linoleic-acid and Insulin-Resistance

As heart disease and type 2 diabetes mellitus (T2DM) cases continue to rise, identifying lifestyle modifications to prevent cardiometabolic disease (CMD) is urgently needed. Clinical evidence consistently shows that higher dietary or biomarker levels of linoleic acid (LA; 18:2n6) reduce metabolic syndrome (Mets) and reduce the risk for CMD. Yet, dietary recommendations to include LA as part of a lifestyle plan with the goal of preventing CMD remain elusive.. Clinical interventions consistently show that dietary the addition of LA to the diet improves body composition, dyslipidemia, and insulin sensitivity while reducing systemic inflammation and fatty liver. These effects of LA position dietary LA-rich oils as a potential dietary strategy to aid in preventing CMD. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are cellular targets for many polyunsaturated fatty acids and oxylipin metabolites. PPAR activation can regulate dyslipidemia, insulin sensitivity, adipose biology, and inflammation, potentially explaining the plethora of effects of dietary LA on aspects of CMD.. Unraveling the cellular mechanism(s) of LA to impact PPAR activity may reset a false dogma that LA, as a member of the omega-6 fatty acid family, promotes inflammation in humans. In fact, LA appears to reduce inflammation and reduce risk for CMD.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Acids, Omega-6; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Peroxisome Proliferator-Activated Receptors

The consumption of linoleic acid (LA, ω-6 18:2), the most common ω-6 polyunsaturated fatty acid (PUFA) in the Modern Western diet (MWD), has significantly increased over the last century in tandem with unprecedented incidence of chronic metabolic diseases like obesity and type 2 diabetes mellitus (T2DM). Although an essential fatty acid for health, LA was a very rare fatty acid in the diet of humans during their evolution. While the intake of other dietary macronutrients (carbohydrates like fructose) has also risen, diets rich in ω-6 PUFAs have been promoted in an effort to reduce cardiovascular disease despite unclear evidence as to how increased dietary LA consumption could promote a proinflammatory state and affect glucose metabolism. Current evidence suggests that sex, genetics, environmental factors, and disease status can differentially modulate how LA influences insulin sensitivity and peripheral glucose uptake as well as insulin secretion and pancreatic beta-cell function. Therefore, the aim of this review will be to summarize recent additions to our knowledge to refine the unique physiological and pathophysiological roles of LA in the regulation of glucose homeostasis.

Topics: Diet, Western; Female; Glucose; Homeostasis; Humans; Insulin Resistance; Insulin Secretion; Linoleic Acid; Male; Risk Factors; Sex Characteristics

Several associations between non-genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta-analyses of observational studies, meta-analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non-genetic biomarkers and CRC risk and meta-analyses of RCTs on supplementary micronutrients. We repeated the meta-analyses using random-effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy-two meta-analyses of observational studies and 18 MR studies on non-genetic biomarkers and six meta-analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta-analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non-genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment-insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types.

Topics: Arachidonic Acid; Biomarkers, Tumor; Colorectal Neoplasms; Helicobacter Infections; Helicobacter pylori; Humans; Insulin Resistance; Linoleic Acid; Mendelian Randomization Analysis; Meta-Analysis as Topic; Micronutrients; Observational Studies as Topic; Oleic Acid; Papillomavirus Infections; Randomized Controlled Trials as Topic; Risk; Vitamin D

Dietary fat quality, especially the intake of specific types of fatty acids, impacts the risk of many chronic diseases, including cardiovascular diseases, certain cancers and type 2 diabetes (T2DM). A recent pooled analysis involving 20 studies from around the world revealed that higher linoleic acid (18:2n-6 LA) biomarker is associated with dose-dependent decreases in the incidence of T2DM. This latest study corroborates earlier cross-sectional studies and intervention trials showing that biomarkers of LA intake are associated with reduced risk of T2DM and better glycemic control and/or insulin sensitivity. This review highlights key clinical trials that have evaluated the role of LA in glycemia and the related condition, insulin sensitivity.

Topics: Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Fats; Humans; Insulin Resistance; Linoleic Acid; Neoplasms; Risk

n-6 Fatty acids, like n-3 fatty acids, play essential roles in many biological functions. Because n-6 fatty acids are the precursors of proinflammatory eicosanoids, higher intakes have been suggested to be detrimental, and the ratio of n-6 to n-3 fatty acids has been suggested by some to be particularly important. However, this hypothesis is based on minimal evidence, and in humans higher intakes of n-6 fatty acids have not been associated with elevated levels of inflammatory markers. n-6 Fatty acids have long been known to reduce serum total and low-density lipoprotein cholesterol, and increases in polyunsaturated fat intake, mostly as n-6 fatty acids, were a cornerstone of dietary advice during the 1960s and 1970s. In the United States, for example, intake of n-6 fatty acids doubled and coronary heart disease (CHD) mortality fell by 50% over a period of several decades. In a series of relatively small, older randomized trials, in which intakes of polyunsaturated fat were increased (even up to 20% of calories), rates of CHD were generally reduced. In a more recent detailed examination of fatty acid intake within the Nurses' Health Study, greater intake of linoleic acid, up to about 8% of energy, has been strongly related to lower incidence of myocardial infarction or CHD death. Because n-3 fatty acids were also related inversely to risk of CHD, the ratio was unrelated to risk. n-6 Fatty acids reduce insulin resistance, probably by acting as a ligand for peroxisome proliferator-activated receptors-gamma, and intakes have been inversely related to risk of type 2 diabetes. Adequate intakes of both n-6 and n-3 fatty acids are essential for good health and low rates of cardiovascular disease and type 2 diabetes, but the ratio of these fatty acids is not useful. Reductions of linoleic acid to "improve" this ratio would likely increase rates of cardiovascular disease and diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Acids, Omega-6; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Lipids; NF-kappa B; Receptors, Tumor Necrosis Factor

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

Conjugated linoleic acid (CLA) isomers, a group of positional and geometric isomers of linoleic acid [18:2(n-6)], have been studied extensively due to their ability to modulate cancer, atherosclerosis, obesity, immune function and diabetes in a variety of experimental models. The purpose of this review was to examine CLA's isomer-specific regulation of adiposity and insulin sensitivity in humans and in cultures of human adipocytes. It has been clearly demonstrated that specific CLA isomers or a crude mixture of CLA isomers prevent the development of obesity in certain rodent and pig models. This has been attributed mainly to trans-10, cis-12 CLA, both in vivo and in vitro. However, CLA's ability to modulate human obesity remains controversial because data from clinical trials using mixed isomers are conflicting. In support of some studies in humans, our group demonstrated that trans-10, cis-12 CLA prevents triglyceride (TG) accumulation in primary cultures of differentiating human preadipocytes. In contrast, cis-9, trans-11 CLA increases TG content. Closer examination has revealed that CLA's antiadipogenic actions are due, at least in part, to regulation of glucose and fatty acid uptake and metabolism. This review presents our current understanding of potential isomer-specific mechanisms by which CLA reduces human adiposity and insulin sensitivity.

Topics: Adipocytes; Adipose Tissue; Body Composition; Cells, Cultured; Fatty Acids; Gene Expression; Glucose; Humans; Insulin Resistance; Linoleic Acid; Receptors, Cytoplasmic and Nuclear; Stem Cells; Transcription Factors; Triglycerides

Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of the omega-6 essential fatty acid linoleic acid (cis-9, cis-12, octadecadienoic acid). In humans evidence is currently ambiguous as to whether CLA supplementation has a significant effect on body composition. Despite favorable changes in lipid levels in animal models, a beneficial effect in humans has not yet been established. While some of the changes reported are consistent with an improved lipid profile, declines in HDL and increases in lipoprotein (a) have also been observed in some subjects. Available evidence suggests CLA supplementation has no impact on immune system performance in healthy subjects.

Topics: Animals; Body Composition; Cardiovascular Diseases; Dietary Supplements; Dose-Response Relationship, Drug; Humans; Insulin Resistance; Linoleic Acid; Neoplasms

N-6 fatty acids are essential for normal growth, development and health, and so extreme care is necessary before deciding that they are harmful. Theoretical and epidemiological evidence suggests the involvement of n-6 polyunsaturated fatty acids (PUFAs) in disease progression or prevention; however, n-6 function cannot be considered in isolation but needs to be seen as part of the complex of nutrient interactions with n-3 fatty acids (which compete for the same enzymatic pathways) and antioxidants. Insulin sensitivity might be the common factor relating disease to fatty acid metabolism both within and between the fatty acid pathways. High linoleate to arachidonate concentrations have been observed in insulin resistance, diabetic complications and some tumours, but these are multifactorial processes that include many lifestyle determinants and it is therefore wrong to condemn only n-6 fatty acids in their etiology. The results based on the criteria for assessing diet and disease are still insufficient to declare n-6 fatty acids a serious health risk; at most, the verdict should be "not proven". The question may never be conclusively answered not only because prospective dietary intervention trials (unlike those with n-3 fish oil capsules) are fraught with dosage and compliance problems, but also because of high background linoleate consumption. Tissue fatty acid composition may be a suitable biomarker for PUFA intake but there are many theoretical and methodological problems concerning other suitable markers because of the multiplicity of their biological effects. Before making evidence-based dietary recommendations, future research should consider: 1) how n-3 and n-6 dietary PUFAs affect the physiological balance (dose-response) of their derivatives such as eicosanoids and the newly-discovered fatty acid amides; 2) the metabolic interactions between n-6 and n-3 fatty acid pathways (including gene-nutrient effects); 3) the need for antioxidant cover (quantity and quality); 4) prospective intervention trials.

