leukotriene-b4 and Diabetes-Mellitus--Type-1

Topics: Adult; Aged; Aging; Alcoholism; Amino Acids; Anesthetics, Local; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Aqueous Humor; Autonomic Nervous System; Biological Transport, Active; Brain Chemistry; Cardiac Glycosides; Catecholamines; Cell Differentiation; Central Nervous System; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Epidermal Growth Factor; Eye; Fibrinolysis; Glaucoma; Granuloma; Graves Disease; Hallucinogens; Humans; Hypertension; Immunity, Cellular; Infant; Infant, Newborn; Leukotriene B4; Metabolism, Inborn Errors; Multiple Sclerosis; Muscle Relaxation; Nutritional Physiological Phenomena; Oxygen; Oxygen Consumption; Pigment Epithelium of Eye; Pineal Gland; Prostaglandin Antagonists; Prostaglandins; Psychotropic Drugs; Retina; Retinal Degeneration; Serotonin; Smoking; SRS-A; Stress, Physiological; Water-Electrolyte Balance

The effects of dietary supplementation with omega-3-polyunsaturated fatty acids (omega-3-PUFA) on the proliferative response of PBMC and on the secretion of monokines and arachidonic acid metabolites from PBMC and monocytes (Mo) from healthy subjects and patients with recent-onset insulin-dependent diabetes mellitus (IDDM) were examined. Three groups of eight to nine healthy individuals were randomized to either 2.0 g/day or 4.0 g/day of omega-3-PUFA devoid of vitamins A and D, or an isocaloric amount of placebo. Furthermore, eight patients with recent-onset IDDM received 4.0 g/day of omega-3-PUFA. IL-1 beta production and TNF-alpha secretion was determined before and after 7 weeks of treatment, and 10 weeks after withdrawal of treatment. Significant increases in platelet and PBMC membrane eicosapentaenoic acid was found in omega-3-PUFA-treated individuals. omega-3-PUFA treatment significantly reduced the content of IL-1 beta in lysates of PBMC, but did not affect PBMC or Mo secretion of IL-1 beta, TNF-alpha or prostaglandin E2 (PGE2) or PBMC leukotriene B4 (LTB4) secretion in healthy subjects or in IDDM patients. A significant inhibition of the PHA-stimulated, but not the spontaneous or PPD-stimulated, proliferative response of PBMC was observed in healthy and diabetic subjects treated with omega-3-PUFA. No correlation was found between PHA-stimulated PBMC proliferation and PBMC secretion of TNF-alpha and IL-1 beta. There were no significant differences in the spontaneous or the PPD- or PHA-stimulated proliferative responses of PBMC between diabetic and healthy individuals at entry. We conclude that although dietary supplementation with 4.0 g/day of omega-3-PUFA inhibits the proliferation of PBMC and reduces IL-1 beta immunoreactivity in PBMC and Mo, it does not alter monokine, PGE2 or LTB4, secretion in healthy or IDDM subjects.

Topics: Adult; Blood Glucose; Blood Sedimentation; Cell Division; Diabetes Mellitus, Type 1; Dinoprostone; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Humans; Interleukin-1; Leukocyte Count; Leukocytes, Mononuclear; Leukotriene B4; Lipopolysaccharides; Male; Monocytes; Monokines; Phenylenediamines; Phytohemagglutinins; Tumor Necrosis Factor-alpha

Serum levels of leukotriene-B4 (LTB4) are increased in type 1 diabetes (T1D) and it mediates systemic inflammation and macrophage reprogramming associated with this condition. Herein, we investigated the involvement of LTB4 in adiposity loss, hyperlipidemia, and changes in macrophage metabolism in a mouse model of streptozotocin-induced T1D. LTB4 receptor (BLT1) antagonist u75302 was employed to block LTB4 effects. As expected, hypoinsulinemia in T1D was associated with hyperglycemia, low levels of glucagon, hyperlipidemia, significant body fat loss, and increased white adipose tissue expression of Fgf21, a marker for lipolysis. With the exception of hyperglycemia and hypoglucagonemia, blockade of LTB4 signaling reverted these parameters in T1D mice. Along with hyperlipidemia, macrophages from T1D mice exhibited higher lipid uptake and accumulation. These cells also had enhanced glycolysis and oxidative metabolism and these parameters were dependent on the mitochondrial uncoupling respiration, as evidenced by elevated expression of oxidation markers carnitine palmitoyltransferase and uncoupling protein 1. Interestingly, all these parameters were at least partially reverted in T1D mice treated with u75302. Altogether, these findings suggest that in T1D mice LTB4/BLT1 is involved in the fat loss, hyperlipidemia, and increased macrophage lipid uptake and metabolism with an important involvement of mitochondrial uncoupling activity. These previously unrecognized LTB4/BLT1 functions may be explored in future to therapeutically alleviate severity of hyperlipidemia and systemic inflammation in T1D.

