linoleic-acid and Diabetes-Mellitus

We developed a novel method to measure hydroxyoctadecadienoic acid (HODE) levels in biological fluids and tissue samples. This method can be used to measure the oxidation products of linoleic acid. Reduction and saponification enabled us to measure hydroperoxides and hydroxides of both free and esterified forms of linoleic acid as total HODE, which includes the enzymatic and non-enzymatic products 9- and 13-(Z, E)-HODEs; the non-enzymatic free radical-mediated products 9- and 13-(E, E)-HODEs; and the specific non-enzymatic singlet oxygen-mediated products 10- and 12-(Z, E)-HODEs. We have recently reported HODE levels in plasma and erythrocytes from healthy volunteers and patients with several diseases and determined that its levels are much higher in patients with lifestyle-related diseases than in healthy volunteers. Furthermore, 10- and 12-(Z, E)-HODE plasma levels can serve as promising biomarkers for the early detection of diabetes. Thus, HODE is a useful biomarker for the assessment of oxidative status, and its efficiency as a biomarker can be improved by using it in combination with other typical biomarkers. This review article focuses on lipid peroxidation biomarkers, including HODE, and discusses their potential in practical and clinical applications in disease prediction.

Topics: Biomarkers; Diabetes Mellitus; Early Diagnosis; Fatty Acids, Unsaturated; Humans; Life Style; Linoleic Acid; Lipid Peroxidation; Lipid Peroxides; Oxidative Stress

Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids found in beef, lamb, and dairy products that exist as positional and stereo-isomers of octadecadienoate (18:2). Over the past two decades numerous health benefits have been attributed to CLA in experimental animal models including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and body fat mass. The accumulation of CLA isomers and several elongated/desaturated and beta-oxidation metabolites have been found in tissues of animals fed diets with CLA. Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism. This review focuses on health benefits, metabolism, and potential mechanisms of action of CLA and postulates the implications regarding dietary CLA for human health.

Topics: Adipose Tissue; Animals; Arteriosclerosis; Dairy Products; Diabetes Mellitus; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Humans; Linoleic Acid; Meat; Mice; Neoplasms; Rats; Stereoisomerism

Linoleic acid is the main dietary essential fatty acid (EFA). To be fully utilized by the body, it must be metabolized to a range of other substances. The first step in this pathway is delta-6-desaturation to gamma-linolenic acid (GLA). This step is slow and rate-limiting, particularly in humans. If delta-6-desaturation is impaired for any reason, the supply of further metabolites may be inadequate for normal function. If the consumption of further metabolites is excessive, then a normal rate of delta-6-desaturation may be inadequate. In these circumstances the direct supply of GLA or further metabolites may be of value. This concept is illustrated by atopic eczema and diabetes, which may represent inherited and acquired examples of inadequate delta-6-desaturation.

Topics: Dermatitis, Atopic; Diabetes Mellitus; Diabetic Neuropathies; Fatty Acid Desaturases; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Linoleoyl-CoA Desaturase

Topics: Diabetes Mellitus; Humans; Linoleic Acid; Linoleic Acids

Topics: Arteriosclerosis; Blood Glucose; Carbohydrate Metabolism; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Glucose Tolerance Test; Humans; Intestinal Absorption; Linoleic Acid; Linoleic Acids; Lipids