Topics: Animals; Arteriosclerosis; Cardiovascular Diseases; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Humans; Insulin Resistance; Linoleic Acid; Neoplasms

Very little is known about how metabolic health status, insulin resistance or metabolic challenges modulate the endocannabinoid (eCB) or polyunsaturated fatty acid (PUFA)-derived oxylipin (OxL) lipid classes. To address these questions, plasma eCB and OxL concentrations were determined at rest, 10 and 20 min during an acute exercise bout (30 min total, ~45% of preintervention V̇O

Topics: Adult; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Epoxide Hydrolases; Exercise Therapy; Female; Humans; Insulin Resistance; Linoleic Acid; Lipoxygenase; Middle Aged; Obesity; Oxylipins; Sedentary Behavior; Weight Reduction Programs

Supplementation with linoleic acid (LA; 18:2Ω6)-rich oils increases lean mass and decreases trunk adipose mass in people. Erythrocyte fatty acids reflect the dietary pattern of fatty acid intake and endogenous metabolism of fatty acids. The aim of this study is to determine the relationship of erythrocyte LA, with aspects of body composition, insulin resistance, and inflammation. Additionally, we tested for relationships of oleic acid (OA) and the sum of long chain omega-three fatty acids (LC-Ω3-SUM), on the same outcomes.. Men and women (N = 139) were evaluated for body composition, insulin resistance, and serum inflammatory markers, IL-6, and c-reactive protein (CRP) and erythrocyte fatty acid composition after an overnight fast. LA was positively related to appendicular lean mass/body mass index and inversely related to trunk adipose mass. Additionally, LA was inversely related to insulin resistance and IL-6. While there was an inverse relationship between OA or LC-Ω3-SUM with markers of inflammation, there were no relationships between OA or LC-Ω3-SUM with body composition or HOMA-IR.. Higher erythrocyte LA was associated with improved body composition, insulin resistance, and inflammation. Erythrocyte OA or LC-Ω3-SUM was unrelated to body composition and insulin resistance. There is much controversy about whether all unsaturated fats have the same benefits for metabolic syndrome and weight gain. We sought to test the strength of the relationships between three unsaturated fatty acid in erythrocytes with measurements of body composition, metabolism, and inflammation in healthy adults. Linoleic acid, but not oleic acid or the sum of long-chain omega 3 fatty acids (w3), was associated with increased appendicular lean mass and decreased trunk adipose mass and insulin resistance.

Topics: Adult; Body Composition; Body Mass Index; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Dietary Supplements; Erythrocytes; Fatty Acids, Omega-3; Female; Humans; Insulin Resistance; Interleukin-6; Linoleic Acid; Male; Middle Aged; Oleic Acid

Pentoxifylline (PTX) improved the histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical-mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH. Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadienoic acids (HODEs), oxo-octadecadienoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial. Therapy with PTX resulted in significant decreases in 9-HODE and 13-oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in nonalcoholic fatty liver disease. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis and between the decrease in HETEs and improved lobular inflammation.. Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical-mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH.

Topics: Adult; Biopsy, Needle; Blood Chemical Analysis; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Fatty Liver; Female; Follow-Up Studies; Humans; Immunohistochemistry; Insulin Resistance; Linoleic Acid; Lipid Metabolism; Lipid Peroxidation; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Patient Selection; Pentoxifylline; Prospective Studies; Reference Values; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome

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

Some studies have proposed a beneficial effect of polyunsaturated fatty acid (PUFA) intake with regard to insulin sensitivity. The aim of this study was to estimate the energy percentage and the daily PUFA intake to investigate the association between PUFAs and insulin resistance in a large sample of Brazilian adolescents.. We evaluated 37 023 adolescents ages 12 to 17 y, who were participants in ERICA (Study of Cardiovascular Risk in Adolescents). Energy percentage and PUFA daily intake were extracted from a 24-h dietary recall. The mean daily intake of total fat, median, and the respective 95% confidence intervals (95% CI) of daily intake of linoleic acid (LA), α-linolenic acid (ALA) and the ratio of LA to ALA were estimated according to sociodemographic variables. Associations of PUFA and markers of glucose homeostasis were analyzed by Poisson regression model.. Mean total fat intake was 30.1% of energy (95% CI, 29.9-30.4). Most participants met the current recommended values of PUFA and LA/ALA ratio ranging from 5:1 to 10:1 (80.9%, 95% CI, 79.8-81.8). ALA intake was inversely associated with higher waist circumference (prevalence ratio [PR], 0.996; 95% CI, 0.994-0.998). LA/ALA ratio ≥9:1 was significantly associated with higher levels of homeostasis model assessment of insulin resistance (HOMA-IR; PR, 1.01; 95% CI, 1.006-1.02), and ratio >10:1 also showed significant association with higher levels of HOMA-IR (PR, 1.02; 95% CI, 1.01-1.03) and glycated hemoglobin (PR, 1.14; 95% CI, 1.04-1.26). These associations remained significant after adjustment.. Promotion of ALA intake and balanced LA/ALA ratio should be considered as a possible health strategy aimed at contributing to better control of glucose homeostasis and insulin resistance in adolescents.

Topics: Adolescent; Brazil; Diet; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Glucose; Humans; Insulin Resistance; Linoleic Acid

Obesity is one of the risk factors concerns of colorectal cancer (CRC), the most common type of gastrointestinal cancer, due to the changing lifestyle and especially diet. There are various molecular pathways associated with obesity and the risk of CRC incidence, such as insulin resistance or elevated plasma free fatty acids, which alter the signaling pathways of intestinal epithelial cells. The aim of this study was to better understand the significance of unsaturated fatty acid biosynthesis on pathogenesis of colon cancer in obese. Based on GSE20931 dataset, obese individuals affected by CRC had higher increased gene expression than non-obese individuals. The analysis showed that in obese individuals, the 16 signaling pathway genes were activated and increased (FDR <0.05) significantly. The biosynthetic pathway of unsaturated fatty acids showed a cross-talk with the arachidonic acid metabolism pathway and the PPAR signaling pathway is influenced and regulated via these pathways. The biosynthetic pathway of unsaturated fatty acids consisting of 22 genes, were analyzed using GEO data and revealed that 4 genes (HSD17B12, TECR, FADS2, ELOVL5) from this pathway were significantly increased (FDR <0.05). These data were validated based on TCGA data (Adj.p.value <0.001). The expression level of candidate genes in HT-29 cells decreased significantly (P.value <0.01), and PPARγ expression increased under linoleic acid treatment (200 μM) compared to control cells. Moreover, in presence of linoleic acid treatment, migration, colony formation, and proliferation decreased (P.value <0.01) in presence of treatment. In summary, the Biosynthesis pathway of unsaturated fatty acids is an interesting and critical pathway in CRC.

Topics: Adipogenesis; Colorectal Neoplasms; Fatty Acids, Unsaturated; Humans; Insulin Resistance; Linoleic Acid; Obesity

Overconsumption of high-fat and cholesterol-containing diets is detrimental for metabolism and mitochondrial function, causes inflammatory responses and impairs insulin action in peripheral tissues. Dietary fatty acids can enter the brain to mediate the nutritional status, but also to influence neuronal homeostasis. Yet, it is unclear whether cholesterol-containing high-fat diets (HFDs) with different combinations of fatty acids exert metabolic stress and impact mitochondrial function in the brain. To investigate whether cholesterol in combination with different fatty acids impacts neuronal metabolism and mitochondrial function, C57BL/6J mice received different cholesterol-containing diets with either high concentrations of long-chain saturated fatty acids or soybean oil-derived poly-unsaturated fatty acids. In addition, CLU183 neurons were stimulated with combinations of palmitate, linoleic acid and cholesterol to assess their effects on metabolic stress, mitochondrial function and insulin action. The dietary interventions resulted in a molecular signature of metabolic stress in the hypothalamus with decreased expression of occludin and subunits of mitochondrial electron chain complexes, elevated protein carbonylation, as well as c-Jun N-terminal kinase (JNK) activation. Palmitate caused mitochondrial dysfunction, oxidative stress, insulin and insulin-like growth factor-1 (IGF-1) resistance, while cholesterol and linoleic acid did not cause functional alterations. Finally, we defined insulin receptor as a novel negative regulator of metabolically stress-induced JNK activation.

Topics: Animals; Brain; Cholesterol; Diet, High-Fat; Fatty Acids; Gene Expression Regulation; Homeostasis; Inflammation; Insulin; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Mitochondria; Neurons; Oxidative Stress; Palmitates; Receptor, Insulin; Soybean Oil; Stress, Physiological

This study examines to what extent plasma linoleic acid (LA) is modified by adiposity, and explores any association between plasma LA, demographics, dietary intakes, markers of metabolic health, and haplotypes of the fatty acid desaturase (FADS) 1/2 genes.. A total of 820 participants with fasting blood samples from the Irish National Adult Nutrition Survey are studied. Plasma fatty acids are determined using GC-MS. Fifteen SNPs of FADS 1/2 genes are genotyped. Plasma LA decreases, while γ-linoleic acid and dihomo-γ-linoleic acid increases in overweight/obese participants (p ≤ 0.002). Participants in the highest quartile of plasma LA show decreased plasma markers of de novo lipogenesis, insulin resistance, and of inflammation (TNF-α, PAI-1) (p ≤ 0.005). Adiposity (waist circumference and body fat) is strongly inversely associated with plasma LA accounting for 11.8% of variance observed, which is followed by FADS1/2 haplotypes (3.9%), quantity and quality of carbohydrate intakes (3.8%), dietary PUFA intakes (3.7%), systolic blood pressure (3.6%), and age (3.2%).. Plasma LA is inversely associated with adiposity, followed by haplotypes of FADS1/2 genes, carbohydrate intakes, and dietary PUFA intakes. The association observed between plasma LA and adiposity may be linked to decreased de novo lipogenesis, insulin resistance, and inflammation.

