endothelin-1 and Diabetes-Mellitus--Type-1

Diabetic nephropathy is a microvascular complication of diabetes. Specifically, it represents a major cause of morbidity and mortality in type 1 and type 2 diabetic subjects and has become the leading cause of end-stage renal disease in the Western world. Diabetic nephropathy appears to develop as a result of interactions between environmental insults and genetic susceptibility. Indeed, hyperglycemia is a clinical prerequisite for this complication, but it should be noted that only a subset of diabetic subjects will ultimately develop nephropathy. Over recent decades, cellular and molecular mechanisms underlying diabetic nephropathy have been increasingly delineated. In particular, diabetic kidney disease appears to occur as a result of the deleterious effects of both metabolic and hemodynamic insults, which at the cellular level lead to the activation of intracellular signaling pathways and transcription factors, thus triggering the production/release of cytokines, chemokines and growth factors, which mediate and/or amplify the renal damage. This ultimately leads to the structural and functional features characteristic of diabetic kidney disease. In the present review we summarize the evidence for key mediators of injury, which appear to be excellent treatment targets in diabetic nephropathy. The targets include various vasoactive hormones, the biochemical processes of the advanced glycation and protein kinase C. Furthermore, we review current and potentially new renoprotective therapies in the setting of diabetes.

Topics: Angiotensin II; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Glycation End Products, Advanced; Humans; Hypertension; Protein Kinase C; Urotensins

In Poland over 40% of patients are hypertensive. Majority of them suffer from essential hypertension. Its pathogenesis despite intensive studies is unclear. Many factors are thought to be involved in the pathogenesis of essential hypertension: sodium intake, obesity with insulin resistance, renin-angiotensin system, sympathetic nervous system as well as genetic factors, low birth weight and endothelial dysfunction. At present, the role of endothelin-1 is emphasized.

Topics: Adult; Angiotensin II; Child; Diabetes Mellitus, Type 1; Endothelin-1; Humans; Hypertension; Nitric Oxide; Obesity; Poland; Risk Factors; Sodium, Dietary

Endothelin-1 is mainly synthesized by the vascular endothelial cells and acts on the vascular smooth muscle. Because of its vasoconstrictor and mitogenic effects it plays a role in the development of vascular diseases. In diabetes mellitus atherosclerosis is accelerated. The authors summarize the available data of the role of endothelin-1 in Type 1 and Type 2 diabetes mellitus and the development of diabetic complication.

Topics: Animals; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Humans; Rats

Social anxiety (SA) and depression are prevalent, often comorbid disorders, associated with poor psychosocial functioning. Experimental psychopathology approaches can clarify the transdiagnostic mechanisms underlying these disorders, but most laboratory tasks are limited. We developed and validated the Audio-Dialogue Inductions of Social Stress (A-DISS) experimental task to model real-time rejection sensitivity in a realistic and developmentally relevant context. Participants are asked to imagine overhearing peers at a party talking badly about them (Rejection) or a teacher at their school (Neutral).. The Rejection condition elicited higher negative affect/lower positive affect while the Neutral condition sustained stable affect. Findings were consistent across gender and race/ethnicity. Moderation analyses were statistically significant; participants with elevated SA or depression reported feeling more rejected, insecure, and anxious after Rejection than those with below average symptoms.. Findings provide preliminary validation of a novel peer rejection task for research on understanding the affective experience of real-time rejection overall, especially for those with elevated SA and depression. SA and depression symptoms each uniquely moderating the effects of Rejection exposure on similar affective states, suggests individuals with SA or depression may benefit from interventions targeting specific reactions to rejection/stress and transdiagnostic risk factors.. Our results suggest that T lymphocyte immune dysfunction does exist in adult ITP patients and plays an important role in the pathogenesis of ITP.. ClinicalTrials.gov, identifier NCT03575988.. Brown/beige adipocyte-specific h

Topics: A549 Cells; Acute Lung Injury; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Adult; Aged; Animals; Anthropometry; Anti-Inflammatory Agents; Antiviral Agents; Arachidonic Acid; Archaeoglobus fulgidus; Australia; Blood Glucose; Blotting, Western; Carcinoma, Hepatocellular; Cathartics; Cell Differentiation; Chemokine CCL2; Child; China; Colonoscopy; Crosses, Genetic; Cyclin B1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Finland; Follow-Up Studies; Genes, Dominant; Glycated Hemoglobin; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Homeodomain Proteins; Humans; Hypothalamus; Incidence; Inflammatory Bowel Diseases; Interleukin-1beta; Interleukin-6; Italy; Lipopolysaccharides; Liver Cirrhosis; Liver Neoplasms; Lung; Male; Mice; MicroRNAs; Middle Aged; Motivational Interviewing; NAD; Neuroendocrine Tumors; NF-kappa B; Nitric Oxide; Nitriles; Outpatients; Oxidoreductases; Phenotype; Pilot Projects; Polyethylene Glycols; Polymorphism, Genetic; Prospective Studies; Protein Interaction Maps; Quality of Life; Reproducibility of Results; Shewanella; Signal Transduction; Spain; Sulfides; Sulfones; Thermogenesis; Transcription Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; United Kingdom

The aim of the study was to evaluate whether normoalbuminuric type 1 diabetic patients with diabetic retinopathy (DR) have an impaired tubular response to desmopressin (dDAVP, a synthetic analog of vasopressin) administration, and its relationship with plasma and urine endothelin-1 (ET-1) levels.. This was an interventional case-control study.. The study was conducted at a referral center.. Fifteen normoalbuminuric type 1 diabetic patients with DR were compared with 30 normoalbuminuric type 1 diabetic patients without DR. Both groups were matched by age, gender, body mass index, glycosylated hemoglobin, and the main laboratory markers of kidney function.. After a 12-h period of water deprivation, dDAVP (0.3 microg/kg) was infused over 20 min. Urine was collected at baseline and 1, 2, and 3 h after dDAVP administration. ET-1 was assessed by ELISA.. dDAVP induced a lower rise in urine osmolality in patients with DR (from 650 +/- 206 to 754 +/- 224 mosmol/kg; P = 0.02) than in diabetic patients without DR (from 714 +/- 194 to 905 +/- 163 mosmol/kg; P < 0.0001). In addition, fractional excretion of Na+ decreased in patients without DR (from 0.45 +/- 0.30 to 0.29 +/- 0.29%; P = 0.04) but not in the diabetic patients with DR (from 0.36 +/- 0.22 to 0.36 +/- 0.40%; P = 0.96). Plasma ET-1 levels were inversely correlated with the response of urinary osmolality after dDAVP administration (r = -0.62; P = 0.008).. Normoalbuminuric type 1 diabetic patients with DR have impaired renal response to dDAVP that is related to plasma ET-1 levels. Further studies are required to elucidate whether this tubular resistance to dDAVP might favor dehydration in these patients.