Conjugated linoleic acid (CLA) is a group of dietary fatty acids with antiobesity and antidiabetic effects in some animals. The trans10cis12 (t10c12) CLA isomer seems to cause these effects, including improved insulin sensitivity. Whether such isomer-specific effects occur in humans is unknown. The aim of this study was to investigate whether t10c12 CLA or a commercial CLA mixture could improve insulin sensitivity, lipid metabolism, or body composition in obese men with signs of the metabolic syndrome.. In a randomized, double-blind controlled trial, abdominally obese men (n = 60) were treated with 3.4 g/day CLA (isomer mixture), purified t10c12 CLA, or placebo. Euglycemic-hyperinsulinemic clamp, serum hormones, lipids, and anthropometry were assessed before and after 12 weeks of treatment.. Baseline metabolic status was similar between groups. Unexpectedly, t10c12 CLA increased insulin resistance (19%; P < 0.01) and glycemia (4%; P < 0.001) and reduced HDL cholesterol (-4%; P < 0.01) compared with placebo, whereas body fat, sagittal abdominal diameter, and weight decreased versus baseline, but the difference was not significantly different from placebo. The CLA mixture did not change glucose metabolism, body composition, or weight compared with placebo but lowered HDL cholesterol (-2%; P < 0.05).. These results reveal important isomer-specific metabolic actions of CLA in abdominally obese humans. A CLA-induced insulin resistance has previously been described only in lipodystrophic mice. Considering the use of CLA-supplements among obese individuals, it is important to clarify the clinical consequences of these results, but they also provide physiological insights into the role of specific dietary fatty acids as modulators of insulin resistance in humans.

Topics: Adult; Aged; Body Composition; Diabetes Mellitus; Double-Blind Method; Humans; Hyperlipidemias; Insulin Resistance; Isomerism; Leptin; Linoleic Acid; Lipoproteins; Male; Metabolic Syndrome; Middle Aged; Obesity

It has been shown recently that troglitazone exerts an anti-inflammatory effect, in vitro, and in experimental animals. To test these properties in humans, we investigated the effect of troglitazone on the proinflammatory transcription factor nuclear factor-kappaB and its inhibitory protein IkappaB in mononuclear cells (MNC) and plasma soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and C-reactive protein. We also examined the effect of troglitazone on reactive oxygen species generation, p47(phox) subunit expression, 9-hydroxyoctadecadienoic acid (9-HODE), 13-HODE, o-tyrosine, and m-tyrosine in obese patients with type 2 diabetes. Seven obese patients with type 2 diabetes were treated with troglitazone (400 mg/day) for 4 weeks. Blood samples were obtained at weekly intervals. Nuclear factor-kappaB binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4. On the other hand, IkappaB protein levels increased significantly after troglitazone treatment at week 1, and this increase persisted throughout the study. Plasma monocyte chemoattractant protein-1 and soluble intracellular adhesion molecule-1 concentrations did not decrease significantly after troglitazone treatment, although there was a trend toward inhibition. Reactive oxygen species generation by polymorphonuclear cells and MNC, p47(phox) subunit protein quantities, plasminogen activator inhibitor-1, and C-reactive protein levels decreased significantly after troglitazone intake. 13-HODE/linoleic acid and 9-HODE/linoleic acid ratios also decreased after troglitazone intake. However, o-tyrosine/phenylalanine and m-tyrosine/phenylalanine ratios did not change significantly. These data show that troglitazone has profound antiinflammatory effects in addition to antioxidant effects in obese type 2 diabetics; these effects may be relevant to the recently described beneficial antiatherosclerotic effects of troglitazone at the vascular level.

Topics: Adult; Anti-Inflammatory Agents; Blood Glucose; C-Reactive Protein; Chemokine CCL2; Cholesterol; Chromans; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; I-kappa B Proteins; Insulin; Intercellular Adhesion Molecule-1; Leukocytes, Mononuclear; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Male; Middle Aged; NADPH Oxidases; Neutrophils; NF-kappa B; Obesity; Phenylalanine; Phosphoproteins; Plasminogen Activator Inhibitor 1; Reactive Oxygen Species; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone; Tyrosine

Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.

