8-11-14-eicosatrienoic-acid and Diabetes-Mellitus--Type-2

Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action of P450 epoxygenases (CYP2C and CYP2J). Effects of EETs are limited by hydrolysis by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. Studies in rodent models provide compelling evidence that epoxyeicosatrienoic acids exert favorable effects on glucose homeostasis, either by enhancing pancreatic islet cell function or by increasing insulin sensitivity in peripheral tissues. Specifically, the tissue expression of soluble epoxide hydrolase appears to be increased in rodent models of obesity and diabetes. Pharmacological inhibition of epoxide hydrolase or deletion of the gene encoding soluble epoxide hydrolase (Ephx2) preserves islet cells in rodent models of type 1 diabetes and enhances insulin sensitivity in models of type 2 diabetes, as does administration of epoxyeicosatrienoic acids or their stable analogues. In humans, circulating concentrations of epoxyeicosatrienoic acids correlate with insulin sensitivity, and a loss-of-function genetic polymorphism in EPHX2 is associated with insulin sensitivity.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin Resistance; Mice; Signal Transduction

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Body Mass Index; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Fatty Acids, Nonesterified; Female; Humans; Male; Middle Aged

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians.. We measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts.. We observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose.. In this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms.. US National Institutes of Health.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Disease Susceptibility; Female; Glucose; Humans; Insulin; Male; Middle Aged; Risk Assessment; Risk Factors; Young Adult

Diabetes mellitus is a metabolic disorder that can lead to blood-brain barrier (BBB) disruption and cognitive decline. However, the mechanisms of BBB breakdown in diabetes are still unclear. Soluble epoxide hydrolase (sEH) is an enzyme that degrades epoxyeicosatrienoic acids (EETs), which have multiple protective effects on vascular structure and functions. In the current study, we showed increased vascular permeability of the BBB, which was accompanied by upregulation of sEH and downregulation of 14,15-EET. Moreover, the sEH inhibitor t-AUCB restored diabetic BBB integrity in vivo, and 14,15-EET prevented ROS accumulation and MEC injury in vitro. t-AUCB or 14,15-EET treatment provoked AMPK/HO-1 activation under diabetic conditions in vivo and in vitro. Thus, we suggest that decreased EET degradation by sEH inhibition might be a potential therapeutic approach to attenuate the progression of BBB injury in diabetic mice via AMPK/HO-1 pathway activation.

Topics: 8,11,14-Eicosatrienoic Acid; AMP-Activated Protein Kinases; Animals; Blood-Brain Barrier; Diabetes Mellitus, Type 2; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Heme Oxygenase-1; Male; Membrane Proteins; Mice; Oxidative Stress; Protective Agents; Reactive Oxygen Species; Signal Transduction

Objective To clarify the associations between serum omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acid (PUFA) levels and obesity-related metabolic abnormalities in patients with type 2 diabetes. Methods and Materials Data from 225 Japanese patients with type 2 diabetes were cross-sectionally analyzed. The serum levels of n-6 PUFAs [dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA)] and n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) were measured, and the estimated Δ-5 desaturase (D5D) activity was calculated based on the AA to DGLA ratio. The associations between the composition of PUFAs and obesity-related parameters, including the body mass index (BMI), waist circumference, alanine amino transferase (ALT) level, homeostatic model assessment of insulin resistance (HOMA-IR), and body fat percentage, as measured by a bioelectrical impedance analysis, were analyzed. Results Among the PUFAs, the DGLA level had the strongest correlations with BMI (p<0.001), waist circumference (p<0.001), ALT level (p<0.001), HOMA-IR (p<0.001), and body fat percentage (p<0.01). AA was positively correlated and D5D was negatively correlated with several obesity-related parameters, while n-3 PUFAs did not have a constant correlation. A multivariate regression analysis revealed that the DGLA level was an independent determinant for HOMA-IR (β=0.195, p=0.0066) after adjusting for sex, age, BMI, and the ALT, triglyceride, and HbA1c levels. Conclusion A high serum DGLA level was associated with obesity, body fat accumulation, a high ALT level, and insulin resistance in patients with type 2 diabetes. The measurement of the serum PUFA levels may be useful for evaluating metabolic abnormalities and estimating the dietary habits of patients.