Topics: Adult; Albuminuria; Creatinine; Deamino Arginine Vasopressin; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Endothelin-1; Female; Humans; Kidney Tubules; Male; Middle Aged; Osmolar Concentration; Young Adult

Endothelin (ET) is a potent vasoconstrictive peptide that may play a role in vascular pathology in general and diabetic nephropathy in particular. The aim of this study was to investigate (1) alterations of urinary ET1 (UET1) in adolescents and young adults with insulin-dependent diabetes mellitus (IDDM) and (2) the relation of UET1 to other indices of diabetic nephropathy and to risk factors of diabetic angiopathy in general. In 130 IDDM subjects aged 15.2+/-4.9 years with a diabetes duration of 7.3+/-5.1 years, UET1 by radioimmunoassay, urinary albumin by nephelometry, plasma renin by immunoradiometric assay, hemoglobin A1c (HbA1c) by high-performance liquid chromatography, and routine biochemistry analyses were determined. Forty-eight controls, healthy siblings of the diabetics of comparable age, were similarly studied. Total 24-hour UET1 excretion was higher in diabetics than in controls (10,866+/-7,270 and 6,598+/-3,294 pg/24 h, respectively, P=.000). This difference was also noted if male and female diabetics were separately compared with controls. In diabetics with normoalbuminuria (<20 microg/min), total 24-hour UET1 excretion was also higher than in controls (P=.002). In diabetics but not in controls, 24-hour UET1 values were higher in males than in females (P=.018). In IDDM subjects, UET1 showed a linear relationship with age (P=.002), urinary albumin (P=.000), serum creatinine (P=.001), systolic blood pressure (P=.038), triglycerides (P=.003), and HbA1c (P=.041). Multiple regression analysis demonstrated that the variables interacting independently with UET1 were urinary albumin (P=.003) and serum creatinine (P=.038). UET1 is elevated early (in adolescence) in IDDM subjects, and it is positively correlated with the degree of albuminuria. These data suggest that the amount of UET1 possibly reflects the severity of diabetic renovascular damage. It may thus be speculated that UET1 could be used as another index of diabetic nephropathy or its progress.

Topics: Adolescent; Adult; Albuminuria; Blood Pressure; Child; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Humans; Male

In search of early signs of autonomic and vascular dysfunction in diabetic subjects, six young men with type I diabetes and six healthy subjects were investigated regarding arterial levels of noradrenaline (NA), neuropeptide Y- (NPY) and endothelin-1-(ET-1) like immunoreactivity (Li) during and after 1 h of exercise at 70% of peak oxygen uptake. Basal NA, NPY-Li and ET-1-Li levels did not differ between groups. NA and NPY-Li rose during exercise in diabetic subjects to only 60% of the control values (P < 0.05, interaction group x time P < 0.001). Disappearance rates for NA and NPY-Li did not differ between groups. Plasma ET-1-Li did not differ between groups during exercise. Values returned to basal levels within 5 min in the diabetic but not in the control group. In conclusion, diabetic subjects show lower NPY-Li and NA levels than control subjects during exercise but similar disappearance rates after exercise, indicating lower releases. Furthermore, plasma ET-1 levels did not differ between groups during exercise.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Endothelin-1; Energy Metabolism; Exercise; Exercise Test; Glycerol; Heart Rate; Humans; Lactic Acid; Male; Neuropeptide Y; Norepinephrine; Supine Position

Type 1 diabetes (T1D) negatively affects both the endothelin system and muscle oxidative capacity. The endothelin pathway is a critical regulator of microcirculatory function and may exhibit sexual dichotomy by which healthy premenopausal women have greater endothelin-B receptor (ETBR) function compared to men. Moreover, T1D may differentially alter muscle oxidative capacity in men and women; however, whether ETBR function is impaired in women compared to men with T1D and its relationship with muscle oxidative capacity has yet to be explored.. The purpose of this investigation was to determine if ETBR-mediated dilation is impaired in women compared to men with T1D and if this is related to their skeletal muscle oxidative capacity.. Men (n = 9; glycated hemoglobin A1c [HbA1c] = 7.8 ± 1.0%) and women (N = 10 women; HbA1c = 8.4 ± 1.3%) with uncomplicated T1D were recruited for this investigation. Near-infrared spectroscopy (NIRS) and intradermal microdialysis (750 nM BQ-123 + ET-1 [10-20-10-8 mol/L]) were used to evaluate skeletal muscle oxidative capacity and assess ETBR-mediated vasodilation, respectively.. Skeletal muscle oxidative capacity was significantly lower (P = .031) in women compared with men with T1D. However, ETBR-mediated dilation induced a significantly greater (P = .012) vasodilatory response in women compared to men with T1D, and the area under the curve was negatively associated with skeletal muscle oxidative capacity (r = -.620; P = .042).. Compared to men with uncomplicated T1D, muscle oxidative capacity was lower and ETBR-mediated vasodilation was higher in women with uncomplicated T1D. ETBR-induced vasodilatory capacity was inversely related to skeletal muscle oxidative capacity, suggesting there may be compensatory mechanisms occurring to preserve microvascular blood flow in women with T1D.

Topics: Diabetes Mellitus, Type 1; Endothelin-1; Endothelins; Female; Glycated Hemoglobin; Humans; Male; Microcirculation; Mitochondria

NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing human ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (Apoe-/-) mice enhanced high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We tested the hypothesis that ET-1 overexpression in the endothelium would worsen atherosclerosis in type 1 diabetes through a mechanism involving NOX1 but not NOX4.. Six-week-old male Apoe-/- and eET-1/Apoe-/- mice with or without Nox1 (Nox1-/y) or Nox4 knockout (Nox4-/-) were injected intraperitoneally with either vehicle or streptozotocin (55 mg/kg/day) for 5 days to induce type 1 diabetes and were studied 14 weeks later. ET-1 overexpression increased 2.5-fold and five-fold the atherosclerotic lesion area in the aortic sinus and arch of diabetic Apoe-/- mice, respectively. Deletion of Nox1 reduced aortic arch plaque size by 60%; in contrast, Nox4 knockout increased lesion size by 1.5-fold. ET-1 overexpression decreased aortic sinus and arch plaque alpha smooth muscle cell content by ∼35% and ∼50%, respectively, which was blunted by Nox1 but not Nox4 knockout. Reactive oxygen species production was increased two-fold in aortic arch perivascular fat of diabetic eET-1/Apoe-/- and eET-1/Apoe-/-/Nox4-/- mice but not eET-1/Apoe-/-/Nox1y/- mice. ET-1 overexpression enhanced monocyte/macrophage and CD3+ T-cell infiltration ∼2.7-fold in the aortic arch perivascular fat of diabetic Apoe-/- mice. Both Nox1 and Nox4 knockout blunted CD3+ T-cell infiltration whereas only Nox1 knockout prevented the monocyte/macrophage infiltration in diabetic eET-1/Apoe-/- mice.. Endothelium ET-1 overexpression enhances the progression of atherosclerosis in type 1 diabetes, perivascular oxidative stress, and inflammation through NOX1.