Topics: Animals; Diabetes Mellitus; Gene Expression; Hypothalamus; Inflammation; Linoleic Acid; Male; Mice; Nervous System Diseases; Obesity; Oxytocin; Soybean Oil; Stigmasterol

A diet high in trans-fatty acids (TFA) induces insulin resistance in rodent models and primates. However, previous epidemiological studies on the association between TFAs, based primarily on self-reported intake from the diet, and diabetes in humans have yielded conflicting results. Herein we examined the associations of objectively measured plasma TFA concentrations with diabetes in a large population-based study among US adults.. We included 3801 participants aged ≥20 years from the National Health and Nutrition Examination Survey 1999-2000 and 2009-10. Four major TFAs, namely palmitelaidic acid (C16:1 n-7t), elaidic acid (C18:1 n-9t), vaccenic acid (C18:1 n-7t), and linolelaidic acid (C18:2 n-6t, 9t), were measured in fasting plasma using gas chromatography-mass spectrometry. Diabetes was defined by self-reported physician diagnosis, plasma fasting glucose ≥126 mg/dL, or HbA1c ≥6.5%.. After adjustment for other major risk factors, the odds ratios (95% confidence intervals) of diabetes comparing the highest with lowest quintile of plasma TFAs was 2.19 (1.27-3.79) for total TFAs (P. In a nationally representative population, plasma TFAs, in particular elaidic acid, were positively associated with diabetes and biomarkers of glucose metabolism.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Fasting; Fatty Acids, Monounsaturated; Female; Humans; Insulin; Insulin Resistance; Linoleic Acid; Male; Middle Aged; Nutrition Surveys; Oleic Acid; Oleic Acids; Risk Factors; Trans Fatty Acids; United States

The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.. We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.. We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.. During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend < 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend < 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction > 0.13).. Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Arachidonic Acid; Biomarkers; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus; Diet; Fatty Acids, Omega-6; Follow-Up Studies; gamma-Linolenic Acid; Humans; Incidence; Linoleic Acid; Male; Middle Aged; Mortality; Neoplasms; Prospective Studies; Risk Factors; Socioeconomic Factors

Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.

Topics: Administration, Oral; Animals; Apoptosis; Arachidonic Acid; Diabetes Mellitus; Dietary Carbohydrates; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Haploinsufficiency; Insulin-Secreting Cells; Linoleic Acid; Male; Mice; Pyrazines; Receptors, Glucagon; Signal Transduction; Sitagliptin Phosphate; Sucrose; Triazoles

In this study, a series of small molecule inhibitors of human FABP4 were identified through virtual screening. Compound 1 is the most potent hit against FABP4 with a selectivity of more than 144-fold preferences over human FABP3. In addition, MD simulation and mutation studies revealed key residues for inhibitory potency and selectivity, which provides a guideline for further drug design against obesity, diabetes and atherosclerosis.

Topics: Atherosclerosis; Binding Sites; Computer Simulation; Diabetes Mellitus; Drug Discovery; Drug Evaluation, Preclinical; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Humans; Mutation; Obesity; Organic Chemicals; Protein Binding; Structure-Activity Relationship; Substrate Specificity

A number of human and animal studies using conjugated linoleic acids (CLA) or diacylglycerol (DAG) oil have shown positive physiological effects on abdominal adiposity, plasma triglycerides, plasma glucose, and insulin sensitivity. A novel DAG composition containing CLA called CLA diacylglyceride (CLA-DAG) may offer potential as a therapeutic agent in reducing some of the symptoms associated with the diabetic phenotype and metabolic syndrome. This study was designed to investigate the effect of CLA-DAG oil on the diabetic phenotype in male Zucker diabetic fatty rats. Animals were assigned to one of four groups: control (C), rosiglitazone (ROS), CLA-DAG, or CLA as free fatty acid (CLA-FFA). After 11 weeks, body weight was higher and kidney weight was lower in the CLA-DAG and ROS groups compared with the C group. The ROS treatment increased the percentage of body fat as compared with all other groups. Final fasting blood glucose was lower in the CLA-DAG and ROS groups than in the C group. Plasma cholesterol was lower in the CLA-DAG group, and plasma triglycerides were lower in the ROS group compared with the C group. We also observed changes in transcript abundance of PPAR-gamma, PPAR-alpha, FAS, LPL, UCP2, UCP3, CPT1, RxR, ObRb, ApoAII, ApoD, and IRS1 in liver, muscle, and adipose tissue, suggesting treatment-induced effects on these genes. Collectively, these data suggest the need for further research on the therapeutic relevance of CLA-DAG oil in obesity and diabetes. Future research should also differentiate between CLA alone and DAG alone compared with the combination.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus; Diglycerides; DNA, Complementary; Eating; Gene Expression; Hypoglycemic Agents; Insulin; Insulin Resistance; Kidney; Linoleic Acid; Liver; Muscle, Skeletal; Myocardium; Phenotype; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Rosiglitazone; Thiazolidinediones; Triglycerides

