and in 12 age-matched control subjects. There were no differences in linoleic acid (PL-9,12-LA) concentrations between the three groups. PL-9,11-LA' was elevated in the microalbuminuric patients compared with control subjects (P less than 0.05), but there was no difference between the two diabetic groups. MDA was elevated in the microalbuminuric diabetic patients compared with those patients without microalbuminuria (P less than 0.05) and control subjects (P less than 0.001). MDA was also increased in the patients without microalbuminuria compared with control subjects (P less than 0.01). Except for B beta 15-42, all the hemostatic variables were increased (P less than 0.05) in the diabetic patients compared with control subjects. The microalbuminuric diabetic patients had further increases in vWf (P less than 0.03) and t-PA (P less than 0.03) compared with patients with microalbuminuria. Our study suggests that there is an increase in free radical activity and abnormalities in hemostatic variables favoring a hypercoagulable state in NIDDM, especially in those with microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Albuminuria; Analysis of Variance; Biomarkers; Blood Coagulation; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Free Radicals; Humans; Linoleic Acid; Linoleic Acids; Malondialdehyde; Middle Aged; Regression Analysis

Topics: Blood Glucose; Diabetic Angiopathies; Dietary Fats; Female; Follow-Up Studies; Humans; Linoleic Acid; Linoleic Acids; Male

Topics: Arteriosclerosis; Chromatography; Diabetes Mellitus; Diabetic Angiopathies; Fatty Acids; Fatty Acids, Essential; Glycerides; Healthy Volunteers; Linoleic Acid; Lipids; Phospholipids