Topics: Animals; Aorta; Atherosclerosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin-1; Endothelium, Vascular; Fibrosis; Humans; Macrophages; Mice, Inbred C57BL; Mice, Knockout, ApoE; Monocytes; NADPH Oxidase 1; Oxidative Stress; Plaque, Atherosclerotic; T-Lymphocytes; Up-Regulation

Better understanding of the timeline and risk factors for the appearance of complications in pediatric Type-1-diabetes is key for developing prevention strategies. We studied endothelial markers and their determinants in adolescents with Type-1-diabetes at different time points from diagnosis.. A cross-sectional study of 58 adolescents, mean age 15.0 ± 2.4 years; 20 with recent-onset Type-1-diabetes, 20 with over 7 years of Type-1-diabetes and 18 controls. Clinical and biochemical data were collected. Fingertip arterial reactive hyperemia (EndoPAT) and carotid intima-media-thickness (cIMT) were measured to assess endothelial function and structure.. Compared to controls, individuals with prolonged Type-1-diabetes had higher mean cIMT (0.49 ± 0.07 mm vs. 0.43 ± 0.05 mm p = 0.021) and maximal cIMT (0.61 ± 0.08 mm 0.52 ± 0.08 mm, p = 0.025). Endothelin-1 levels were significantly lower in subjects with prolonged Type-1-diabetes (1.2 ± 1.0 pg/ml) compared to controls (3.0 ± 1.7, p = 0.008 pg/ml); they negatively correlated with the mean cIMT (c = - 0.291, p = 0.031) and mean 6 months hemoglobin A1c (c = - 0.301, p = 0.022) and positively correlated with mean c-peptide levels (c = 0.356, p = 0.006) and the weekly exercise time (c = 0.485, p < 0.001). Endothelin-1 levels did not correlate with EndoPAT results.. Our results suggest that the early years after the diagnosis of Type-1-diabetes are an important window for prevention of arterial damage in the pediatric population. The trajectories of relationships of Endothelin-1 with metabolic and vascular measures were opposite from the anticipated, yet consistent. Endothelin-1 related indirectly to adverse measures and directly to favorable measures. Decreased Endothelin-1 levels might reflect early stages in endothelial impairment in Type-1-diabetes, yet its' exact role in the development of complications is yet to be unraveled.

Topics: Adolescent; Carotid Intima-Media Thickness; Case-Control Studies; Child; Diabetes Mellitus, Type 1; Endothelin-1; Female; Humans; Male; Young Adult

Endothelial dysfunction in type 1 diabetes mellitus (T1DM) is an important factor in the pathogenesis of micro- and macrovascular complications. The present study was to investigate the impact of combined vanadium and insulin for proper control and protection against endothelial dysfunction in T1DM rats. Sixty male Sprague-Dawley rats were randomly divided into six groups; control non-treated; control vanadium treated; T1DM; T1DM + insulin; T1DM + vanadium; T1DM + insulin + vanadium treated groups. At the end of the experiment (6 weeks), serum C-reactive protein, tumour necrosis factor-alpha, IL-6, endothelin-1, plasminogen activator inhibitor-1, fasting glucose serum lipogram, liver homogenate SOD activity and MDA levels were determined. Concomitant insulin and vanadium treatment improved the diabetic metabolic disturbances in addition to endothelial dysfunction and inflammatory markers. We can conclude that concomitant administration of both vanadium and insulin in T1DM decreased the risk for the development of endothelial dysfunction, micro- and macrovascular complications.

Topics: Animals; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin-1; Endothelium, Vascular; Insulin; Interleukin-6; Male; Malondialdehyde; Plasminogen Activator Inhibitor 1; Prospective Studies; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Vanadium

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKβ. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKβ abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKβ as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1β, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Coculture Techniques; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Female; Glucose; Humans; I-kappa B Kinase; Inflammation; Inflammation Mediators; Male; Mice, Inbred NOD; Mitogen-Activated Protein Kinase 8; Monocytes; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Topics: Adaptor Proteins, Signal Transducing; Diabetes Mellitus, Type 1; Endothelial Cells; Endothelin-1; Glucose; Humans; Inflammation; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1-Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Albuminuria; Animals; Antioxidants; Chromatography, High Pressure Liquid; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Susceptibility; DNA, Mitochondrial; Endothelin-1; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Kidney Glomerulus; Male; Mesangial Cells; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Organophosphorus Compounds; Oxygen Consumption; Piperidines; Podocytes; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; Signal Transduction; Young Adult

Objective Endothelial dysfunction (ED) plays an important role in the pathogenesis of diabetic nephropathy. The purpose of the study was to determine flow mediated endothelial dependent vasodilatation (FMD) measurements and serum soluble (s) endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) levels in patients with type 1 diabetes mellitus (T1DM) with or without increased urinary albumin excretion (UAE) and compare them with the healthy controls. Subjects and methods Seventy three patients with T1DM were enrolled. Patients were divided into two subgroups according to microalbumin measurements in 24-hr urine collections. The diabetic patients without microalbuminuria (41 patients) were defined as Group I and those with microalbuminuria (32 patients) were defined as group II. A hundred age and sex matched healthy subjects participated as the control group (Group III). Serum sET-1, sICAM-1, sVCAM-1 levels and FMD measurements were determined in all participants. Results Median FMD measurement was significantly lower in the diabetic groups compared with the control group (6.6, 6.4 and 7.8% in Group I, II and III, respectively) (p < 0.05). FMD was negatively correlated with age (p = 0.042). Median serum sICAM-1 level was higher in the patient groups compared to the control group (p < 0.05). Median serum sVCAM-1 level was higher in the group of patients with increased albuminuria compared to the normoalbuinuric and the control group (p < 0.05). Serum sVCAM-1 level was found to be positively correlated with degree of urinary albumin excretion (p < 0.001). Conclusion We assume that sVCAM-1 may be used as a predictive marker for risk stratification for nephropathy development and progression.