We examined relationships between visceral fat amount and alterations in serum fatty acid composition, both of which represent critical factors in the development of metabolic syndrome.. Correlations were analyzed between visceral fat thickness as measured by ultrasonography and proportions of individual fatty acids in 21 normal-weight and 24 overweight Japanese men.. Significant associations were identified in overweight subjects. Visceral fat thickness displayed positive correlations to levels of palmitic acid and saturated fatty acids (r=0.475, P<0.05 and r=0.545, P<0.01, respectively); and negative correlations to levels of linoleic acid and polyunsaturated fatty acids (r=-0.513, P<0.05 and r=-0.428, P<0.05, respectively). Visceral fat thickness was also correlated with estimated desaturase activities, with positive correlations to Delta9- and Delta6-desaturase activities and negative correlations to Delta5-desaturase activity (r=0.580, P<0.01, r=0.669, P<0.01 and r=-0.559, P<0.01, respectively). No significant associations were identified in normal-weight subjects.. Significant associations between visceral fat amount and alterations in serum fatty acid composition were identified, but only in overweight individuals.

Topics: Adiposity; Adult; Aged; Alcohol Drinking; Body Mass Index; Chromatography, Gas; Diabetes Mellitus; Fatty Acids; Fatty Acids, Unsaturated; Flame Ionization; Humans; Hypertension; Japan; Linoleic Acid; Linoleoyl-CoA Desaturase; Male; Metabolic Syndrome; Middle Aged; Overweight; Palmitic Acid; Smoking; Ultrasonography; Waist Circumference

This study investigated the association between dietary intake of polyunsaturated fatty acids (PUFAs) and peripheral neuropathy in the U.S. population.. We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 for adults >or=40 years of age with diagnosed diabetes, an assessment of peripheral neuropathy, and reliable 24-h dietary recall. The dietary intake of PUFAs was analyzed by peripheral neuropathy status. Multivariate logistic regression models were used to estimate the odds of having peripheral neuropathy in higher quintiles of PUFA intake compared with the lowest quintile.. The mean dietary intake of linolenic acid was 1.25 +/- 0.07 g among adults with peripheral neuropathy, significantly lower than the 1.45 +/- 0.05 g intake among those without peripheral neuropathy. After controlling for potential confounding variables, adults whose linolenic acid intake was in the highest quintile had lower odds of peripheral neuropathy than adults in the lowest quintile (adjusted odds ratio 0.40 [95% CI 0.21-0.77]).. Among adults with diagnosed diabetes, dietary intake of linolenic acid is positively associated with lower odds of peripheral neuropathy.

Topics: Adult; Diabetes Mellitus; Diabetic Neuropathies; Dietary Fats; Fatty Acids, Unsaturated; Health Surveys; Humans; Linoleic Acid; Multivariate Analysis; Nutritional Status; Peripheral Nervous System Diseases; United States