Topics: 8,11,14-Eicosatrienoic Acid; Adipose Tissue; Adult; Aged; Aged, 80 and over; Asian People; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Male; Middle Aged; Multivariate Analysis; Obesity

Vasculogenic erectile dysfunction (VED) is considered as a common complication among people with type 2 diabetes (T2D). We tested whether changes in fatty acid (FAs) classes measured in erythrocytes are associated with increased risk of diabetic VED along with related risk factors.. We assessed erythrocyte FAs composition, lipid peroxidation parameters and inflammatory cytokines among 72 T2D men with VED, 78 T2D men without VED and 88 healthy volunteers with similar age. Biochemical, hepatic, lipid and hormonal profiles were measured.. T2D people with VED had significant decrease in the indexes of Δ6-desaturase and elongase activities compared to the other studied groups. The same group of participants displayed lower erythrocytes levels of dihomo-γ-linolenic acid (C20:3n-6) (P < .001), precursor of the messenger molecule PGE1 mainly involved in promoting erection. Moreover, absolute SFAs concentration and HOMA IR levels were higher in T2D people with VED when compared to controls and associated with impaired NO concentration (1.43 vs 3.30 ng/L, P < .001). Our results showed that IL-6 and TNF-α were significantly increased and positively correlated with MDA levels only in T2D people with VED (r = 0.884, P = .016 and r = 0.753, P = .035; respectively) suggesting a decrease in the relative availability of vasodilator mediators and an activation of vasoconstrictors release.. Our findings show that the deranged FAs metabolism represents a potential marker of VED in progress, or at least an indicator of increased risk within men with T2D.

Topics: 8,11,14-Eicosatrienoic Acid; Acetyltransferases; Aged; Alprostadil; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Erythrocytes; Fatty Acid Elongases; Gene Expression; Humans; Impotence, Vasculogenic; Interleukin-6; Linoleoyl-CoA Desaturase; Lipid Metabolism; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Tumor Necrosis Factor-alpha

The role of n-6 (ω-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations.. We investigated the associations of serum n-6 PUFAs and activities of enzymes involved in PUFA metabolism, Δ5 desaturase (D5D) and Δ6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations.. The study included 2189 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y and free of T2D at baseline in 1984-1989. T2D was assessed by self-administered questionnaires, by fasting and 2-h oral-glucose-tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline, and by record linkage to the hospital discharge registry and the reimbursement register on diabetes medication expenses. Multivariate-adjusted Cox proportional hazards regression models were used to analyze associations.. During the average follow-up of 19.3 y, 417 men developed T2D. Those with higher estimated D5D activity (extreme-quartile HR: 0.55; 95% CI: 0.41, 0.74; P-trend < 0.001) and higher concentrations of total n-6 PUFAs (HR: 0.54; 95% CI: 0.41, 0.73; P-trend < 0.001), linoleic acid (LA; HR: 0.52; 95% CI: 0.39, 0.70; P-trend < 0.001), and arachidonic acid (AA; HR: 0.62; 95% CI: 0.46, 0.85; P-trend = 0.007) had a lower risk and those with higher concentrations of γ-linolenic acid (GLA; HR: 1.28; 95% CI: 0.98, 1.68; P = 0.021) and dihomo-γ-linolenic acid (DGLA; HR: 1.38; 95% CI: 1.04, 1.84; P-trend = 0.005) and higher D6D activity had a higher (HR: 1.50; 95% CI: 1.14, 1.97; P-trend < 0.001) multivariate-adjusted risk of T2D. Zinc mainly modified the association with GLA on T2D risk, with a higher risk observed among those with serum zinc concentrations above the median (P-interaction = 0.04).. Higher serum total n-6 PUFA, LA, and AA concentrations and estimated D5D activity were associated with a lower risk of incident T2D, and higher GLA and DGLA concentrations and estimated D6D activity were associated with a higher risk. In addition, a higher serum zinc concentration modified the association of GLA on the risk of T2D.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Arachidonic Acid; Diabetes Mellitus, Type 2; Fatty Acids, Omega-6; Finland; Follow-Up Studies; gamma-Linolenic Acid; Glucose Tolerance Test; Humans; Linoleic Acid; Linoleoyl-CoA Desaturase; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Proportional Hazards Models; Prospective Studies; Risk Factors; Zinc