Topics: Adult; Albuminuria; Analysis of Variance; Biomarkers; Blood Flow Velocity; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Male; Predictive Value of Tests; Reference Values; Risk Factors; Statistics, Nonparametric; Vascular Cell Adhesion Molecule-1; Vasodilation

To examine the relationships of serum markers of inflammation and endothelial function to diabetic retinopathy.. We recruited 224 patients with diabetes (85 with Type 1 and 139 with Type 2 diabetes) aged 18-70 years. Serum markers of inflammation (high-sensitivity C-reactive protein) and endothelial function (soluble intercell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, endothelin-1 and total nitrite) were assessed using nephelometry, immunoassays and spectroscopy. Diabetic retinopathy was graded from two-field fundus photographs according to the Airlie House Classification system and was categorized into no diabetic retinopathy, mild non-proliferative diabetic retinopathy, moderate non-proliferative diabetic retinopathy and vision-threatening diabetic retinopathy, the latter comprising severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or clinically significant macular oedema. Multinomial logistic regression was used to assess the associations between serum markers and diabetic retinopathy.. In the study, 64% of patients (144/224) had diabetic retinopathy and 25% (57/244) had vision-threatening diabetic retinopathy. After controlling for age, gender, diabetes duration, HbA1c , systolic blood pressure, total and HDL cholesterol, smoking, the use of insulin or oral hypoglycaemic agents, nephropathy and cardiovascular disease, a positive association was found between increasing high-sensitivity C-reactive protein levels and the presence of vision-threatening diabetic retinopathy (odds ratio 1.26; 95% CI 1.05-1.51, per sd increase in high-sensitivity C-reactive protein). After stratifying by BMI ( ≥ 30 and < 30 kg/m(2) ), this association was found to be more pronounced in people with a BMI ≥ 30 kg/m(2) (odds ratio 2.9; P for interaction = 0.019). No associations were found between serum markers of endothelial activation and diabetic retinopathy.. Higher C-reactive protein levels, but not markers of endothelial function, may be related to more severe diabetic retinopathy. This finding suggests that inflammatory processes are involved in severe diabetic retinopathy, particularly in patients with a BMI ≥ 30 kg/m(2) .

Topics: Adolescent; Adult; Aged; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; E-Selectin; Endothelin-1; Endothelium, Vascular; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Logistic Models; Male; Middle Aged; Nitrates; Ophthalmoscopes; Severity of Illness Index; Vascular Cell Adhesion Molecule-1; Young Adult

Endothelial dysfunction plays an important role in the development of diabetic retinopathy. The aim of this study was to evaluate endothelial dysfunction using different approaches in patients with type 1 diabete mellitus with early stages of diabetic retinopathy. For this purpose, we investigated the serum levels of cellular adhesion molecules, including intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1) and endothelin-1 (ET-1), which have emerged as specific markers of endothelial dysfunction, and measured the flow-mediated dilatation (FMD), a noninvasive technique used to evaluate endothelial dysfunction.. The study group included 59 patients with type 1 diabetes mellitus (DM) and 30 age-matched healthy control subjects. The diabetic patients were divided into two groups according to the ophthalmoscopic findings: Group 1, composed of type 1 diabetic patients having no signs of diabetic retinopathy (DRP), and Group 2, composed of type 1 diabetic patients having findings of the early stages of nonproliferative diabetic retinopathy (NPDR).. The serum levels of ET-1 (fmol/mL), ICAM-1 (ng/mL) and VCAM-1 (ng/mL) were 8.52±0.699 vs. 478.39±46.22 vs. 728.64±35.081 in the patients without retinopathy, 8.91±1.354 vs. 451.79±48.262 vs. 863.59±62.37 in the diabetic patients with NPDR and 10.73±1.04 vs. 608.15±74.92 vs. 872.95±57.63 in the control group. There were no significant differences in the serum levels of the three molecules between the groups. The FMD values were 6.51±0.46% in the diabetic patients without retinopathy, 6.66±0.29% in the diabetic patients with NPDR and 6.68±0.51% in the control group. No significant differences were found between the groups.. The early stages of diabetic retinopathy cannot be considered in the evaluation of systemic markers of endothelial dysfunction.

Topics: Adult; Biomarkers; Blood Flow Velocity; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Endothelin-1; Female; Humans; Intercellular Adhesion Molecule-1; Male; Vascular Cell Adhesion Molecule-1; Vasodilation

This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [(125)I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K-n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.

Topics: Amides; Animals; Cardiomegaly; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin-1; Endothelium, Vascular; Exenatide; Fumarates; Hypoglycemic Agents; Insulin; Male; Myocytes, Cardiac; Peptides; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Streptozocin; Time Factors; Venoms

Although exogenous administration of Angiotensin-(1-7) [Ang-(1-7)] can prevent development of diabetes induced end-organ damage, little is known about the role of endogenous Ang-(1-7) in diabetes and requires further characterization. Here, we studied the effects of chronically inhibiting endogenous Ang-(1-7) formation with DX600, a selective angiotensin converting enzyme-2 (ACE2) inhibitor, on renal and cardiac NADPH oxidase (NOX) activity, vascular reactivity and cardiac function in a model of Type-1 diabetes. The contribution of endogenous Ang-(1-7) to the protective effects of Losartan and Captopril and that of prostaglandins to the cardiovascular effects of exogenous Ang-(1-7) were also examined. Cardiac and renal NOX activity, vascular reactivity to endothelin-1 (ET-1) and cardiac recovery from ischemia/reperfusion (I/R) injury were evaluated in streptozotocin-treated rats. Chronic treatment with DX600 exacerbated diabetes-induced increase in cardiac and renal NOX activity. Diabetes-induced abnormal vascular reactivity to ET-1 and cardiac dysfunction were improved by treatment with Ang-(1-7) and worsened by treatment with DX600 or A779, a Mas receptor antagonist. Ang-(1-7)-mediated improvement in cardiac recovery or vascular reactivity was attenuated by Indomethacin. Captopril and Losartan-induced improvement in cardiovascular function was attenuated when these drugs were co-administered with A779. Ang-(1-7)-mediated decrease in renal NOX activity was prevented by indomethacin. Losartan also decreased renal NOX activity that could be attenuated with A779 co-treatment. In conclusion, endogenous Ang-(1-7) inhibits diabetes-induced cardiac/renal NOX activity and end-organ damage, and mediates the actions of Captopril and Losartan. Further, prostaglandins are important intermediaries in the beneficial effects of Ang-(1-7) in diabetes. Combining either Losartan or Captopril with Ang-(1-7) had additional beneficial effects in preventing diabetes-induced cardiac dysfunction and this may represent a novel therapeutic strategy. Collectively, these data shed new insights into the likely mechanism of action through which the ACE2/Ang-(1-7)/Mas receptor axis prevents Type 1 diabetes-induced cardiovascular dysfunction.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Captopril; Cardiovascular System; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Endothelin-1; Hyperglycemia; Kidney; Losartan; Male; NADPH Oxidases; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Prostaglandins; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Reperfusion Injury