Pre-clinical studies suggest that both omega-6 and omega-3 fatty acids have beneficial effects on peripheral nerve function. Rats feed a diet rich in polyunsaturated fatty acids (PUFAs) showed modification of phospholipid fatty acid composition in nerve membranes and improvement of sciatic nerve conduction velocity (NCV). We tested the hypothesis that baseline plasma omega-6 and omega-3 fatty acids levels predict accelerated decline of peripheral nerve function. Changes between baseline and the 3-year follow-up in peripheral nerve function was assessed by standard surface ENG of the right peroneal nerve in 384 male and 443 female participants of the InCHIANTI study (age range: 24-97 years). Plasma concentrations of selected fatty acids assessed at baseline by gas chromatography. Independent of confounders, plasma omega-6 fatty acids and linoleic acid were significantly correlated with peroneal NCV at enrollment. Lower plasma PUFA, omega-6 fatty acids, linoleic acid, ratio omega-6/omega-3, arachidonic acid and docosahexanoic acid levels were significantly predicted a steeper decline in nerve function parameters over the 3-year follow-up. Low plasma omega-6 and omega-3 fatty acids levels were associated with accelerated decline of peripheral nerve function with aging.

Topics: Adult; Aged; Aged, 80 and over; Aging; alpha-Linolenic Acid; Anthropometry; Arachidonic Acid; Cholesterol; Cohort Studies; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Follow-Up Studies; Humans; Italy; Linoleic Acid; Male; Middle Aged; Neural Conduction; Peripheral Nervous System Diseases; Peripheral Vascular Diseases; Peroneal Nerve; Predictive Value of Tests; Triglycerides

Arachidonic acid (AA), a precursor of prothrombotic eicosanoids, is potentially atherogenic, but epidemiologic data are scarce. We evaluated the hypothesis that increased AA in adipose tissue is associated with increased risk of nonfatal acute myocardial infarction (MI), and if so, whether this association is related to dietary or adipose tissue linoleic acid. We studied the association between AA and MI in 466 cases of a first nonfatal acute MI, matched on age, gender, and residence to 466 population controls. Fatty acids (FA) were assessed by GC in adipose tissue samples collected from all subjects. Odds ratios (OR) and 95% CI were calculated from multivariate conditional logistic regression models. Subjects in the highest quintile of adipose tissue AA (0.64% of total FA) had a higher risk of nonfatal acute MI than those in the lowest quintile (0.29% of total FA), after adjusting for potential confounders including (n-3) and trans FAs (OR = 1.94, 95% CI: 1.07, 3.53, P for trend = 0.026). Adipose tissue AA was not correlated with dietary AA (r = 0.07), linoleic acid (r = 0.04), or other dietary (n-6) FAs, or with adipose tissue linoleic acid (r = -0.07). These data suggest that the association between MI and adipose tissue AA is not related to dietary intake of (n-6) FAs including linoleic acid. Better understanding of the metabolic factors that increase AA in adipose tissue is urgently needed.

Topics: Adipose Tissue; Age Factors; Aged; Arachidonic Acid; Body Size; Body Weight; Chromatography, Gas; Costa Rica; Diabetes Mellitus; Diet; Dietary Fats, Unsaturated; Female; Humans; Hypertension; Linoleic Acid; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Risk Factors; Sex Factors

Maillard or browning reactions between reducing sugars and protein lead to formation of advanced glycation end products (AGEs) and are thought to contribute to the pathogenesis of diabetic complications. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) inhibit both the formation of AGEs and development of complications in animal models of diabetes. PM also inhibits the chemical modification of protein by advanced lipoxidation end products (ALEs) during lipid peroxidation reactions in vitro. We show here that several PM adducts, formed in incubations of PM with linoleate and arachidonate in vitro, are also excreted in the urine of PM-treated animals. The PM adducts N-nonanedioyl-PM (derived from linoleate), N-pentanedioyl-PM, N-pyrrolo-PM, and N-(2-formyl)-pyrrolo-PM (derived from arachidonate), and N-formyl-PM and N-hexanoyl-PM (derived from both fatty acids) were quantified by liquid chromatography-mass spectrometry analysis of rat urine. Levels of these adducts were increased 5-10-fold in the urine of PM-treated diabetic and hyperlipidemic rats, compared with control animals. We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions. We also conclude that ALEs derived from polyunsaturated fatty acids are increased in diabetes and hyperlipidemia and may contribute to development of long term renal and vascular pathology in these diseases.