Topics: Adiposity; Adult; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Cross-Sectional Studies; Delta-5 Fatty Acid Desaturase; Fatty Acid Desaturases; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Insulin Resistance; Ireland; Linoleic Acid; Male; Middle Aged; Nutrition Surveys; Obesity; Overweight; Polymorphism, Single Nucleotide; Waist Circumference; Young Adult

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

Topics: Asian People; Blood Glucose; Body Fat Distribution; Diabetes Mellitus, Type 2; Fatty Acids; Female; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin Resistance; Intra-Abdominal Fat; Japan; Linear Models; Linoleic Acid; Male; Middle Aged; Subcutaneous Fat, Abdominal; Tomography, X-Ray Computed

While the cause of Type 2 diabetes remains poorly defined, the accumulation of reactive lipids within white adipose tissue, skeletal muscle, and liver have been repeatedly implicated as underlying mechanisms. The ability of polyunsaturated fatty acids (PUFAs) to prevent the development of insulin resistance has gained considerable interest in recent years; however, the mechanisms-of-action remain poorly described. Therefore, we determined the efficacy of diets supplemented with either linoleic acid (LA) or α-linolenic acid (ALA) in preventing insulin resistance and reactive lipid accumulation in key metabolic tissues of the obese Zucker rat. Obese Zucker rats displayed impaired glucose homeostasis and reduced n-3 and n-6 PUFA content in the liver and epididymal white adipose tissue (EWAT). After the 12-wk feeding intervention, both LA- and ALA-supplemented diets prevented whole body glucose and insulin intolerance; however, ALA had a more pronounced effect. These changes occurred in association with n-3 and n-6 accumulation in all tissues studied, albeit to different extents (EWAT > liver > muscle). Triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and sphingolipid accumulation were not attenuated in obese animals supplemented with either LA or ALA, suggesting that preservation of glucose homeostasis occurred independent of changes in reactive lipid content. However, PUFA-supplemented diets differentially altered the fatty acid composition of TAGs, DAGs, and PLs in a tissue-specific manner, suggesting essential fatty acid metabolism differs between tissues. Together, our results indicate that remodeling of the fatty acid composition of various lipid fractions may contribute to the improved glucose tolerance observed in obese rats fed PUFA-supplemented diets.

Topics: Adipose Tissue; Administration, Oral; alpha-Linolenic Acid; Animals; Dietary Fats, Unsaturated; Dietary Supplements; Fatty Acids; Glucose; Glucose Tolerance Test; Insulin Resistance; Linoleic Acid; Lipid Metabolism; Liver; Male; Muscle, Skeletal; Rats; Rats, Zucker

White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue, White; Animals; Anti-Inflammatory Agents; Cells, Cultured; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Esters; Fatty Acids, Unsaturated; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Lipopolysaccharides; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; Obesity; Phagocytosis

Maternal consumption of a high-fat diet significantly impacts the fetal environment and predisposes offspring to obesity and metabolic dysfunction during adulthood. We examined the effects of a high-fat diet during pregnancy and lactation on metabolic and inflammatory profiles and whether maternal supplementation with the anti-inflammatory lipid conjugated linoleic acid (CLA) could have beneficial effects on mothers and offspring. Sprague-Dawley rats were fed a control (CD; 10% kcal from fat), CLA (CLA; 10% kcal from fat, 1% total fat as CLA), high-fat (HF; 45% kcal from fat) or high fat with CLA (HFCLA; 45% kcal from fat, 1% total fat as CLA) diet ad libitum 10days prior to and throughout gestation and lactation. Dams and offspring were culled at either late gestation (fetal day 20, F20) or early postweaning (postnatal day 24, P24). CLA, HF and HFCLA dams were heavier than CD throughout gestation. Plasma concentrations of proinflammatory cytokines interleukin-1β and tumour necrosis factor-α were elevated in HF dams, with restoration in HFCLA dams. Male and female fetuses from HF dams were smaller at F20 but displayed catch-up growth and impaired insulin sensitivity at P24, which was reversed in HFCLA offspring. HFCLA dams at P24 were protected from impaired insulin sensitivity as compared to HF dams. Maternal CLA supplementation normalised inflammation associated with consumption of a high-fat diet and reversed associated programming of metabolic dysfunction in offspring. This demonstrates that there are critical windows of developmental plasticity in which the effects of an adverse early-life environment can be reversed by maternal dietary interventions.

Topics: Animals; Body Weight; Diet; Diet, High-Fat; Dietary Supplements; Female; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Insulin; Insulin Resistance; Interleukin-1beta; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Male; Maternal Nutritional Physiological Phenomena; Obesity; Phenotype; Pregnancy; Pregnancy, Animal; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Nowadays no researches has been performed on fatty acid profile (FA) and desaturase activity in metabolically healthy obesity (MHO). The aim of this study was to assessed gender and BMI-related difference in FA, estimated desaturase activities and the efficacy on metabolic changes produced by 2-months well-balance diet in MHO subjects.. In 103 MHO subjects (30/73 M/F; age:42.2 ± 9.5) FA, estimated desaturase activity, body composition (by DXA), Body Mass Index (BMI), lipid profile, adipokines (leptin, adiponectin, grelin, glucagon-like peptide-1), insulin resistence (by Homestasis metabolic assessment), C-reactive proteine, Atherogenic index of plasma (AIP) and Body Shape Index (ABSI) have been assessed. Gender and BMI related difference have been evaluated and the efficacy produced by 2-months well-balance diet has been considered.. At baseline, obese subjects, compared to overweight, show a significantly higher oleic (p <0.050), monounsaturated fatty acids (p <0.040), C18:0 delta-9 desaturase activity (D9D) (p <0.040) and lower linoleic acid (p <0.020), polyunsaturated fatty acids (p <0.020) and n-6 LCPUFA (p <0.010). Concerning gender-related difference, women show a significantly higher arachidonic acid (p <0.001), polyunsaturated fatty acids (p <0.001), n-6 LCPUFA (p <0.002), and lower monounsaturated fatty acids (p <0.001), D6D activity (p <0.030), C18:0 D9D (0.000) and C16:0 D9D (p <0.030). The 2-months diet was associated with a significantly increase in arachidonic acid (p = 0.007), eicosapentaenoic acid (p = 0.030), docosahexaenoic acid (p <0.001), long chain omega 3 polyunsaturated fatty acids (n-3 LCPUFA) (p <0.001), delta-5 desaturase activity (D5D) (p = 0.002), glucagon like peptide-1 (p <0.001) and a significant decrease in palmitoleic acid (p = <0.030), n-6/n-3 LCPUFA (p <0.001), insulin resistance (p = 0.006), leptin (p = 0.006), adiponectin (p <0.001), grelin (p = 0.030), CRP (p = 0.004), BMI (p <0.001) and android fat mass (p <0.001).. The balanced diet intervention was effective in improving metabolic indices.

Topics: Adiponectin; Adult; Arachidonic Acid; Body Composition; Body Mass Index; C-Reactive Protein; Delta-5 Fatty Acid Desaturase; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Fatty Acid Desaturases; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Leptin; Linoleic Acid; Male; Middle Aged; Obesity, Metabolically Benign; Sex Factors; Triglycerides

The causes of the multiple metabolic disorders of individuals with chronic kidney disease (CKD) are not fully known. We investigated the relationships between dietary fat quality, the metabolic syndrome (MetS), insulin sensitivity and inflammation in individuals with CKD.. Two population-based surveys were conducted in elderly Swedish individuals (aged 70 years) with serum cystatin C-estimated glomerular filtration rate <60 mL min(-1) /1.73 m2: the Uppsala Longitudinal Study of Adult Men (ULSAM) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) surveys. The present population comprised 274 men and 187 subjects (63% women) from the ULSAM and PIVUS cohorts, respectively.. Factor analyses of serum fatty acids were used to evaluate dietary fat quality. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance (IR) and, in ULSAM, also by euglycaemic clamp.. Factor analyses generated two fatty acid patterns of (i) low linoleic acid (LA)/high saturated fatty acid (SFA) or (ii) high n-3 polyunsaturated fatty acid (n-3 PUFA) levels. In both surveys, the low LA/high SFA pattern increased the odds of having MetS [adjusted odds ratio 0.60 [95% confidence interval (CI) 0.44-0.81] and 0.45 (95% CI 0.30-0.67) per SD decrease in factor score in the ULSAM and PIVUS surveys, respectively] and was directly associated with both IR and C-reactive protein. The n-3 PUFA pattern was not consistently associated with these risk factors.. A serum fatty acid pattern reflecting low LA and high SFA was strongly associated with MetS, IR and inflammation in two independent surveys of elderly individuals with CKD. At present, there are no specific dietary guidelines for individuals with CKD; however, these findings indirectly support current recommendations to replace SFAs with PUFAs from vegetable oils.