The article deals with studying the degree of increase of the von Willebrand factor and the concentration of endothelin-1 in blood plasma in the subgroups of patients with diabetes mellitus formed depending on of type of disease and presence of phenotype with affection of kidneys. The sampling of 176 patients with diabetes mellitus (65 patients with diabetes mellitus type 1, 111 patients with diabetes mellitus type II) was examined. The control group consisted of 30 healthy persons. In the capacity of biochemical markers of endothelium dysfunction the activity of the von Willebrand factor and the concentration of endothelin-1 in blood were considered. In all patients with diabetes mellitus the biochemical characteristics of endothelium dysfunction are present manifesting by increase of concentration of endothelin-1 in blood which is especially expressed under disease phenotype with affection of kidneys. Despite of the apparent lesion of endothelium in patients with diabetes mellitus compromised with diabetic nephropathy the thrombocytes aggregation induced by ristomicine does not undergo natural changes. Hence, to consider in these patients the increasing activity of the von Willebrand factor as a reliable marker of endothelium dysfunction is not seemed possible.

Topics: Adult; Aged; Biomarkers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Platelet Aggregation; von Willebrand Factor

Although hyperglycemia is implicated in retinal vascular dysfunction associated with the development of diabetic retinopathy, the temporal influence of hyperglycemia on retinal arteriolar reactivity remains unclear. Development of a large animal model of diabetes relevant to the human retina for evaluation of vascular function is also lacking. Herein, we examined nitric oxide (NO)-mediated dilation and endothelin-1 (ET-1)-induced constriction in retinal arterioles at various time periods in a porcine model of type 1 diabetes.. Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2, 6, and 12 weeks of hyperglycemia, 427 ± 23 mg/dL) and age-matched control pigs (73 ± 4 mg/dL), and then cannulated and pressurized for vasoreactivity study using videomicroscopic techniques.. Retinal arterioles isolated from control and diabetic pigs developed comparable levels of myogenic tone. The endothelium-dependent NO-mediated vasodilations to bradykinin and stepwise increases in luminal flow were significantly reduced within 2 weeks of hyperglycemia. The inhibitory effect was comparable following 6 and 12 weeks of hyperglycemia. However, the endothelium-independent vasodilation to sodium nitroprusside was unaffected. Constriction of retinal arterioles to ET-1 was unaltered at all time periods of hyperglycemia.. Our findings provide the first direct evidence for selective impairment of endothelium-dependent NO-mediated dilation of retinal arterioles within 2 weeks of hyperglycemia in a pig model of diabetes. By contrast, the ability of arteriolar smooth muscle to dilate to NO donor or contract to ET-1 was unaffected throughout the study period. This endothelial vasodilator dysfunction during early diabetes may contribute to development of retinopathy with chronic hyperglycemia.

Topics: Animals; Arterioles; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Male; Muscle, Smooth, Vascular; Nitric Oxide; Retinal Artery; Sus scrofa; Time Factors; Vasodilator Agents

Hypoglycemia is associated with increased cardiovascular mortality, but the reason for this association is poorly understood. We tested the hypothesis that the myocardial blood flow reserve (MBFR) is decreased during hypoglycemia using myocardial contrast echocardiography in patients with type 1 diabetes mellitus (DM) and in healthy control subjects.. Twenty-eight volunteers with DM and 19 control subjects underwent hyperinsulinemic clamps with maintained sequential hyperinsulinemic euglycemia (plasma glucose, 90 mg/dL [5.0 mmol/L]) followed by hyperinsulinemic hypoglycemia (plasma glucose, 50 mg/dL [2.8 mmol/L]) for 60 minutes each. Low-power real-time myocardial contrast echocardiography was performed with flash impulse imaging using low-dose dipyridamole stress at baseline and during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia. In control subjects, MBFR increased during hyperinsulinemic euglycemia by 0.57 U (22%) above baseline (B coefficient, 0.57; 95% confidence interval, 0.38 to 0.75; P<0.0001) and decreased during hyperinsulinemic hypoglycemia by 0.36 U (14%) below baseline values (B coefficient, -0.36; 95% confidence interval, -0.50 to -0.23; P<0.0001). Although MBFR was lower in patients with DM at baseline by 0.37 U (14%; B coefficient, -0.37; 95% confidence interval, -0.55 to -0.19; P=0.0002) compared with control subjects at baseline, the subsequent changes in MBFR during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia in DM patients were similar to that observed in control subjects. Finally, the presence of microvascular complications in the patients with DM was associated with a reduction in MBFR of 0.52 U (24%; B coefficient, -0.52; 95% confidence interval, -0.70 to -0.34; P<0.0001).. Hypoglycemia decreases MBFR in both healthy humans and patients with DM. This finding may explain the association between hypoglycemia and increased cardiovascular mortality in susceptible individuals.

Topics: Acute Disease; Adult; Blood Glucose; C-Reactive Protein; Coronary Circulation; Diabetes Mellitus, Type 1; Echocardiography; Endothelin-1; Epinephrine; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Microbubbles; Single-Blind Method; Young Adult

Endothelin (ET) A receptor antagonism causes decreased vasodilation in hypertensive coronary arteries and decreased effects on coronary artery compliance in diabetic patients.. We investigate the mRNA expression of ET-1, ET(A) and ET(B) receptors, using real time RT-PCR, in biopsies from the internal mammary artery obtained from 49 patients, 18 diabetics and 34 hypertensives, all undergoing coronary artery bypass grafting.. Hypertensive patients had higher ET-1 mRNA expression (16438 [8417, 23917]), than normotensive patients (2974 [2283, 18055], p=0.008). Diabetic patients had significantly lower ET(A) receptor levels than non-diabetic patients (455 [167, 1496] vs. 1660 [700, 3190], respectively, p = 0.003).. Multivariate analysis demonstrated that the presence of systemic hypertension was the only independent predictor of log ET(A) receptor expression and log ET-1 expression, while insulin-dependent diabetes was negatively correlated with ET(A) receptor expression. ETB receptor expression was not correlated with any predictor. Systemic hypertension is associated with increased ET-1 and ET(A) receptor mRNA expression, whereas insulin-dependent diabetes down-regulates ET(A) receptor mRNA expression in the internal mammary artery in patients with coronary artery disease undergoing bypass grafting.