Topics: Animals; Arachidonic Acid; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Fatty Acids, Unsaturated; Female; Hyperlipidemias; Linoleic Acid; Lipid Peroxidation; Pyridoxamine; Rats; Rats, Sprague-Dawley; Rats, Zucker; Triglycerides

Dietary fatty acid intake is reflected in serum fatty acid composition. Studies prospectively investigating serum fatty acids and development of impaired fasting glycaemia (IFG) or diabetes mellitus (DM) are largely lacking. We assessed the association of serum fatty acid composition with development of IFG or DM.. Middle-aged normoglycaemic men (n = 895) participating in a prospective cohort study were followed up after 4 years.. At baseline proportions of serum esterified and non-esterified saturated fatty acids were increased and polyunsaturated fatty acids decreased in men who after 4 years had developed IFG (n = 56) or DM (n = 34). No differences in dietary fatty acid composition as recorded in 4-day dietary records were noted. In logistic regression analyses adjusting for age; obesity; and fasting lipid, glucose and insulin concentrations, men with proportions of non-esterified and esterified linoleate in the upper third had nearly half the risk for IFG or DM compared with the lower third. In covariate analyses, baseline non-esterified linoleate proportions were associated with changes in fasting insulin and glucose concentrations over the 4-year follow-up. Baseline esterified fatty acid composition was also associated with changes in insulin.. High serum linoleate proportions decreased the risk of developing IFG or DM in middle-aged men over a 4-year follow-up, possibly mediated in part by insulin resistance. These findings support recommendations to substitute vegetable fat for animal and dairy fat in the prevention of disturbances of glucose and lipid metabolism.

Topics: Adult; Age Factors; Blood Glucose; Body Mass Index; Diabetes Mellitus; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids; Fatty Acids, Nonesterified; Follow-Up Studies; Glucose Intolerance; Humans; Insulin; Linoleic Acid; Male; Middle Aged; Predictive Value of Tests; Risk Factors; Time Factors

This study for the first time confirmed the peroxidative role of the Amadori product derived from the glycation of phosphatidylethanolamine (PE), namely Amadori-PE. The product was synthesized from the reaction of dioleoyl PE with D-glucose, and then purified by a solid-phase extraction procedure, which was a key step in the next HPLC technique for the isolation of essentially pure Amadori-PE. When the synthetically prepared Amadori-PE was incubated with linoleic acid in the presence of Fe(3+) in micellar system, a remarkable formation of thiobarbituric acid reactive substances was observed together with increases in lipid hydroperoxides. In addition, the lipid peroxidation caused by Amadori-PE was effectively inhibited by superoxide dismutase, mannitol, catalase and metal chelator. These results indicated that Amadori-PE triggers oxidative modification of lipids via the generation of superoxide, and implied the involvement of 'lipid glycation' along with membrane lipid peroxidation in the pathogenesis of diabetes and aging.

Topics: Aging; Animals; Catalase; Chelating Agents; Chromatography, High Pressure Liquid; Diabetes Mellitus; Free Radicals; Glucose; Hydrogen-Ion Concentration; Iron; Linoleic Acid; Lipid Peroxidation; Lipid Peroxides; Mannitol; Mass Spectrometry; Micelles; Models, Biological; Phosphatidylethanolamines; Reactive Oxygen Species; Reducing Agents; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

