8-11-14-eicosatrienoic-acid and Hyperglycemia

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

Cytochrome P-450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play important roles in regulating cardiovascular functions. The anti-inflammatory, antiapoptotic, proangiogenic, and antihypertensive properties of EETs suggest a beneficial role for EETs in diabetic nephropathy. Endogenous EET levels are maintained by a balance between synthesis by CYP epoxygenases and hydrolysis by epoxide hydrolases into physiologically less active dihydroxyeicosatrienoic acids. Genetic disruption of soluble epoxide hydrolase (sEH/EPHX2) results in increased EET levels through decreased hydrolysis. This study investigated the effects of sEH gene disruption on diabetic nephropathy in streptozotocin-induced diabetic mice. Streptozotocin-induced diabetic manifestations were attenuated in sEH-deficient mice relative to wild-type controls, with significantly decreased levels of Hb A(1c), creatinine, and blood urea nitrogen and urinary microalbumin excretion. The sEH-deficient diabetic mice also had decreased renal tubular apoptosis that coincided with increased levels of antiapoptotic Bcl-2 and Bcl-xl, and decreased levels of the proapoptotic Bax. These effects were associated with activation of the PI3K-Akt-NOS3 and AMPK signaling cascades. sEH gene inhibition and exogenous EETs significantly protected HK-2 cells from TNFα-induced apoptosis in vitro. These findings highlight the beneficial role of the CYP epoxygenase-EETs-sEH system in the pathogenesis of diabetic nephropathy and suggest that the sEH inhibitors available may be potential therapeutic agents for this condition.

Topics: 8,11,14-Eicosatrienoic Acid; Albuminuria; Animals; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Transformed; Cytoplasm; Diabetic Nephropathies; Disease Models, Animal; Epoxide Hydrolases; Gene Silencing; Humans; Hyperglycemia; Kidney Cortex; Kidney Tubules, Proximal; Mice; Molecular Targeted Therapy; RNA, Small Interfering; Signal Transduction; Streptozocin; Tumor Necrosis Factor-alpha

The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-beta1 increases glomerular permeability to albumin (P(alb)), whereas 20-HETE and EETs reduce P(alb). To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-beta1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-beta1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-beta1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-beta1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.

Topics: 8,11,14-Eicosatrienoic Acid; Amino Acids; Animals; Clofibrate; Cytochrome P-450 CYP4A; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epoxide Hydrolases; Epoxy Compounds; Hydroxyeicosatetraenoic Acids; Hyperglycemia; Hyperlipidemias; Kidney; Kidney Glomerulus; Male; Polymerase Chain Reaction; Protein Isoforms; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Streptozocin; Transforming Growth Factor beta1