Topics: Aged; Coronary Artery Bypass; Coronary Artery Disease; Diabetes Mellitus, Type 1; Down-Regulation; Endothelin-1; Female; Gene Expression; Humans; Hypertension; Male; Mammary Arteries; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Vasodilation

Mechanisms associated with the enhanced contractile response to endothelin-1 in hyperinsulinaemic diabetes have been examined using the rat aorta. Functions for angiotensin II, endothelin-1 receptor expression and extracellular signal-regulated kinase (ERK) have been investigated.. Streptozotocin-induced diabetic rats were infused with angiotensin II or, following insulin treatment, were treated with losartan, an angiotensin II receptor antagonist. Contractions of aortic strips with or without endothelium, in response to endothelin-1 and angiotensin II, were examined in vitro. Aortic ET(A) receptors and ERK/MEK expression were measured by western blotting.. Insulin-treated diabetic rats exhibited increases in plasma insulin, angiotensin II and endothelin-1. The systolic blood pressure and endothelin-1-induced contractile responses in aortae in vitro were enhanced in insulin-treated diabetic rats and blunted by chronic losartan administration. LY294002 (phosphatidylinositol 3-kinase inhibitor) and/or PD98059 (MEK inhibitor) diminished the enhanced contractile response to endothelin-1 in aortae from insulin-treated diabetic rats. ET(A) and ET(B) receptors, ERK-1/2 and MEK-1/2 protein expression and endothelin-1-stimulated ERK phosphorylation were all increased in aortae from insulin-treated diabetic rats. Such increases were blunted by chronic losartan administration. Endothelin-1-induced contraction was significantly higher in aortae from angiotensin II-infused diabetic rats. angiotensin II-infusion increased ERK phosphorylation, but the expression of endothelin receptors and ERK/MEK proteins remained unchanged.. These results suggest that the combination of high plasma angiotensin II and insulin with a diabetic state induced enhancement of endothelin-1-induced vasoconstriction, ET(A) receptor expression and ERK expression/activity in the aorta. Losartan improved both the diabetes-related abnormalities and the diabetic hypertension.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin A Receptor Antagonists; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Hypertension; Insulin; Losartan; Male; Mitogen-Activated Protein Kinases; Rats; Rats, Wistar; Receptor, Endothelin A; Streptozocin; Vasoconstriction

To evaluate the relationship between oxidative stress and endothelial dysfunction (ED) in diabetic patients without clinical macrovascular complications.. In 27 type 1, 56 type 2 diabetic patients and 35 healthy controls the redox state (GSH, GSSG; enzymatic method), endothelin-1 (ET-1; ELISA) and von Willebrand factor (vWF; ELISA) plasma levels, urinary vascular endothelial growth factor (VEGF; ELISA) were measured.. Decreased GSH levels (p<0.05, type 1 and type 2), GSH/GSSG ratio (p<0.05 type 1, p<0.001 type 2) and elevated vWF levels (p<0.001, type 1 and type 2) were observed in diabetic patients in comparison with controls. A negative correlation between GSH and vWF (p<0.02 and p<0.001, in type 1 and type 2, respectively) and GSH and BMI (p<0.02 in type 1 and type 2) was observed. ET-1 was positively correlated to age (p<0.05) and diabetes duration (p<0.03) in type 1, while vWF was correlated to systolic blood pressure (p<0.05) in type 2 diabetic patients. Urinary VEGF was higher in type 2 (p<0.05) in comparison with type 1 diabetic patients and was correlated to glycemia (p<0.05) and systolic blood pressure (p<0.05).. These data might indicate that markers of oxidative stress and ED are altered in diabetic patients without clinical macrovascular complications.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelin-1; Endothelium, Vascular; Female; Glutathione; Humans; Male; Middle Aged; Oxidative Stress; Reference Values; Vascular Endothelial Growth Factor A; von Willebrand Factor

Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.

Topics: Acetylcholine; Animals; Aorta; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Genetic Predisposition to Disease; Immunohistochemistry; Mice; Mice, Inbred NOD; Mice, Inbred Strains; Muscle Relaxation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Perfusion; Phenylephrine; Vasoconstrictor Agents

To investigate the potential role of endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties, in the pathogenesis of proliferative diabetic retinopathy (PDR).. Plasma and vitreous samples were collected from normal patients (controls; n = 25), diabetic patients with PDR (n = 25), and diabetic patients with non-PDR (n = 25). The patients had to have epiretinal membranes (ERMs) or other ocular conditions that made them candidates for vitrectomy. Immunoreactive ET-1 (IR-ET-1) was assayed in plasma and vitreous samples by radioimmunoassay. IR-ET-1 was immunohistochemically localized in ERMs. Expression of endothelin receptors A (ETA) and B (ETB) was confirmed by reverse transcription-polymerase chain reaction analysis.. IR-ET-1 levels in plasma and vitreous samples from diabetic patients were higher (P < 0.0001) than those in samples from the control group. The levels for patients with PDR were even higher (P < 0.0001) than those for patients with non-PDR. Eyes with ERMs in the PDR group had the highest vitreous IR-ET-1 levels (14.67 +/- 0.67 pg/mL). IR-ET-1 was localized in the cellular and stromal components of ERMs in diabetic and nondiabetic patients. Furthermore, the ETA and ETB receptors were expressed in both diabetic and nondiabetic ERMs.. Diabetic patients with PDR and ERMs had the highest plasma and vitreous IR-ET-1 levels. ET-1 and its ETA and ETB receptors were present in ERMs. These data suggest that ET-1 is involved in diabetic vitreoretinal disease.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelin-1; Epiretinal Membrane; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vitreous Body

This project assesses the treatment role with insulin and (or) angiotensin II receptor subtype-1 (AT1-R) blocker (ARB) on insulin receptor and endothelin-1 receptor subtype (ETA-R and ETB-R) regulation in rat hearts suffering from insulin-dependent diabetes mellitus (IDDM). Animals were divided into 6 groups: groups 1, 3, and 5 were controls consisting of normal, diabetic (streptozotocin-treated, once at 0 time), and diabetic supplemented daily with insulin, respectively, whereas groups 2, 4, and 6 were the controls treated daily with losartan. One month after enrollment, rats were sacrificed and samples of cardiac tissue were snapped frozen for immunostaining and Western blotting. Insulin receptor density was observed to be upregulated in the cardiomyocytes of diabetic animals, but downregulated with insulin supplementation alone. Cotreatment with insulin and an ARB resulted in drastic increase in insulin-receptor density in the diabetic rats. In addition, expression of ETA-R in cardiomyocytes was upregulated and was consistently maintained within the various treatment modalities. However, ETB-R expression was significantly reduced in the diabetic group treated with both insulin and an ARB. The changes in the expression of the insulin, the ETA-Rs, and the ETB-Rs at the various sites of the myocardium and the effect of both insulin treatment and blockade of the AT1-R explain the new benefits related to the halting of myocardial remodeling in IDDM rats.