It has been suggested that lipid peroxidation of polyunsaturated fatty acids (PUFA) may play a role in the pathogenesis of diabetic complications. To test this hypothesis, we aimed to compare PUFA composition of small arteries and veins (< 500 microm diameter) obtained from diabetic or non-diabetic Guadeloupean patients undergoing arterio-venous shunt surgery before renal dialysis. Small forearm subcutaneous vessels were analysed by a new TLC method which involved inclusion of vascular biopies directly in alveoles made in the TLC gel and lyophilization onto the plate. The TLC plate was then chromatographed and lipids were both extracted and eluted during this step. Fatty acid composition of phospholipid and neutral lipid fractions were determined. Similar fatty acid composition was obtained for arteries and veins from diabetic or non-diabetic subjects. In phospholipids from diabetic vessels, major changes consisted of a 20% decrease of arachidonic acid (20:4 n-6), a 40% decrease of its elongation product 22:4 n-6 and 30% increase of 18:2 n-6. In neutral lipids, 20:4 n-6 was also diminished by 60% whereas oleic acid increased by 15%. This loss of arachidonic acid in small diabetic vessels suggests impaired delta6-desaturase forming 20:4 n-6 or alternatively increased peroxide formation, in the vascular wall of small vessels in diabetic patients.

Topics: Adipose Tissue; Adult; Aged; Animals; Aorta; Arachidonic Acid; Arteries; Chromatography, Thin Layer; Cricetinae; Diabetes Mellitus; Fatty Acids; Fatty Acids, Monounsaturated; Female; Humans; Linoleic Acid; Lipids; Male; Middle Aged; Oleic Acid; Phospholipids; Veins

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

Non-enzymatic glycation of reactive amino groups in model proteins increased the rate of free radical production at physiologic pH by nearly fifty-fold over non-glycated protein. Superoxide generation was confirmed by electron paramagnetic resonance measurements with the spin-trap phenyl-t-butyl-nitrone. Both Schiff base and Amadori glycation products were found to generate free radicals in a ratio of 1:1.5. Free radicals generated by glycated protein increased peroxidation of membranes of linoleic/arachidonic acid vesicles nearly 2-fold over control, suggesting that the increased glycation of proteins in diabetes may accelerate vascular wall lipid oxidative modification.

Topics: Arteriosclerosis; Catalase; Cell Membrane; Cyclic N-Oxides; Cytochrome c Group; Diabetes Complications; Diabetes Mellitus; Electron Spin Resonance Spectroscopy; Free Radicals; Glucose; Humans; Hyperglycemia; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Nitroblue Tetrazolium; Nitrogen Oxides; Schiff Bases; Spin Labels; Superoxide Dismutase

We measured the platelet total phospholipid fatty acid profiles of 20 insulin treated (Type I) diabetics, 20 non-insulin treated (Type II) diabetics and 20 matched non-diabetic controls to determine the relationship between the omega 6 and omega 3 series of fatty acids in diabetes. A significant inverse correlation between linoleic acid and arachidonic acid occurred in the normal subjects (r = -0.61; P less than 0.001) but was not seen in the Type I diabetics (r = -0.13; P = NS) or in the Type II diabetics (r = -0.27; P = NS). No significant correlation was seen between linolenic acid and eicosapentaenoic acid in the normal controls (r = -0.34; P = NS) or in the Type I diabetics (r = 0.21; P = NS) or in the Type II diabetics (r = -0.20; P = NS). The results suggest that a functional impairment of platelet delta 5 and delta 6 desaturase may occur in diabetes which disrupts the normal equilibrium between linoleic acid and arachidonic acid. However, the level of eicosapentaenoic acid appears to be less dependent on conversion from linolenic acid. Our findings are of importance to studies designed to reduce platelet aggregation in diabetics and non-diabetics by manipulation of the levels of the precursor fatty acids of thromboxane.

