8-hydroxylinoleic-acid and 13-hydroxy-9-11-octadecadienoic-acid

Oxidative stress plays a key role in the development of type 2 diabetes. However, it is still unknown what kind of oxidative stress underlies the development of type 2 diabetes. We investigated hydroxyoctadecadienoic acid (HODE) isomers, which have been proposed as a biomarker for evaluating oxidative stress in vivo, during the development of diabetes in Tsumura Suzuki Obese Diabetes (TSOD) mouse, a type 2 diabetes model. It was revealed that glucose tolerance and insulin resistance index HOMA-IR in TSOD mice at 5 weeks of age were approximately normal, namely, the mice were in the prediabetic state, but these levels were significantly exacerbated from 8 weeks of age compared with those in Tsumura Suzuki Non Obesity (TSNO) mice (control). Concomitantly, the plasma levels of free-radical-mediated oxidation products, 9- and 13-(E,E)-HODE and 7β-hydroxycholesterol, in TSOD mice were significantly higher than those in TSNO mice at 8, and 8 and 11 weeks of age, respectively. Interestingly, the plasma levels of 10- and 12-(Z,E)-HODE, which are produced specifically by singlet-oxygen-mediated oxidation, in TSOD mice were higher than those in TSNO mice only at 5 weeks of age, and not at 8, 11, and 13 weeks of age. We demonstrated that singlet-oxygen-mediated oxidation occurred in TSOD mice before development of the diabetic phenotypes, including impaired glucose tolerance and insulin resistance. These results suggest that excessive singlet-oxygen-mediated oxidation plays an important role in the pathogenesis of type 2 diabetes.

Topics: Animals; Biomarkers; Diabetes Mellitus, Type 2; Disease Models, Animal; Free Radicals; Glucose Intolerance; Insulin Resistance; Linoleic Acids; Linoleic Acids, Conjugated; Male; Mice; Mice, Inbred Strains; Mice, Obese; Oxidative Stress; Singlet Oxygen

13-Hydroxyoctadecadienoic acid (13-HODE), hydroxylinoleic acid, is a major lipoxygenase metabolite which is produced by myeloid inflammatory cells and modifies inflammatory cell activity. The biological effects of 13-HODE in non-haemopoietic cells (HUVEC) have been attributed to the incorporation of 13-HODE into 13-HODE containing diacylglycerol and the selective inhibition of protein kinase C. Our studies, using whole promyeloid cells (HL60) and recombinant PKC isoenzymes in an in vitro assay, showed that 13-HODE inhibited PKC-alpha, beta1, and PKC-betall, but did not affect the activity of PKC-delta. These data suggest that the actions of hydroxylinoleic acid on myeloid cells include the selective inhibition of classical PKC isoenzymes.

Topics: Cell Membrane; Cytosol; Enzyme Activation; HL-60 Cells; Humans; Isoenzymes; Linoleic Acids; Lipoxygenase; Precipitin Tests; Protein Kinase C; Recombinant Proteins; Signal Transduction; Tetradecanoylphorbol Acetate; Time Factors