Topics: Animals; Blotting, Western; Diabetes Mellitus, Type 1; Endothelin-1; Fluorescent Antibody Technique; Losartan; Male; Myocardium; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptor, Insulin

We examined the role of endothelial dysfunction in the development and progression of cardiorenal syndrome in 93 patients with type 1 diabetes mellitus.. According to the stage of renal insufficiency all patients were divided into equal groups: those with normal albumin excretion rate, with microalbuminuria, with proteinuria, and with chronic renal failure. We analyzed endothelial flow-mediated dilation of the brachial artery, levels of endothelin-1, von Willerbrand factor, C-reactive protein, renal:albumin and protein excretion rates, glomerular filtration rate (GFR), and cardiovascular (ECG, echocardiography, blood pressure monitoring) functions.. There were negative correlations between the GFR, BP level and endothelial dysfunction markers. At the same time GFR correlated positively with the coefficient of sensitivity of endothelium to shear stress. There were also positive correlations between BP, permeability of glomerular filter and endothelial dysfunction markers and negative correlation with the coefficient of sensitivity of endothelium to shear stress and GFR. Left ventricle mass correlated with markers of endothelial dysfunction and stage of renal disease. Patients with chronic renal failure had negative correlations between LVM and GFR, ILVM and GFR and a positive correlation between ejection fraction and GFR.. There is a close relationship between endothelial dysfunction and development and progression of renal and cardiovascular pathology in patients with type 1 diabetes mellitus.

Topics: Adolescent; Adult; Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Echocardiography; Endothelin-1; Endothelium, Vascular; Female; Glomerular Filtration Rate; Heart Diseases; Humans; Male; Middle Aged; Ventricular Dysfunction, Left; Ventricular Function, Left

To elucidate the role of endothelial dysfunction in formation of cardiorenal syndrome in patients with type 1 diabetes and diabetic nephropathy.. Sixty patients with type 1 diabetes were divided according to severity of nephropathy into the following groups: with normal albuminuria (n=15), microalbuminuria (n=15), proteinuria (n=15), and chronic renal failure (n=15). Control group consisted of 15 healthy subjects of similar age and sex. Methods of investigation included assessment of brachial artery endothelium dependent dilation by duplex scanning during test with reactive hyperemia, measurement of levels of serum markers of endothelial dysfunction (endothelin-1, von-Willebrand factor), and inflammation (C-reactive protein), analysis of parameters of 24-hour blood pressure monitoring and echocardiography data.. More severe diabetic nephropathy was associated with higher prevalence of cardiac pathology. Frequency of ischemic heart disease was 13 (2/15), 33 (5/15) and 53% (8/15), frequency of left ventricular concentric hypertrophy and remodeling - 33 (5/15), 40 (6/15) and 60% (9/15) among patients with microalbuminuria, proteinuria and chronic renal failure, respectively. Abnormalities of 24-hour blood pressure rhythm as well as signs of endothelial dysfunction were more pronounced in patients with more severe nephropathy. Correlation analysis revealed significant relationships between markers of endothelial dysfunction, parameters of renal function, blood pressure level and mass of left ventricular myocardium.. In patients with type 1 diabetes: endothelial dysfunction represents a link integrating processes of progression of nephropathy and development of cardiovascular pathology; close relationship between these processes constitutes a basis of cardiorenal syndrome; active search for cardiac pathology should be initiated on the stage of microalbuminuria.

Topics: Adolescent; Adult; Biomarkers; Brachial Artery; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Heart Diseases; Humans; Male; Middle Aged; Prognosis; Syndrome; Ultrasonography, Doppler, Duplex; Vasodilation; von Willebrand Factor

This study investigated the role of endothelin-1 for hyperglycemia, vascular, and pancreatic injury in early type I diabetes in non-obese-diabetic (NOD) mice. Endothelium dependent relaxation to acetylcholine and vascular gene expression of endothelin converting enzyme (ECE) isoforms 1 and 2 were studied as indicators of vascular injury. Endothelial NO bioactivity in the aorta was reduced in diabetic NOD mice while vascular expression of ECE-1 and ECE-2 mRNA was increased compared with controls (all p<0.05). Vascular histology was normal in all animals. Unexpectedly, treatment of prediabetic NOD mice for 6 weeks with the orally active ET(A) receptor antagonist BSF461314 prevented onset of diabetes without affecting insulitis severity. ET(A) receptor blockade also restored abnormal endothelial NO bioactivity and reduced ECE-1 and ECE-2 gene expression in NOD mice to levels comparable with healthy controls (p<0.05). Moreover, secretion of endothelin-1 in a time-dependent fashion was observed by pancreatic islet beta-cells cultured in vitro. These data suggest a critical role for ET(A) receptor signaling in the development of autoimmune forms of diabetes and the early vascular injury associated with it.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Hyperglycemia; Islets of Langerhans; Mice

In the aorta of prediabetic non-obese diabetic mice, a model of human type 1 diabetes, we investigated gene expression of the endothelin receptors and contractility to big endothelin-1 and endothelin-1 at the ages of 10 and 16 weeks. A subgroup of 10- week-old animals was treated with the endothelin ETA receptor antagonist LU461314 (30 mg/kg per day for 6 weeks). Blood glucose levels were normal in all animals. Real-time polymerase chain reaction analysis revealed that vascular ETB receptor expression was higher in 10-week-old non-obese diabetic (NOD) mice compared with controls. In 16-week-old NOD mice, but not in control mice, ETB receptor mRNA was twofold lower (P < 0.05 vs 10-week-old NOD mice). In all groups ETA receptor expression was unaffected by age or treatment. Contractions to big endothelin-1 and endothelin-1 were lower in 10-week-old NOD mice compared with controls. Treatment with LU461314 increased ETB receptor expression in 16-week-old NOD mice, but had no effect on vascular contractility. These data indicate that dysregulation of ETB receptor expression and a decreased contractile response to big endothelin-1 and endothelin-1 are present in the prediabetic state of a model of human type 1 diabetes. These alterations occur independent of glucose levels. Furthermore, ETA receptor blockade is effective in increasing ETB receptor gene expression, suggesting a potential role for endothelin ETA antagonists in the treatment of type 1 diabetes.