Topics: Aged; Aged, 80 and over; Dietary Fats; Fatty Acids; Female; Glomerular Filtration Rate; Glucose Clamp Technique; Health Surveys; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Longitudinal Studies; Male; Metabolic Syndrome; Middle Aged; Renal Insufficiency, Chronic; Sweden

The significance of erythrocyte membrane fatty acids (EMFAs) and their ratios to predict hyperglycemia and incident type 2 diabetes is unclear.. We investigated EMFAs as predictors of the worsening of hyperglycemia and incident type 2 diabetes in a 5-y follow-up of a population-based study.. We measured EMFAs in 1346 Finnish men aged 45-73 y at baseline [mean ± SD age: 55 ± 6 y; body mass index (in kg/m(2)): 26.5 ± 3.5]. Our prospective follow-up study included only men who were nondiabetic at baseline and who had data available at the 5-y follow-up visit (n = 735).. Our study showed that, after adjustment for confounding factors, palmitoleic acid (16:1n-7; P = 2.8 × 10(-7)), dihomo-γ-linolenic acid (20:3n-6; P = 2.3 × 10(-4)), the ratio of 16:1n-7 to 16:0 (P = 1.6 × 10(-8)) as a marker of stearoyl coenzyme A desaturase 1 activity, and the ratio of 20:3n-6 to 18:2n-6 (P = 9.4 × 10(-7)) as a marker of Δ(6)-desaturase activity significantly predicted the worsening of hyperglycemia (glucose area under the curve in an oral-glucose-tolerance test). In contrast, linoleic acid (18:2n-6; P = 0.0015) and the ratio of 18:1n-7 to 16:1n-7 (P = 1.5 × 10(-9)) as a marker of elongase activity had opposite associations. Statistical significance persisted even after adjustment for baseline insulin sensitivity, insulin secretion, and glycemia. Palmitoleic acid (P = 0.010) and the ratio of 16:1n-7 to 16:0 (P = 0.004) nominally predicted incident type 2 diabetes, whereas linoleic acid had an opposite association (P = 0.004), and n-3 polyunsaturated fatty acids did not show any associations.. EMFAs and their ratios are associated longitudinally with changes in glycemia and the risk type 2 diabetes.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Biomarkers; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Erythrocyte Membrane; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Finland; Follow-Up Studies; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Linear Models; Linoleic Acid; Male; Middle Aged; Prospective Studies; Risk Factors; Stearoyl-CoA Desaturase; White People

Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation.. We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt- and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine307phosphorylation - events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.. Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A.

Topics: Adult; Animals; Enzyme Activation; Fatty Acids; Humans; Insulin; Insulin Resistance; Linoleic Acid; Methylation; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle Fibers, Skeletal; Muscle, Skeletal; Oleic Acid; Palmitates; Phosphorylation; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction

Elevated circulating levels of saturated free fatty acids (sFFAs; e.g. palmitate) are known to provoke inflammatory responses and cause insulin resistance in peripheral tissue. By contrast, mono- or poly-unsaturated FFAs are protective against sFFAs. An excess of sFFAs in the brain circulation may also trigger neuroinflammation and insulin resistance, however the underlying signaling changes have not been clarified in neuronal cells. In the present study, we examined the effects of palmitate on mitochondrial function and viability as well as on intracellular insulin and nuclear factor-κB (NF-κB) signaling pathways in Neuro-2a and primary rat cortical neurons. We next tested whether oleate preconditioning has a protective effect against palmitate-induced toxicity. Palmitate induced both mitochondrial dysfunction and insulin resistance while promoting the phosphorylation of mitogen-activated protein kinases and nuclear translocation of NF-κB p65. Oleate pre-exposure and then removal was sufficient to completely block subsequent palmitate-induced intracellular signaling and metabolic derangements. Oleate also prevented ceramide-induced insulin resistance. Moreover, oleate stimulated ATP while decreasing mitochondrial superoxide productions. The latter were associated with increased levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Inhibition of protein kinase A (PKA) attenuated the protective effect of oleate against palmitate, implicating PKA in the mechanism of oleate action. Oleate increased triglyceride and blocked palmitate-induced diacylglycerol accumulations. Oleate preconditioning was superior to docosahexaenoic acid (DHA) or linoleate in the protection of neuronal cells against palmitate- or ceramide-induced cytotoxicity. We conclude that oleate has beneficial properties against sFFA and ceramide models of insulin resistance-associated damage to neuronal cells.

Topics: Animals; Cattle; Cell Line, Tumor; Cell Survival; Cerebral Cortex; Cyclic AMP-Dependent Protein Kinases; Docosahexaenoic Acids; Embryo, Mammalian; Gene Expression Regulation, Developmental; Insulin Resistance; Linoleic Acid; Mice; Mitochondria; Mitogen-Activated Protein Kinases; Neurons; Oleic Acid; Palmitic Acid; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine; Signal Transduction; Transcription Factor RelA; Transcription Factors

Because alterations in blood fatty acid (FA) composition by dietary lipids are associated with insulin resistance and related metabolic disorders, we hypothesized that serum phospholipid FA composition would reflect the early alteration of fasting glycemic status, even in people without metabolic syndrome (MetS). To examine this hypothesis, serum phospholipid FA, desaturase activities, fasting glycemic status, and cardiometabolic parameters were measured in study participants (n = 1022; 30-69 years; male, n = 527; female, n = 495; nondiabetics without disease) who were stratified into normal fasting glucose (NFG) and impaired fasting glucose (IFG) groups. Total monounsaturated FA (MUFA), oleic acid (OA; 18:1n-9), dihomo-γ-linolenic acid (DGLA; 20:3n-6), Δ-9-desaturase activity (D9D; 18:1n-9/18:0), and DGLA/linoleic acid (20:3n-6/18:2n-6) in serum phospholipids were significantly higher in IFG subjects than NFG controls. Study subjects were subdivided into 4 groups, based on fasting glucose levels and MetS status. Palmitoleic acid (16:1n-7) was highest in IFG-MetS and lowest in NFG-non-MetS subjects. Oleic acid and D9D were higher in IFG-MetS than in the other 3 groups. Dihomo-γ-linolenic acid and DGLA/linoleic acid were higher in MetS than in non-MetS, regardless of fasting glucose levels. The high-sensitivity C-reactive proteins (hs-CRPs) and 8-epi-prostaglandin-F2α were higher in IFG than in NFG, regardless of MetS status. Oxidized low-density lipoproteins were higher in IFG-MetS than in the other 3 groups. Total MUFAs, OA, and D9D were positively correlated with homeostasis model assessment of insulin resistance, fasting glucose, triglyceride, hs-CRP, and 8-epi-prostaglandin-F2α. Palmitoleic acid was positively correlated with triglyceride and hs-CRP. Lastly, total MUFA, OA, palmitoleic acid, and D9D were associated with early alteration of fasting glycemic status, therefore suggesting that these may be useful markers for predicting the risk of type 2 diabetes and cardiometabolic diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Biomarkers; Blood Glucose; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dinoprost; Fasting; Fatty Acids, Monounsaturated; Female; Humans; Insulin; Insulin Resistance; Linoleic Acid; Lipoproteins, LDL; Male; Metabolic Syndrome; Middle Aged; Oleic Acid; Phospholipids; Stearoyl-CoA Desaturase; Triglycerides

Inflammasome-mediated inflammation is a critical regulator of obesity-induced insulin resistance (IR). We hypothesized that saturated fatty acids (SFA) directly prime the NLRP3 inflammasome via TLR4 concurrent with IR. We focused on dendritic cells (DCs) (CD11c(+) CD11b(+) F4/80(-) ), which are recruited into obese adipose tissue following high-fat diet (HFD) challenge and are a key cell in inflammasome biology.. C57BL/6 mice were fed HFD for 16 weeks (45% kcal palm oil), glucose homeostasis was monitored by glucose and insulin tolerance tests. Stromal vascular fraction (SVF) cells were isolated from adipose and analyzed for CD11c(+) CD11b(+) F480(-) DC. Following coculture with bone marrow derived DC (BMDC) insulin-stimulated (3) H-glucose transport into adipocytes, IL-1β secretion and caspase-1 activation was monitored. BMDCs primed with LPS (100 ng/mL), linoleic acid (LA; 200 μM), or palmitic acid (PA; 200 μM) were used to monitor inflammasome activation. We demonstrated significant infiltration of DCs into adipose after HFD. HFD-derived DCs reduce adipocyte insulin sensitivity upon coculture co-incident with enhanced adipocyte caspase-1 activation/IL-1β secretion. HFD-derived DCs are skewed toward a pro-inflammatory phenotype with increased IL-1β secretion, IL-1R1, TLR4, and caspase-1 expression. Complementary in vitro experiments demonstrate that TLR4 is critical in propagating SFA-mediated inflammasome activation.. SFA represent metabolic triggers priming the inflammasome, promoting adipocyte inflammation/IR, suggesting direct effects of SFA on inflammasome activation via TLR4.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Carrier Proteins; Caspase 1; Coculture Techniques; Cytokines; Dendritic Cells; Diet, High-Fat; Dietary Fats; Fatty Acids; Inflammasomes; Insulin Resistance; Interleukin-1beta; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Toll-Like Receptor 4

