12-hydroxy-5-8-10-14-eicosatetraenoic-acid and Diabetes-Mellitus--Type-1

To investigate the relationship between serum 12-Hydroxyeicosatetraenoic acid (12-HETE) and diabetic retinopathy (DR) in children with type 1 diabetes mellitus (T1DM) and adults with type 2 diabetes mellitus (T2DM).. Children from the Shanghai Children and Adolescent Diabetes Eye (SCADE) study and adults from the Shanghai Cohort Study of Diabetic Eye Disease (SCODE) were examined in 2021. Serum 12-HETE levels were detected and compared. Multivariate logistic regression was used to analyze the relationship between 12-HETE and the rate of DR in diabetic patients.. The child study included 4 patients with new-onset DR and 24 patients with T1DM without DR. In children with T1DM, the 12-HETE level was significantly higher in those with DR (P = 0.003). The adult study had two sets, for testing and verification. The test set included 28 patients with new-onset DR and 24 T2DM patients with a course of ≥ 20 years who had never developed DR. The verification set included 41 patients with DR, 50 patients without DR and 50 healthy controls. In the adult test set, the 12-HETE level was significantly higher in patients with DR than in those with T2DM without DR (P = 0.003). In the verification set, the 12-HETE level of patients with DR was significantly higher than that of patients without DR (P < 0.0001) and the healthy controls (P < 0.0001). Multivariate logistic regression indicated that 12-HETE was independently associated with DR in both children (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00-1.13, P = 0.041) and adults (test set [OR 9.26, 95% CI 1.77-48.59, P = 0.008], verification set [OR 10.49, 95% CI 3.23-34.05, P < 0.001]).. Higher serum 12-HETE levels are positively correlated with an increased risk of DR in children with T1DM and adults with T2DM.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Child; China; Cohort Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Risk Factors

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Biomarkers; Child; Diabetes Mellitus, Type 1; Humans

(1) BACKGROUND: 12-lipoxygenase (12-LO) is involved in the development of diabetic nephropathy (DN). In the present study, we investigated whether 12-LO inhibition may ameliorate type-2 DN (T2DN) by interfering with insulin resistance (IR); (2) METHODS: Rat glomerular mesangial cells, glomeruli and skeletal muscles were isolated and used in this study. Kidney histological changes were confirmed by periodic-acid Schiff staining; mRNA expression was detected by competitive reverse transcription polymerase chain reaction; and the protein level was determined by Western blot and the enzyme-linked immunosorbent assay, respectively; (3) RESULTS: The inhibition of 12-LO attenuated microalbuminuria (MAU) increases in type-2 diabetic rats, but not in type-1 diabetic rats. Infusion of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) significantly increased the expression of angiotensin II (Ang II) and Ang II type 1 receptor (AT1R), but decreased the expression of AT1R-associated protein (ATRAP) in rat glomeruli, compared to the control. An in vitro study revealed that both 12(S)-HETE and insulin upregulated AT1R expression in rat mesangial cells. In the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, the 12(S)-HETE-induced ATRAP reduction was significantly abolished. Interestingly, 12-LO inhibition did not influence AT1R expression in type-1 diabetic rats, but significantly abolished the increased AT1R and Ang II expression in glomeruli of type-2 diabetic rats. Furthermore, the inhibition of 12-LO significantly corrected impaired insulin sensitivity and fast serum insulin level, as well as the p-AMP-activated protein kinase (AMPK) reduction in skeletal muscle of type-2 diabetic rats; (4) CONCLUSION: The inhibition of 12-LO potentially ameliorated MAU by preventing IR through the downregulation of glomerular AT1R expression in T2DN.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Albuminuria; Animals; Arachidonate 12-Lipoxygenase; Cells, Cultured; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Down-Regulation; Insulin Resistance; Kidney Glomerulus; Lipoxygenase Inhibitors; Male; Muscle, Skeletal; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1

Angiotensin II and its type 1 receptor (AT1R) play important roles in the pathogenesis of renal disease and diabetic nephropathy. The 12/15-lipoxygenase pathway of arachidonate metabolism and its lipid products have also been implicated in diabetic nephropathy. However, it is unclear whether 12/15-lipoxygenase regulates expression of AT1R. In cultured rat mesangial cells, we found that the 12/15-lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) increased AT1R mRNA and protein expression, primarily by stabilizing AT1R mRNA. Pretreatment with 12(S)-HETE also amplified the signaling effects of angiotensin II, likely due to the increased AT1R expression. Levels of AT1R protein expression decreased when 12/15-lipoxygenase was knocked down with specific short hairpin RNA (shRNA) compared with control cells. Similarly, levels of the AT1 receptor, but not the AT2 receptor, were significantly lower in mesangial cells and glomeruli derived from 12/15-lipoxygenase knockout mice compared with control mice. Reciprocally, stable overexpression of 12/15-lipoxygenase increased AT1R expression in cultured mesangial cells. In vivo, modified siRNA targeting 12/15-lipoxygenase reduced glomerular AT1R expression in a diabetic mouse model. Interestingly, angiotensin II induced greater levels of 12/15-lipoxygenase, TGF-beta1, and fibronectin (FN) in AT1R-overexpressing mesangial cells compared with control cells. Therefore, oxidized lipids generated by the 12/15-lipoxygenase-mediated metabolism of arachidonic acid can enhance AT1R expression in mesangial cells and augment the profibrotic effects of angiotensin II.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Angiotensin II; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Cells, Cultured; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Lipid Metabolism; Mesangial Cells; Mice; Mice, Inbred C57BL; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Messenger; RNA, Small Interfering; Up-Regulation

Vitamin E content and biosynthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) have been measured in platelets from type I diabetic subjects and age- and sex-matched, nondiabetic control subjects. Platelets from diabetic subjects synthesized significantly greater quantities of 12-HETE than did platelets from control subjects when 12-HETE synthesis was induced by thrombin or collagen, either in the presence or absence of indomethacin. Platelet conversion of exogenously added arachidonic acid (AA) to 12-HETE was not significantly different between the diabetic and control groups in the absence of indomethacin, although a small but significant increase in the conversion of AA to 12-HETE was present in the diabetic group platelets when indomethacin was added to the reaction. Vitamin E content was significantly reduced in platelets from the diabetic subjects, when compared with platelets from the control subjects, although plasma vitamin E levels were not significantly different between the two groups. Thrombin- and collagen-induced platelet 12-HETE synthesis demonstrated a significant negative linear correlation with platelet vitamin E content when measurements from both diabetic and control groups were combined. The above data suggest a relationship between low vitamin E content and increased 12-HETE synthesis in platelets from type I diabetic subjects.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Chromatography, High Pressure Liquid; Collagen; Diabetes Mellitus, Type 1; Female; Humans; Hydroxyeicosatetraenoic Acids; Male; Middle Aged; Radioimmunoassay; Thrombin; Vitamin E