Topics: Adiposity; Animals; Biomarkers; Diabetes Mellitus, Type 1; Down-Regulation; Energy Metabolism; Fatty Acids; Glycolysis; Hyperlipidemias; Leukotriene B4; Lipogenesis; Liver; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Signal Transduction; Uncoupling Protein 1

Type 1 diabetes mellitus (T1DM) is associated with chronic systemic inflammation and enhanced susceptibility to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations in T1DM trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B4 (LTB4), which triggers systemic inflammation that may increase susceptibility to polymicrobial sepsis. Consistent with chronic inflammation, peritoneal macrophages from two mouse models of T1DM had greater abundance of the adaptor MyD88 (myeloid differentiation factor 88) and its direct transcriptional effector STAT-1 (signal transducer and activator of transcription 1) than macrophages from nondiabetic mice. Expression of Alox5, which encodes 5-LO, and the concentration of the proinflammatory cytokine interleukin-1β (IL-1β) were also increased in peritoneal macrophages and serum from T1DM mice. Insulin treatment reduced LTB4 concentrations in the circulation and Myd88 and Stat1 expression in the macrophages from T1DM mice. T1DM mice treated with a 5-LO inhibitor had reduced Myd88 mRNA in macrophages and increased abundance of IL-1 receptor antagonist and reduced production of IL-β in the circulation. T1DM mice lacking 5-LO or the receptor for LTB4 also produced less proinflammatory cytokines. Compared to wild-type or untreated diabetic mice, T1DM mice lacking the receptor for LTB4 or treated with a 5-LO inhibitor survived polymicrobial sepsis, had reduced production of proinflammatory cytokines, and had decreased bacterial counts. These results uncover a role for LTB4 in promoting sterile inflammation in diabetes and the enhanced susceptibility to sepsis in T1DM.

Topics: Analysis of Variance; Animals; Arachidonate 5-Lipoxygenase; Chromatin Immunoprecipitation; Cytokines; Diabetes Mellitus, Type 1; Female; Gene Expression Regulation; Immunoblotting; Inflammation; Inflammation Mediators; Insulin; Leukotriene B4; Macrophages; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; STAT1 Transcription Factor

Elevated cholesteryl ester transfer protein (CETP) activity has been reported in type 1 diabetic subjects and may be one cause of the high incidence of macrovascular complications in these patients. LDL delivers arachidonic acid (AA), in the form of cholesteryl ester (CE), to cells such as monocytes and fibroblasts, as precursor for eicosanoid synthesis. We discovered that AA content in LDL CE was significantly correlated with CETP activity, even after controlling for CETP concentration, in type 1 diabetic children. The production of LTB(4), a potent chemotactic and pro-inflammatory factor which plays a role in atherogenesis, has been shown to be increased in type 1 diabetic patients. We hypothesized that in these subjects, increased AA content in LDL CE, resulting from increased CETP activity and transient hyperinsulinemia, may lead to enhanced synthesis of LTB(4) and subsequently the higher incidence of cardiovascular disease.

Topics: Arachidonic Acid; Blood Glucose; Cardiovascular Diseases; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Diabetes Mellitus, Type 1; Eicosanoids; Glycoproteins; Humans; Hyperinsulinism; Insulin; Leukotriene B4; Lipoproteins, LDL; Models, Biological

In order to evaluate polymorphonuclear leukocyte (PMN) activity in diabetes mellitus, leukotriene B4 (LTB4) levels were measured in sixty patients, 31 affected with Type 1 diabetes mellitus and 29 affected with Type 2 diabetes mellitus. The LTB4 levels (12.1+/-0.2 pg/100 microl) in diabetic patients were higher compared to those of the control group (7.9+/-0.1 pg/100 microl) (P < 0.001), and remained significantly higher (P < 0.001) (12.8+/-0.2 pg/100 microl) than in the control group (11.0+/-0.2 pg/100 microl) after stimulation with calcium ionophore. A significant and positive correlation between glycated hemoglobin and LTB4 was demonstrated (P < 0.001, r = 0.80). This study demonstrates that in diabetic patients there is a PMN activation and that this activation is correlated to glycated hemoglobin level.

Topics: Adult; Aged; Blood Glucose; Calcimycin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; In Vitro Techniques; Leukotriene B4; Male; Middle Aged; Neutrophils; Reference Values; Regression Analysis

Leukotriene B4 (LTB4) synthesis and release by polymorphonuclear leukocytes (PMNL) from 17 male patients with type I diabetes mellitus was decreased (407.1 +/- 55.6 vs 709.4 +/- 62.7 ng/30 X 10(6) cells/10 min, mean +/- SE, p less than 0.001) as compared with 17 normal subjects matched for sex and age. There was an inverse correlation (r = -0.50, p less than 0.04) between LTB4 synthesis and plasma glucose concentration in the diabetic patients. The same correlation (r = -0.71, p less than 0.01) was observed in three diabetic patients studied weekly for one month. Because LTB4 is a potent chemoattractant and stimulates PMNL function, the defect in its synthesis may contribute to the predisposition to infections in the diabetic patient.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Humans; Infections; Leukotriene B4; Male; Neutrophils