The association of fatty acid composition with insulin resistance and type 2 diabetes has been reported in Western populations, but there is limited evidence of this association among the Japanese, whose populace consume large amounts of fish. To test the hypothesis that high palmitic, palmitoleic, and dihomo-γ-linolenic acids and low levels of linoleic and n-3 fatty acids are associated with higher insulin resistance among the Japanese, the authors investigated the relationship between serum fatty acid composition and serum C-peptide concentrations in 437 Japanese employees aged 21 to 67 years who participated in a workplace health examination. Serum cholesterol ester and phospholipid fatty acid compositions were measured by gas-liquid chromatography. Desaturase activity was estimated by fatty acid product-to-precursor ratios. A multiple regression was used to assess the association between fatty acid and C-peptide concentrations. C-peptide concentrations were associated inversely with linoleic acid levels in cholesterol ester and phospholipid (P for trend = .01 and .02, respectively) and positively with stearic and palmitoleic acids in cholesterol ester (P for trend =.02 and .006, respectively) and dihomo-γ-linolenic acid in cholesterol ester and phospholipid (P for trend < .0001 for both). C-peptide concentrations were not associated with n-3 polyunsaturated fatty acids. C-peptide concentrations significantly increased as δ-9-desaturase (16:1 n-7/16:0) and δ-6-desaturase (18:3 n-6/18:2 n-6) increased (P for trend = .01 and .03, respectively) and δ-5-desaturase (20:4 n-6/20:3 n-6) decreased (P for trend = .004). In conclusion, a fatty acid pattern with high levels of serum stearic, palmitoleic, or dihomo-γ-linolenic acids; δ-9-desaturase (16:1 n-7/16:0) or δ-6-desaturase (18:3 n-6/18:2 n-6) activities; and low levels of serum linoleic acid or δ-5-desaturase (20:4 n-6/20:3 n-6) activity might be associated with higher insulin resistance in Japanese adults.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Asian People; C-Peptide; Cholesterol Esters; Chromatography, Gas; Cross-Sectional Studies; Delta-5 Fatty Acid Desaturase; Fatty Acid Desaturases; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Female; Humans; Insulin Resistance; Linoleic Acid; Linoleoyl-CoA Desaturase; Male; Middle Aged; Multivariate Analysis; Phospholipids; Regression Analysis; Stearic Acids; Stearoyl-CoA Desaturase; Young Adult

In addition to decreased insulin sensitivity, diabetes is a pathological condition associated with increased inflammation. The ω-3 fatty acids have been proposed as anti-inflammatory agents. Thus, the major goal of this study was to analyze the effects of fatty acid supplementation on both insulin sensitivity and inflammatory status in an animal model of type 2 diabetes. Diabetic rats (Goto-Kakizaki model) were treated with eicosapentaenoic acid (EPA) or linoleic acid at 0.5 g/kg body weigh (bw) dose. In vivo incorporation of (14)C-triolein into adipose tissue was improved by the ω-3 administration. In vitro incubations of adipose tissue slices from EPA-treated rats showed an increase in (14)C-palmitate incorporation into the lipid fraction. These observations were linked with a decreased rate of fatty acid oxidation. EPA treatment resulted in a decreased fatty acid oxidation in incubated strips from extensor digitorum longus (EDL) muscles. The changes in lipid utilization were associated with a decrease in insulin plasma concentration, suggesting an improvement in insulin sensitivity. These changes in lipid metabolism were associated with an activation of AMP-activated protein kinase (AMPK) in white adipose tissue. In addition, EPA treatment resulted in a decreased content of peroxisome proliferator-activated receptor-α (PPARα) and PPARδ and in increased GLUT4 expression in skeletal muscle. Moreover, EPA increased 2-deoxy-D-[(14)C]glucose (2-DOG) uptake in C2C12 myotubes, suggesting an improvement in glucose metabolism. Concerning the inflammatory status, EPA treatment resulted in a decreased gene expression for both tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) both in skeletal muscle and adipose tissue. The data suggest that EPA treatment to diabetic rats clearly improves lipid metabolism although the evidences on insulin sensitization are less clear.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Lipid Metabolism; Male; Muscle, Skeletal; Rats

Obesity with excessive levels of circulating free fatty acids (FFAs) is tightly linked to the incidence of type 2 diabetes. Insulin resistance of peripheral tissues and pancreatic β-cell dysfunction are two major pathological changes in diabetes and both are facilitated by excessive levels of FFAs and/or glucose. To gain insight into the mitochondrial-mediated mechanisms by which long-term exposure of INS-1 cells to excess FFAs causes β-cell dysfunction, the effects of the unsaturated FFA linoleic acid (C 18:2, n-6) on rat insulinoma INS-1 β cells was investigated. INS-1 cells were incubated with 0, 50, 250 or 500 μM linoleic acid/0.5% (w/v) BSA for 48 h under culture conditions of normal (11.1 mM) or high (25 mM) glucose in serum-free RPMI-1640 medium. Cell viability, apoptosis, glucose-stimulated insulin secretion, Bcl-2, and Bax gene expression levels, mitochondrial membrane potential and cytochrome c release were examined. Linoleic acid 500 μM significantly suppressed cell viability and induced apoptosis when administered in 11.1 and 25 mM glucose culture medium. Compared with control, linoleic acid 500 μM significantly increased Bax expression in 25 mM glucose culture medium but not in 11.1 mM glucose culture medium. Linoleic acid also dose-dependently reduced mitochondrial membrane potential (ΔΨm) and significantly promoted cytochrome c release from mitochondria in both 11.1 mM glucose and 25 mM glucose culture medium, further reducing glucose-stimulated insulin secretion, which is dependent on normal mitochondrial function. With the increase in glucose levels in culture medium, INS-1 β-cell insulin secretion function was deteriorated further. The results of this study indicate that chronic exposure to linoleic acid-induced β-cell dysfunction and apoptosis, which involved a mitochondrial-mediated signal pathway, and increased glucose levels enhanced linoleic acid-induced β-cell dysfunction.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Survival; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Gene Expression Regulation; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Linoleic Acid; Membrane Potential, Mitochondrial; Mitochondria; Osmolar Concentration; Proto-Oncogene Proteins c-bcl-2; Rats; RNA, Messenger; Time Factors

The present study investigates whether excessive fat accumulation and hyperinsulinaemia during catch-up growth on high-fat diets are altered by n-6 and n-3 PUFA derived from oils rich in either linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA) or DHA. It has been shown that, compared with food-restricted rats refed a high-fat (lard) diet low in PUFA, those refed isoenergetically on diets enriched in LA or ALA, independently of the n-6:n-3 ratio, show improved insulin sensitivity, lower fat mass and higher lean mass, the magnitude of which is related to the proportion of total PUFA precursors (LA+ALA) consumed. These relationships are best fitted by quadratic regression models (r2>0·8, P < 0·001), with threshold values for an impact on body composition corresponding to PUFA precursors contributing 25-30 % of energy intake. Isoenergetic refeeding on high-fat diets enriched in AA or DHA also led to improved body composition, with increases in lean mass as predicted by the quadratic model for PUFA precursors, but decreases in fat mass, which are disproportionately greater than predicted values; insulin sensitivity, however, was not improved. These findings pertaining to the impact of dietary intake of PUFA precursors (LA and ALA) and their elongated-desaturated products (AA and DHA), on body composition and insulin sensitivity, provide important insights into the search for diets aimed at counteracting the pathophysiological consequences of catch-up growth. In particular, diets enriched in essential fatty acids (LA and/or ALA) markedly improve insulin sensitivity and composition of weight regained, independently of the n-6:n-3 fatty acid ratio.

Topics: alpha-Linolenic Acid; Analysis of Variance; Animals; Arachidonic Acids; Body Composition; Docosahexaenoic Acids; Food, Fortified; Glucose Tolerance Test; Insulin Resistance; Linoleic Acid; Malnutrition; Rats; Rats, Sprague-Dawley; Refeeding Syndrome; Regression Analysis

Plasma leptin and adiponectin, and membrane phospholipid fatty acid composition are implicated into the mechanism of insulin resistance but no clear pattern has emerged. Hence, this study examined these variables in subjects presenting to the diabetic clinic for a diagnostic glucose tolerance test.. Body composition, glucose, glycated hemoglobin, insulin, leptin, adiponectin, and red cell and plasma phospholipid fatty acids were assessed from 42 normal and 28 impaired glucose tolerant subjects. Insulin sensitivity was determined by homeostatic model assessment.. The plasma phosphatidylcholine fatty acid composition of the impaired glucose tolerant subjects was similar to that of normal subjects. However, the impaired glucose tolerant subjects had significantly lower linoleic (P<0.05), eicosapentaenoic (P<0.05) and docosahexaenoic (P<0.01) acids in the red cell phosphatidylcholine and phosphatidylethanolamine compared with the normal subjects. Moreover, red cell phosphatidylcholine docosahexaenoic acid correlated positively with adiponectin (r=0.290, P<0.05) but negatively with leptin (r=-0.252, P<0.05), insulin (r=-0.335, P<0.01) and insulin resistance (r=-0.322, P<0.01). Plasma triglycerides, leptin and glucose combined predicted about 60% of variation in insulin level whereas insulin was the only component that predicted the membrane fatty acids.. We postulate that membrane phospholipids fatty acids have an indirect role in determining insulin concentration but insulin has a major role in determining membrane fatty acid composition.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Cell Membrane; Docosahexaenoic Acids; Erythrocytes; Fatty Acids; Fatty Acids, Omega-3; Female; Glucose Intolerance; Glycerophospholipids; Humans; Insulin; Insulin Resistance; Leptin; Linoleic Acid; Male; Middle Aged; Triglycerides

Data on intake of oleic acid (OA) and insulin resistance (IR) are inconsistent. We investigated whether OA in serum phosphatidylcholine relates to surrogate measures of IR in dyslipidaemic subjects from a Mediterranean population.. Cross-sectional study of 361 non-diabetic subjects (205 men, 156 women; mean age 44 and 46 y, respectively; BMI 25.7 kg/m(2)). IR was diagnosed by BMI and HOMA values using published criteria validated against the euglycemic clamp. Alternatively, IR was defined by the 75th percentile of HOMA-IR of our study population. The fatty acid composition of serum phosphatidylcholine was determined by gas-chromatography.. The mean (±SD) proportion of OA was 11.7 ± 2.0%. Ninety-two subjects (25.5%) had IR. By adjusted logistic regression, including the proportions of other fatty acids known to relate to IR, the odds ratios (OR) (95% confidence intervals) for IR were 0.75 (0.62-0.92) for 1% increase in OA and 0.84 (0.71-0.99) for 1% increase in linoleic acid. Other fatty acids were unrelated to IR. When using the alternate definition of IR, OA remained a significant predictor (0.80 [0.65-0.99]).. Higher phospholipid proportions of OA relate to less IR, suggesting an added benefit of increasing olive oil intake within the Mediterranean diet.