Topics: Adult; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Fatty Acid Desaturases; Humans; Insulin; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Platelet Aggregation; Thromboxanes

Genetically diabetic mice (db/db) and their non-diabetic litter-mates were maintained for 15 weeks on diets supplemented with safflower oil or evening primrose (Oenothera bienis) oil, both essential fatty acid (EFA)-rich sources, or hydrogenated coconut oil (devoid of EFA). Plasma glucose was higher in the diabetic mice supplemented with the oils than in the unsupplemented diabetic mice. In the oil-supplemented non-diabetic mice, plasma glucose did not differ compared with the unsupplemented non-diabetic mice. The proportional content of arachidonic acid in the phospholipids of the pancreas was significantly decreased in diabetic mice, an effect which was completely prevented by supplementation with safflower or evening primrose oil but not hydrogenated coconut oil. In the liver phospholipids of the diabetic mice, dihomo-gamma-linolenic acid was proportionally increased, an effect reduced by supplementation with safflower oil but not evening primrose or hydrogenated coconut oils. In the liver triglycerides of the diabetic mice, gamma-linolenic acid, dihomo-gamma-linolenic acid and arachidonic acid were all proportionally decreased, effects which were also prevented by safflower or evening primrose oil but not hydrogenated coconut oil. Alopecia and dry scaly skin were prominent in the diabetic mice but less extensive in the diabetic mice supplemented with EFA.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Fatty Acids, Essential; gamma-Linolenic Acid; Linoleic Acid; Linoleic Acids; Linolenic Acids; Lipids; Liver; Mice; Mice, Inbred C57BL; Organ Size; Pancreas; Phospholipids; Skin; Triglycerides

Water-soluble fluorescent substances like lipofuscin were found in the protein fraction of mouse and human sera and had fluorescence characteristics with excitation and emission maxima at 335-340 and 435-440 nm for mice, and at 355-360 and 430-435 nm for human, respectively. When oxidized [U-14 C]linoleic acid was given intraperitoneally to mice, or added to the serum in vitro, both the fluorescence intensity and radioactivity of serum protein increased dose-dependently in the two tests. Also, the fluorescent substances responded well to acceleration of in vivo lipid peroxidation caused by carbon tetrachloride. These results indicate that the substances were some binding compounds between the degraded lipids and serum proteins, and that they could be taken as a parameter of in vivo lipid peroxidation. The distribution of the pigments in the serum proteins, albumin and globulins, was shown to depend upon the number of free amino groups in each protein which appear to be binding sites of degraded lipids. Spectral characteristics and some chemical properties of the substances suggest that they might not be conjugated Schiff bases formed from protein and malondialdehyde but might be due to some other stable compounds. Significantly high levels of the substances were observed in sera of patients with diabetes and hypertension.

Topics: Adult; Amino Acids; Animals; Binding Sites; Blood Proteins; Carbon Tetrachloride; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Lipofuscin; Male; Mice; Middle Aged; Pigments, Biological; Solubility; Spectrometry, Fluorescence; Vitamin E

Topics: Angina Pectoris; Blood Coagulation; Blood Coagulation Tests; Cholesterol; Diabetes Mellitus; Dietary Fats; Geriatrics; Humans; Linoleic Acid; Lipids; Myocardial Infarction; Palmitic Acid; Pharmacology; Stearic Acids; Thromboplastin; Triolein

Topics: Arteriosclerosis; Chemical Phenomena; Chemistry; Deficiency Diseases; Diabetes Mellitus; Dietary Fats; Fats; Fatty Acids; Fatty Acids, Essential; Humans; Hypothyroidism; Linoleic Acid; Lipids; Oils; Oleic Acid; Oleic Acids

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

Topics: Anemia; Anemia, Pernicious; Butter; Celiac Disease; Cottonseed Oil; Diabetes Mellitus; Dietary Fats; Fats; Feces; Gastroenterostomy; Geriatrics; Glycerides; Glycerol; Humans; Intestinal Absorption; Linoleic Acid; Stearic Acids; Steatorrhea

Topics: Aortic Valve Stenosis; Arteriosclerosis; Bronchitis; Cholelithiasis; Diabetes Mellitus; Fatty Acids; Geriatrics; Hypertension; Injections, Intravenous; Kidney Function Tests; Linoleic Acid; Lung Diseases; Myocardial Infarction; Neurocirculatory Asthenia; Oleic Acid; Pharmacology; Phosphatidylcholines; Phospholipids; Pleurisy