Increasing evidences support that metabolically healthy obese (MHO) is a transient state. However, little is known about the early markers associated with the development of metabolic abnormalities in MHO individuals. Serum free fatty acids (FFAs) profile is highlighted in its association with obesity-related insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). To examine the association of endogenous fatty acid metabolism with future development of metabolic abnormalities in MHO individuals, we retrospectively analyzed 24 [product FFA]/[precursor FFA] ratios in fasting sera and clinical data from 481 individuals who participated in three independent studies, including 131 metabolic healthy subjects who completed the 10-year longitudinal Shanghai Diabetes Study (SHDS), 312 subjects cross-sectionally sampled from the Shanghai Obesity Study (SHOS), and 38 subjects who completed an 8-week very low carbohydrate diet (VLCD) intervention study. Results showed that higher baseline level of oleic acid/stearic acid (OA/SA), and lower levels of stearic acid/palmitic acid (SA/PA) and arachidonic acid/dihomo-γ-linolenic acid (AA/DGLA) ratios were associated with higher rate of MHO to MUO conversion in the longitudinal SHDS. Further, the finding was validated in the cross-sectional and interventional studies. This panel of FFA ratios could be used for identification and early intervention of at-risk obese individuals.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Arachidonic Acid; Area Under Curve; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Fatty Acids, Nonesterified; Female; Humans; Logistic Models; Longitudinal Studies; Male; Middle Aged; Obesity; Oleic Acid; Palmitic Acid; Retrospective Studies; ROC Curve; Stearic Acids

Cytochrome P450 metabolites of arachidonic acid (AA) belong to eicosanoids and are potent lipid mediators of inflammation. It is well-known that eicosanoids play an important role in numerous pathophysiological processes. Therefore, quantitative analysis of cytochrome P450 metabolites of AA, including hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatreinoic acids (EETs), and dihydroxyeicosatrienoic acids (DHETs) can provide crucial information to uncover underlying mechanisms of cytochrome P450 metabolites of AA related diseases. Herein, we developed a highly sensitive method to identify and quantify HETEs, EETs, and DHETs in lipid extracts of biological samples based on stable isotope probe labeling coupled with ultra high-performance liquid chromatography/mass spectrometry. To this end, a pair of stable isotope probes, 2-dimethylaminoethylamine (DMED) and d4-2-dimethylaminoethylamine (d4-DMED), were utilized to facilely label eicosanoids. The heavy labeled eicosanoid standards were prepared and used as internal standards for quantification to minimize the matrix and ion suppression effects in mass spectrometry analysis. In addition, the detection sensitivities of DMED labeled eicosanoids improved by 3-104 folds in standard solution and 5-138 folds in serum matrix compared with unlabeled analytes. Moreover, a good separation of eicosanoids isomers was achieved upon DMED labeling. The established method provided substantial sensitivity (limit of quantification at sub-picogram), high specificity, and broad linear dynamics range (3 orders of magnitude). We further quantified cytochrome P450 metabolites of AA in rat liver, heart, brain tissues and human serum using the developed method. The results showed that 19 eicosanoids could be distinctly detected and the contents of 11-, 15-, 16-, 20-HETE, 5,6-EET, and 14,15-EET in type 2 diabetes mellitus patients and 5-, 11-, 12-, 15-, 16-, 20-HETE, 8,9-EET, and 5,6-DHET in myeloid leukemia patients had significant changes, demonstrating that these eicosanoids may have important roles on the pathogenesis of type 2 diabetes mellitus and myeloid leukemia.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Brain; Case-Control Studies; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Deuterium; Diabetes Mellitus, Type 2; Eicosanoids; Humans; Hydroxyeicosatetraenoic Acids; Isotope Labeling; Leukemia, Myeloid; Liver; Male; Myocardium; Organ Specificity; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

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

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

Eicosanoids derived from omega-6 (n6) polyunsaturated fatty acids (PUFAs) have proinflammatory functions whereas eicosanoids derived from omega-3 (n3) PUFAs have anti-inflammatory properties. This study was designed to evaluate the effect of insulin analog initiation therapy on n6 and n3 PUFAs in type 2 diabetic patients during early phase.. Sixteen type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of arachidonic acid (AA, C20:4n6), dihomo-gamma-linolenic acid (DGLA, C20:3n6), eicosapentaenoic acid (EPA, C20:5n3) and docosahexaenoic acid (DHA, C22:6n3) were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Prostaglandin E2 (PGE2) was measured in serum samples by enzyme immunoassay.. All measured PUFAs were significantly increased after treatment with insulin analogs plus metformin compared to before treatment levels. The mean AA/EPA ratio was significantly lower after treatment with insulin analogs plus metformin. A 22% decrease was observed in PGE2 levels after treatment with insulin analogs plus metformin compared to pretreatment levels (p > 0.05).. The significant decrease in AA/EPA ratio indicates that insulin analog initiation therapy has anti-inflammatory properties by favoring the increase of n3 fatty acid EPA.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Arachidonic Acid; Chromatography, Liquid; Diabetes Mellitus, Type 2; Dinoprostone; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Tandem Mass Spectrometry

Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10⁻⁹) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10⁻⁵). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10⁻⁵) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10⁻⁷) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10⁻⁷) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Arachidonic Acid; Black or African American; Delta-5 Fatty Acid Desaturase; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Family Health; Fatty Acid Desaturases; Female; Gene Frequency; Genetic Association Studies; Humans; Linkage Disequilibrium; Male; Metabolic Syndrome; Middle Aged; Multigene Family; Polymorphism, Single Nucleotide; Siblings; United States; White People

We have demonstrated over a decade ago that hepoxilins cause the release of insulin from isolated pancreatic islets of Langerhans in vitro. However, no studies are available so far to indicate whether these compounds are active in vivo. The present study is the first to our knowledge which demonstrates that hepoxilins administered intra-arterially in the anaesthetized rat cause the release of insulin in the circulation. This release is dependent on the glucose status of the rat. Hence, animals fasted overnight do not respond to hepoxilin administration, while animals that have had free access to food respond to hepoxilins with a rise in insulin concentrations in blood. The hepoxilin effect is rapid and varies with different hepoxilins, the most potent of which is hepoxilin A(3) (HxA(3)) (both the 8S and the 8R enantiomers). Administration of 100 microg HxA(3) produces a rise in blood insulin equivalent to that caused by the administration of 5 mg glucose. In view of earlier evidence showing that these compounds cause a rise in intracellular calcium levels in vitro at a <1 microg/ml concentration through a receptor-mediated mechanism, we speculate that the actions of hepoxilins in causing the release of insulin from the pancreas may be due to alterations in calcium levels within the beta-cell. We believe that hepoxilins may represent new lead compounds as therapeutics in type II diabetes mellitus.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Diabetes Mellitus, Type 2; Drug Design; Insulin; Insulin Secretion; Islets of Langerhans; Male; Rats; Rats, Wistar; Secretory Rate; Stimulation, Chemical

Lipid-lowering fibrate drugs are known to affect the synthesis of fatty acids, which may alter the prostacyclin synthesis in diabetic patients. Therefore, the serum levels of precursor fatty acids and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha) were determined in ten hyperlipidemic patients with Type 2 diabetes before and after administration of gemfibrozil (900 mg/day) for 3 months, in comparison with the results in seven non-diabetic hyperlipidemic patients. Gemfibrozil significantly reduced the serum concentration of dihomo-7-linolenic acid, total cholesterol and triglycerides, but did not affect the serum levels of arachidonic acid and 6-keto PGF1alpha in diabetic and non-diabetic patients. Thus, gemfibrozil did not affect the synthesis of prostacyclin in spite of the reduction of precursor fatty acids in diabetic and non-diabetic patients.

Topics: 6-Ketoprostaglandin F1 alpha; 8,11,14-Eicosatrienoic Acid; Aged; Arachidonic Acid; Cholesterol; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Time Factors; Triglycerides

This investigation was undertaken to study whether the risk to develop non-insulin-dependent diabetes mellitus (NIDDM) among 50-year-old men during a 10-year follow-up period was related to the fatty acid composition of their serum cholesterol esters. There were highly significant differences in the initial health survey between the fatty acid composition in serum in subjects who remained normoglycemic (n = 1,753) and in those who later developed NIDDM (n = 75). The main differences were that the latter had higher proportions of saturated fatty acids and palmitoleic acid (16:1 omega-7), a low proportion of linoleic acid (18:2 omega-6), and a relatively high content of gamma-linolenic (18:3 omega-6) and dihomo-gamma-linolenic (20:3 omega-6) acids in the serum cholesterol esters. The picture was similar also after adjusting for differences in body mass index. In a logistic model, a high proportion of dihomo-gamma-linolenic acid remained a significant contributor to the development of diabetes, along with the height of the insulin index, the blood glucose concentration at 60 min, and the fasting insulin concentration. The increased risk to develop NIDDM related to the serum cholesterol ester fatty acid composition may be mediated by diet and/or genetic factors.

Topics: 8,11,14-Eicosatrienoic Acid; Blood Glucose; Cholesterol Esters; Cohort Studies; Diabetes Mellitus, Type 2; Fatty Acids; Follow-Up Studies; Humans; Insulin; Logistic Models; Male; Middle Aged; Risk Factors