Topics: Adult; Biomarkers; Body Mass Index; Cross-Sectional Studies; Diet, Mediterranean; Dyslipidemias; Female; Fruit; Glucose Clamp Technique; Humans; Insulin Resistance; Linoleic Acid; Male; Middle Aged; Olea; Oleic Acid; Olive Oil; Phosphatidylcholines; Phospholipids; Plant Oils; Spain

Thiazolidinediones are insulin sensitizing drugs that target the peroxisome proliferator-activated receptor (PPAR) gamma. An n-hexane extract of the flowers of Echinacea purpurea was found to activate PPARgamma without stimulating adipocyte differentiation. Bioassay-guided fractionations yielded five alkamides, of which one was new, and three fatty acids that all activated PPARgamma. The new alkamide hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutylamide (5) was identified by analysis of spectroscopic data and found to activate PPARgamma with no concurrent stimulation of adipocyte differentiation. Compound 5 was further shown to increase insulin-stimulated glucose uptake. The data suggest that flowers of E. purpurea contain compounds with potential to manage insulin resistance and type 2 diabetes.

Topics: 3T3-L1 Cells; Animals; Denmark; Diabetes Mellitus, Type 2; Echinacea; Fatty Acids, Unsaturated; Flowers; Glucose; Insulin Resistance; Mice; Plants, Medicinal; PPAR gamma

Mice are increasingly used in studies where measuring insulin sensitivity (IS) is a common procedure. The glucose clamp is labor intensive, cannot be used in large numbers of animals, cannot be repeated in the same mouse, and has been questioned as a valid tool for IS in mice; thus, the minimal model with 50-min intravenous glucose tolerance test (IVGTT) data was adapted for studies in mice. However, specific software and particular ability was needed. The aim of this study was to establish a simple procedure for evaluating IS during IVGTT in mice (CS(I)). IVGTTs (n = 520) were performed in NMRI and C57BL/6J mice (20-25g). After glucose injection (1 g/kg), seven samples were collected for 50 min for glucose and insulin measurements, analyzed with a minimal model that provided the validated reference IS (S(I)). By using the regression CS(I) = alpha(1) + alpha(2) x K(G)/AUC(D), where K(G) is intravenous glucose tolerance index and AUC(d) is the dynamic area under the curve, IS was calculated in 134 control animals randomly selected (regression CS(I) vs. S(I): r = 0.66, P < 0.0001) and yielded alpha(1) = 1.93 and alpha(2) = 0.24. K(G) is the slope of log (glucose(5-20)) and AUC(D) is the mean dynamic area under insulin curve in the IVGTT. By keeping fixed alpha(1) and alpha(2), CS(I) was validated in 143 control mice (4.7 +/- 0.2 min*microU(-1)*ml(-1), virtually identical to S(I): 4.7 +/- 0.3, r = 0.89, P < 0.0001); and in 123 mice in different conditions: transgenic, addition of neuropeptides, incretins, and insulin (CS(I): 6.0 +/- 0.4 vs. S(I): 6.1 +/- 0.4, r = 0.94, P < 0.0001). In the other 120 animals, CS(I) revealed its ability to segregate different categories, as does S(I). This easily usable formula for calculating CS(I) overcomes many experimental obstacles and may be a simple alternative to more complex procedures when large numbers of mice or repeated experiments in the same animals are required.

Topics: Animals; Blood Glucose; Galanin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Injections, Intravenous; Insulin; Insulin Resistance; Linoleic Acid; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Models, Biological; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide

Preeclampsia has many characteristics similar to the metabolic syndrome. One of these is aberrant lipid metabolism. We studied free fatty acid (FFA) profiles at baseline and after oral glucose load in 21 preeclamptic and 11 normotensive pregnant women. Insulin sensitivity was measured by intravenous glucose tolerance test. We found that serum total FFA concentrations at baseline were 67% higher in preeclamptic than in normotensive pregnancies (P=0.0002). The difference between the two groups was largest in the concentrations of oleic (75%), linoleic (129%) and arachidonic (315%) acids. Oral intake of glucose suppressed total FFA in preeclamptic women by 40% (95% CI 32.1-46.1%, P<0.0001) but only 24% in control women (95% CI 0.01-42.0%, P=0.045). Insulin sensitivity, which in preeclamptic women was 37% lower (P=0.009), was unrelated to total or any individual FFA concentration. We concluded that preeclamptic women have higher circulating FFA concentrations, which despite insulin resistance are suppressed by oral glucose loading.

Topics: Arachidonic Acid; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Linoleic Acid; Oleic Acid; Pre-Eclampsia; Pregnancy

To analyze the effects of high-fat high-sucrose (HFHS) feeding, energy restriction, and trans-10,cis-12 conjugated linoleic acid (CLA) on visfatin and apelin.. A randomized dietary intervention study.. Free-living individuals studied in metabolic cages.. Thirty-two male Syrian Golden hamsters (82.6 +/- 1.4 g).. Standard and HFHS feeding for 7 weeks. After that, some hamsters fed the HFHS diet were submitted for 3 weeks to a 25% energy restriction with or without trans-10,cis-12 CLA supplementation (0.5%).. Feeding animals an HFHS diet resulted in increased body fat and reduced insulin sensitivity. No changes were observed in the expression and serum levels of visfatin and apelin, or in peroxisome proliferator-activated receptor (PPAR)gamma and Sirt1 expression. Energy restriction reduced body fat and normalized insulin sensitivity. Visfatin showed increased serum levels without changes in expression. No modifications were found as far as apelin was concerned. Sirt1 expression was increased, and PPARgamma remained unchanged. With regard to trans-10,cis-12 CLA, no changes were induced by its addition to the restricted diet.. Insulin function impairment induced by HFHS feeding is not mediated by visfatin and apelin. However, visfatin can play a role in improving insulin sensitivity associated with energy restriction. These results suggest that visfatin may not have evolved as a molecule that reserves the action of insulin when food is widely available, but rather that its function seems to be associated with energy restriction adaptation. In general terms, trans-10,cis-12 CLA did not modify changes induced by energy restriction.

Topics: Adipose Tissue; Analysis of Variance; Animals; Body Weight; Carrier Proteins; Cricetinae; Dietary Fats; Dietary Sucrose; Enzyme-Linked Immunosorbent Assay; Insulin; Insulin Resistance; Leptin; Linoleic Acid; Male; Mesocricetus; Nicotinamide Phosphoribosyltransferase; PPAR gamma; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction

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

To study the effects of conjugated linoleic acid (CLA) on expression of glucose transporter 4 (GLUT4) protein in skeletal muscle of insulin resistant rat, and explore the mechanism of resisting diabetes by CLA.. Male Wistar rats were randomly separated into control group, high-fat group and high fat plus CLA group (0.75 g%, 1.50 g%, 3.00 g% by deit weight), and the effects of CLA on blood glucose and insulin levels of insulin resistant rat were observed , by using Western blot technique to measure the expression level of GLUT4 protein in skeletal muscle of insulin resistant rat.. The serum insulin and glucose levels of obese rats were (11.11 +/- 2.73) microU/ml, and (5.09 +/- 0.66) mmol/L, the supplement of CLA might decrease the hyperinsulinemia and hyperglycemia, and in CLA groups (0.75 g%, 1.50 g%, 3.00 g% by deit weight) the serum insulin was (6.99 +/- 1.77) microU/ml, (7.36 +/- 1.48) microU/ml and (7.85 +/- 1.60) microU/ml (P < 0.05), and the glucose levels were (4.28 +/- 0.72) mmol/L, (4.18 +/- 0.55) mmol/L (P < 0.05), (4.06 +/- 0.63) mmol/L (P < 0.05) respectively. The expression of GLUT4 protein in skeletal muscle of rat fed with high fat diet were decreased as compared with those fed with basic deit, and CLA might increase the expression of GLUT4 protein in skeletal muscle fed with high fat diet.. CLA improve the insulin resistance of obese rat, possibly acting through increasing the expression of GLUT4 protein in skeletal muscle of rat fed with high fat diet.

Topics: Animals; Blood Glucose; Glucose Transporter Type 4; Insulin; Insulin Resistance; Linoleic Acid; Male; Random Allocation; Rats; Rats, Wistar

While conjugated linoleic acid (CLA) has received a great deal of attention as a supplement that can favourably modify body composition, its potential impact on insulin sensitivity has not received equal attention. The aim of the present work was to analyse the effects of trans-10,cis-12 CLA isomer on insulin sensitivity in hamsters fed an atherogenic diet. Hamsters were divided into three groups: one group was fed a chow diet (control) and the other two a semipurified atherogenic diet supplemented with 0.5% linoleic acid (LA) or trans-10,cis-12 CLA, respectively. Serum glucose, FFAs, insulin, leptin and adiponectin were measured using commercial kits. HOMA-IR was calculated using the formula of Matthews et al. PPARgamma mRNA was assessed in epididymal adipose tissue by reverse transcription-polymerase chain reaction (RT-PCR). After 6 weeks, atherogenic feeding produced an increase in body fat accumulation as compared with control feeding. The addition of trans-10,cis-12 CLA to the atherogenic diet avoided this feature. Atherogenic feeding also led to significantly higher serum concentrations of glucose, insulin, FFAs, as well as greater HOMA-IR values. trans-10,cis-12 CLA did not prevent these effects. No significant differences were found among experimental groups in serum leptin and adiponectin concentrations, nor in PPARgamma expression. In summary, although the addition of trans-10,cis-12 CLA to an atherogenic diet reduces fat accumulation, it does not improve the impairment of insulin action associated with this feeding. The maintenance of insulin resistance in hamsters fed the atherogenic CLA-enriched diet is probably due to the high serum FFA concentration observed in these animals.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Blood Glucose; Cricetinae; Diet; Diet, Atherogenic; Dietary Fats, Unsaturated; Epididymis; Fatty Acids, Nonesterified; Insulin; Insulin Resistance; Leptin; Linoleic Acid; Linoleic Acids, Conjugated; Male; Mesocricetus; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

Topics: Animals; Blood Glucose; Ceramides; Diglycerides; Fatty Acids; Fatty Acids, Omega-6; Gene Expression Regulation, Enzymologic; Glucose Tolerance Test; Insulin; Insulin Resistance; Linoleic Acid; Lipid Metabolism; Lipids; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Palmitates; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stearoyl-CoA Desaturase; Triglycerides

Increased lipid availability is associated with diminished insulin-stimulated glucose uptake and glycogen synthesis in muscle, but it is not clear whether alterations in glycogen synthase activity itself play a direct role. Because intracellular localization of this enzyme is involved in its regulation, we investigated whether fat oversupply causes an inhibitory redistribution. We examined the recovery of glycogen synthase in subcellular fractions from muscle of insulin-resistant, fat-fed rats and chow-fed controls, either maintained in the basal state or after a euglycaemic-hyperinsulinaemic clamp. Although glycogen synthase protein and activity were mostly recovered in an insoluble fraction, insulin caused translocation of activity from the smaller soluble pool to the insoluble fraction. Fat-feeding, which led to a reduction in glycogen synthesis during the clamp, was associated with a depletion in the soluble pool, consistent with an important role for this component. A similar depletion was also observed in cytosolic fractions of muscles from obese db/db mice, another model of lipid-induced insulin resistance. To investigate this in more detail, we employed lipid-pretreated L6 myotubes, which exhibited a reduction in insulin-stimulated glycogen synthesis independently of alterations in glucose flux or insulin signalling through protein kinase B. In control cells, insulin caused redistribution of a minor cytosolic pool of glycogen synthase to an insoluble fraction, which was again forestalled by lipid pretreatment. Glycogen synthase recovered in the insoluble fraction from pre-treated cells exhibited a low fractional velocity that was not increased in response to insulin. Our results suggest that the initial localization of glycogen synthase in a soluble pool plays an important role in glycogen synthesis, and that its sequestration in an insulin-resistant insoluble pool may explain in part the reduced glycogen synthesis caused by lipid oversupply.

Topics: Animals; Biological Transport; Cell Line; Cell Membrane; Cells, Cultured; Cytosol; Dietary Fats; Glucose; Glucose Clamp Technique; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Immunoblotting; Insulin; Insulin Resistance; Linoleic Acid; Mice; Mice, Obese; Muscle Fibers, Skeletal; Neptune; Rats; Rats, Wistar

This study describes the effect of substituting dietary linoleic acid (18:2 n-6) with alpha-linolenic acid (18:3 n-3) on sucrose-induced insulin resistance (IR). Wistar NIN male weanling rats were fed casein based diet containing 22 energy percent (en%) fat with approximately 6, 9 and 7 en% saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) respectively for 3 months. IR was induced by replacing starch (ST) with sucrose (SU). Blends of groundnut, palmolein, and linseed oil in different proportions furnished the following levels of 18:3 n-3 (g/100 g diet) and 18:2 n-6/18:3 n-3 ratios respectively: ST-220 (0.014, 220), SU-220 (0.014, 220), SU-50 (0.06, 50), SU-10 (0.27, 10) and SU-2 (1.1, 2). The results showed IR in the sucrose fed group (SU-220) as evidenced by increase in fasting plasma insulin and area under the curve (AUC) of insulin in response to oral glucose load. In SU-220, the increase in adipocyte plasma membrane cholesterol/phospholipid ratio was associated with a decrease in fluidity, insulin stimulated glucose transport, antilipolytic effect of insulin and increase in basal and norepinephrine stimulated lipolysis in adipocytes. In SU-50, sucrose induced alterations in adipocyte lipolysis and antilipolysis were normalized. However, in SU-2, partial corrections in plasma insulin, AUC of insulin and adipocyte insulin stimulated glucose transport were observed. Further, plasma triglycerides and cholesterol decreased in SU-2. In diaphragm phospholipids, the observed dose dependent increase in long chain (LC) n-3 PUFA was associated with a decrease in LC-n-6 PUFA but insulin stimulated glucose transport increased only in SU-2. Thus, this study shows that the substitution of one-third of dietary 18:2 n-6 with 18:3 n-3 (SU-2) results in lowered blood lipid levels and increases peripheral insulin sensitivity, possibly due to the resulting high LCn-3 PUFA levels in target tissues of insulin action. These findings suggest a role for 18:3 n-3 in the prevention of insulin resistant states. The current recommendation to increase 18:3 n-3 intake for reducing cardiovascular risk may also be beneficial for preventing IR in humans.

Topics: Adipocytes; alpha-Linolenic Acid; Animals; Biological Transport, Active; Blood Glucose; Cardiovascular Diseases; Cell Membrane; Diaphragm; Dietary Fats; Glucose; Insulin; Insulin Resistance; Linoleic Acid; Lipolysis; Male; Norepinephrine; Rats; Rats, Wistar; Sucrose

Conjugated linoleic acids (CLA) affect atherogenesis, but mechanisms are not well understood. We explored how two isomers of CLA, cis9, trans11-CLA and trans10, cis12-CLA, affected lipid and glucose metabolism, as well as hepatic protein expression, in apolipoprotein E knockout mice. After 12 wk of intervention, plasma triglyceride, NEFA, and glucose concentrations were significantly higher in the trans10, cis12-CLA group, whereas plasma triglyceride, NEFA, glucose, and insulin concentrations were significantly lower in the cis9, trans11-CLA group, compared with control mice consuming linoleic acid. Proteomics identified significant up- or down-regulation of 113 liver cytosolic proteins by either CLA isomer. Principal component analysis revealed that the treatment effect of cis9, trans11-CLA was mainly explained by the up-regulation of different posttranslational forms of heat shock protein 70 kD. In contrast, the treatment effect of trans10, cis12-CLA was mainly explained by up-regulation of key enzymes in the gluconeogenic, beta-oxidation, and ketogenesic pathways. Correlation analysis again emphasized the divergent effects of both CLA isomers on different pathways, but also revealed a linkage between insulin resistance and increased levels of hepatic serotransferrin. Thus, our systems biology approach provided novel insights into the mechanisms by which individual CLA isomers differentially affect pathways related to atherogenesis, such as insulin resistance and inflammation.

Topics: Animal Feed; Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Blotting, Western; Body Composition; Body Weight; Cytosol; Diet; Fatty Acids; Genetic Linkage; Glucose; HSP70 Heat-Shock Proteins; Inflammation; Insulin; Insulin Resistance; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Male; Mice; Mice, Knockout; Oxygen; Perfusion; Principal Component Analysis; Proteomics; Systems Biology; Triglycerides

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of insulin, nonesterified fatty acids (NEFAs), and lipoprotein remnants. Extracellular matrix proteoglycan (PG) alterations are also common in macro- and microvascular complications of type 2 diabetes. In liver, extracellular heparan sulfate (HS) PGs contribute to the uptake of triglyceride-rich lipoprotein remnants. We found that HepG2 cells cultured with 10 or 50 nmol/l insulin or 300 micromol/l albumin-bound linoleic acid changed their PG secretion. The glycosaminoglycans (GAGs) of the secreted PGs from insulin-treated HepG2 cells were enriched in chondroitin sulfate (CS) PGs. In contrast, cells exposed to linoleic acid secreted PGs with decreased content of CS. Insulin caused a moderate increase in mRNA for versican (secreted CS PG), whereas linoleic acid markedly decreased mRNA for versican in HepG2 cells, as did the peroxisomal proliferator-activated receptor-alpha agonist bezafibrate. The effects of insulin or linoleic acid on syndecan 1, a cell surface HS PG, were similar to those on versican, but less pronounced. The livers of obese Zucker fa/fa rats, which are insulin-resistant and have high levels of insulin, NEFAs, and triglyceride-rich remnants, showed increased expression of CS PGs when compared with lean littermates. These changes in PG composition decreased the affinity of remnant beta-VLDL particles to PGs isolated from insulin-treated HepG2 cells and obese rat livers. The results indicated that insulin and NEFAs modulate the expression of PGs in hepatic cells. We speculate that in vivo this exchange of CS for HS may reduce the clearance of remnant beta-VLDLs and contribute to the dyslipidemia of insulin resistance.

Topics: Animals; Cell Line; Extracellular Matrix; Fatty Acids; Humans; Hyperlipidemias; Insulin; Insulin Resistance; Linoleic Acid; Lipoproteins, VLDL; Liver; Obesity; Proteoglycans; Rats; Rats, Zucker; Thinness

Relationships have been demonstrated between insulin sensitivity and the fatty acid (FA) composition of serum and tissue lipids in adult humans. The present study aimed to investigate the above relationships in different groups of type 2 diabetic patients (DM2). The FA composition of serum phospholipids (S-PL) measured by gas liquid chromatography and insulin action during a 2-step hyperinsulinemic isoglycemic clamp (1 and 10 mU/kg. min) were determined in 21 newly diagnosed DM2 subjects (DMN), in groups of long-term DM2 patients treated with hypoglycemic agents (DMH; n = 21) or diet alone (DMD; n = 11), and in 24 healthy subjects (HS). In diabetics, the metabolic clearance rates of glucose at both insulin levels (MCR(glu)submax and MCR(glu)max) were significantly reduced compared with HS (MCR(glu)submax DMN, 5.35 +/- 2.7 mL x kg(-1) x min(-1), DMH, 5.38 +/- 2.17 mL x kg(-1) x min(-1); DMD, 5.48 +/- 2.35 mL x kg(-1) x min(-1) v HS, 10.9 +/- 3.3 mL x kg(-1) x min(-1); P <.01; MCR(glu)max DMN, 13.3 +/- 3.3 mL x kg(-1) x min(-1); DMH, 12.5 +/- 3.0 mL x kg(-1) x min(-1); DMD, 13.3 +/- 3.0 mL x kg(-1) x min(-1) v HS, 17.4 +/- 3.8 mL x kg(-1) x min(-1); P <.05). Increased contents of highly unsaturated n-6 family FA (P <.01), arachidonic acid in particular (DMN, 10.98% +/- 1.79%; DMD, 10.78% +/- 1.64%; DMH, 10.97% +/- 1.7% v HS, 8.51% +/- 1.53%; P <.001), were found in all groups of diabetics compared with HS, while lower levels of linoleic acid were seen in DMN (P <.001) and DMH (P <.05). The contents of saturated FA and monounsaturated FA were comparable in HS, DMN, and DMD. While in HS there were significant negative correlations between MCR(glu) and the contents of saturated FA and a positive association between insulin action and proportions of linoleic and arachidonic acids, no significant relationships were found in diabetic subjects. Different groups of DM2 patients show an altered FA pattern of S-PL, which is not related to insulin action. The above data support the hypothesis that changes in FA composition may play a role in modulating insulin action in peripheral tissues, but cannot explain the insulin resistance (IR) in DM2 patients.

Topics: Adult; Arachidonic Acid; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Kinetics; Linoleic Acid; Male; Metabolic Clearance Rate; Middle Aged; Phospholipids

Insulin resistance can be induced by diets high in simple carbohydrates or fatty acids. To determine whether these nutrients also affect arterial pressure in genetic models of salt sensitive and salt resistant hypertension, Dahl salt sensitive (S) and salt resistant (R) rats were each fed the following isocaloric diets containing 3% NaCl for 4 weeks (10 rats/group): 1) control; 2) high sucrose (60%); 3) high linoleic acid (LA, provided as 10% safflower oil); and 4) high sucrose plus high LA. Tail systolic blood pressures (SBP) were measured weekly, and at 4 weeks, direct mean arterial pressures (MBP) were measured in conscious animals. Insulin sensitivity was assessed by in vitro uptake of tritiated glucose by adipocytes in response to graded doses of insulin. Weight gain did not differ among groups. High sucrose alone and high LA alone did not affect blood pressure in either strain. However, SBP and MBP were increased (P < .05) by the high sucrose plus high LA diet in Dahl-S but not in Dahl-R rats. Sucrose alone and LA alone decreased (P < .05) insulin sensitivity in Dahl-S and Dahl-R rats. In both strains, sucrose plus LA decreased insulin sensitivity to a greater extent (P < .05) than sucrose alone or LA alone. Thus, the sucrose plus LA diet decreased insulin sensitivity in both Dahl-S and Dahl-R rats, whereas blood pressure was increased only in Dahl-S rats. The phenotype of elevated arterial pressure is influenced both by a genetic-nutrient interaction and by an interaction among specific nutrients resulting in insulin resistance.

Topics: Adipocytes; Animals; Blood Glucose; Blood Pressure; Dietary Fats, Unsaturated; Dietary Sucrose; Disease Models, Animal; Follow-Up Studies; Hypertension; Insulin; Insulin Resistance; Linoleic Acid; Male; Rats; Rats, Inbred Dahl; Sodium Chloride

Coronary artery disease (CAD), hypertension and diabetes mellitus are more common in Indians compared to their incidence in the Western population. The exact reason for this is not known. One of the risk factors for the development of and complications due to CAD, hypertension and diabetes mellitus could be hyperinsulinemia and insulin resistance and low plasma levels of arachidonic acid and eicosapentaenoic acid, metabolites of dietary essential fatty acids (EFAs), cis-linoleic and alpha-linolenic acids. Fatty acid analysis of the plasma phospholipid (PL) fraction of normal Indians showed that they have low concentrations of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid in comparison to those seen in Canadian and Minnesota (USA) normals. Since insulin can activate EFA metabolism, this alteration in the EFA metabolism may, at least, in part explain the high incidence of CAD, hypertension and diabetes mellitus and insulin resistance and hyperinsulinemia that are common in Indians.

Topics: Adult; alpha-Linolenic Acid; Arachidonic Acid; Coronary Disease; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Essential; Female; Humans; Hypertension; India; Insulin; Insulin Resistance; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Risk Factors; White People

The incidence of obesity, noninsulin-dependent diabetes mellitus (NIDDM), hypertension, and coronary artery disease has increased in the developed world. At the same time, major changes in the type and amount of fatty acid intake have occurred over the past 40-50 years, reflected in increases in saturated fat (from both animal sources and hydrogenated vegetable sources), trans fatty acids, vegetable oils rich in linoleic acid, and an overall decrease in long chain polyunsaturated fatty acids (arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid--C20-C22). Recent findings that C20-C22 in muscle membrane phospholipids are inversely related to insulin resistance, whereas linoleic acid is positively related to insulin resistance, suggest that diet may influence the development of insulin resistance in obesity, insulin-dependent diabetes mellitus (IDDM), hypertension, and coronary artery disease (including asymptomatic atherosclerosis and microvascular angina). These conditions are known to have genetic determinants and have a common abnormality in smooth muscle response and insulin resistance. It is proposed that the current diet influences the expression of insulin resistance in those who are genetically predisposed. Therefore, clinical investigations are needed to evaluate if lowering or preventing insulin resistance through diet by increasing arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, while lowering linoleic acid and decreasing trans fatty acids from the diet, will modify or prevent the development of these diseases.

Topics: Animals; Coronary Disease; Diabetes Mellitus, Type 1; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Humans; Hypertension; Insulin Resistance; Linoleic Acid; Linoleic Acids; Models, Biological; Obesity; Vegetables

We altered the cellular lipid composition of an insulin sensitive rat hepatoma cell line through supplementation of the culture medium with linoleic acid (18:2) or 25-hydroxycholesterol, and we studied the effects on insulin stimulation of aminoacid transport system A and glycogen synthesis. The basal rate of sodium-dependent aminoisobutyric acid uptake was slightly reduced in hydroxysterol-treated cells and increased in 18:2-enriched cells. Maximal insulin stimulation of transport was decreased by about 40% in both 18:2 and 25-hydroxycholesterol modified cells, as compared to control cells. In addition to reduced responsiveness, the hydroxysterol-treated cells also showed a diminished sensitivity to insulin, as revealed by a right-shift of the dose-response curve leading to a ED50 of 1.2 X 10(-8) M (P less than 0.02), as compared to 2.45 X 10(-9) M in control cells and 2.13 X 10(-9) M in 18:2 enriched cells. Concerning glycogen synthesis, the basal rate was unaffected by 25-hydroxycholesterol supplementation and slightly reduced in cells enriched in 18:2. Maximal insulin stimulation of glycogen synthesis was reduced by about 40% in both types of lipid modified cells. 25-Hydroxycholesterol again provoked a decrease in sensitivity to insulin: the ED50 was enhanced to 4.9 X 10(-9) M (P less than 0.05), as compared to 1.25 X 10(-9) M in control cells and 1.57 X 10(-9) M in 18:2-supplemented cells. Taken together with the previously reported changes of insulin binding to lipid modified hepatoma cells (Bruneau et al. (1987) Biochim. Biophys. Acta 928, 287-296) our results demonstrate an influence of alterations of the cellular lipid composition on both binding and biological actions of insulin, leading to an insulin-resistant state. Divergences between insulin binding and action were obtained and it was suggested that post-binding events may be responsible for the observed changes. Our findings may be relevant to experimental and clinical states of insulin resistance.

Topics: Amino Acids; Animals; Biological Transport; Hydroxycholesterols; Insulin; Insulin Resistance; Kinetics; Linoleic Acid; Linoleic Acids; Liver; Liver Glycogen; Liver Neoplasms, Experimental; Membrane Fluidity; Membrane Lipids; Rats; Receptor, Insulin; Sodium