Topics: Age Factors; Animals; Aorta; Blood Glucose; Cardiovascular Agents; Diabetes Mellitus, Type 1; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Female; Mice; Mice, Inbred NOD; Prediabetic State; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Up-Regulation; Vasoconstriction

Type I diabetes is associated with vascular endothelial abnormalities. Vasoactive mediators such as endothelins and reactive oxygen species are modulated in diabetic patients. We studied the hemodynamic profile and the release of mediators alongside the onset of streptozotocin-induced type I diabetes in rats. Arterial plasma samples were collected from chronically instrumented, unrestrained and conscious normotensive versus streptozotocin-diabetic rats. Streptozotocin-diabetic rats developed severe hypoinsulinemia and subsequent hyperglycemia within 5 days. Mean arterial blood pressure and heart rate decreased from 107 to 87 mmHg (19%) and from 386 to 282 beats per minute (bpm) (27%), respectively over 21 days. On day 20 post-streptozotocin administration, markers of oxidative stress (reactive oxygen species: hydrogen peroxide, total peroxides) and related vasodilatory nitric oxide metabolites, increased. Plasma concentrations of atrial natriuretic peptide were not affected, while vasocontractile endothelin-1 and big endothelin-1 increased in streptozotocindiabetic rats versus chronically instrumented, unrestrained and conscious normotensive rats. In addition, the ratios of endothelin-1 : big endothelin-1 and nitric oxide : endothelin-1 were increased. The depressed hemodynamic profile may result from an imbalance between vasocontracting and relaxing factors. Their interactions with reactive oxygen species may affect vascular tone and lead to vascular complications prevalent in this pathological condition. Defining the complex regulation and roles of these factors merits further investigations, especially in the later endstages of vascular complications, because the development of these complications is linked to the duration of the diabetic state.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelin-1; Heart Rate; Hemodynamics; Hydrogen Peroxide; Insulin; Lipid Peroxides; Male; Nitric Oxide; Oxidative Stress; Peptide Fragments; Rats; Rats, Wistar; Time Factors

Endothelial injury is the main stimulus for endothelin-1 (ET-1) secretion - a strong vasoconstricting agent. The role of endothelial dysfunction in the pathogenesis of hypertension and atherosclerosis which already develops in childhood, has been recently underlined.. To asses plasma ET-1 concentration in children and adolescents with such atherogenic risk factors as hypertension, obesity or diabetes.. The study group consisted of 105 children and adolescents in the mean age of 15.3+/-2.4 years who were divided into 5 groups: (1) hypertension, (2) obesity and hypertension, (3) obesity, (4) diabetes and (5) diabetes with hypertension. The control group was composed of 32 healthy subjects of appropriate weight, aged 14.7+/-2.9 years. Plasma concentration of ET-1 was measured using the enzymatic method ELISA (R and D Systems).. ET-1 plasma concentration was significantly higher in the whole study group than in controls (0.71 vs 0.40 pg/mL; p<0.05) as well as in each studied subgroup compared with healthy subjects (0.63 pg/mL, p<0.05; 0.88 pg/mL p<0.05; 0.96 pg/mL, p<0.05, 0.60 pg/mL, p<0.05, and 0.63, p<0.05, respectively). There was a significant correlation between ET-1 concentration and body mass index in the whole study group (p=0.001) as well as cholesterol (p=0.018) and triglyceride (p=0.001) levels. In the group of patients with hypertension, ET-1 correlated with body mass index (p=0.023) and systolic blood pressure (p=0.02).. Children and adolescents with hypertension, obesity or diabetes have higher ET-1 plasma concentration than healthy subjects. ET-1 level correlates with body mass index, lipid parameters and systolic blood pressure.

Topics: Adolescent; Adult; Child; Coronary Artery Disease; Diabetes Mellitus, Type 1; Endothelin-1; Female; Humans; Hypertension; Male; Obesity; Risk Factors

This study compares plasma endothelin-1 (ET-1) levels in patients with diabetes mellitus or hypertension with healthy controls, and investigates whether ET-1 levels are correlated with glycemic control, metabolic parameters, and vascular complications.. The study population consisted of 103 patients with type 1 diabetes, 124 patients with type 2 diabetes, 35 hypertensive patients without diabetes mellitus, and 99 controls.. Plasma ET-1 concentrations were significantly higher in patients with type 1 diabetes (0.28 +/- 0.34 fmol/mL, P =.001), type 2 diabetes (0.31 +/- 0.32 fmol/mL, P <.0001), and hypertension (0.35 +/- 0.26 fmol/mL, P <.0001) compared to controls (0.08 +/- 0.13 fmol/mL). Diabetic patients taking angiotensin converting enzyme (ACE) inhibitors had significantly lower plasma ET-1 levels than patients without (0.22 +/- 0.20 fmol/mL v 0.38 +/- 0.39 fmol/mL, P =.029). There were significant associations between ET-1 levels and age (r = 0.38, P <.05) and systolic blood pressure (BP) (r = 0.27, P <.05) in healthy controls. In diabetes we found only nonsignificant associations between ET-1 levels and age or vascular complications and a weak association between plasma ET-1 levels and glycemic control.. Patients with diabetes or hypertension have elevated ET-1 levels, but do not exhibit positive correlations between ET-1 levels and BP, which was observed in healthy controls. Increased ET-1 levels do not induce hypertension in diabetes, but were lower in diabetic patients taking ACE inhibitors compared to those without ACE inhibitors. There is no significant association between ET-1 levels and vascular complications. These findings suggest that the plasma ET-1 level is not a marker of endothelial dysfunction but changes in plasma ET-1 levels may precede vascular complications associated with hypertension and diabetes.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 1; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged

It has been reported that improvement of metabolic control by intensified insulin therapy in patients with Type I (insulin-dependent) diabetes mellitus is associated with alterations in ocular blood flow. We hypothesized that these changes in ocular blood flow could be associated with alterations of plasma insulin, glucose or endothelin concentration.. In 16 patients with Type I diabetes ocular haemodynamic parameters were assessed daily during the first 5 days of institution of intensified insulin therapy and plasma concentrations of glucose, insulin, and endothelin-1 plasma were measured. Retinal white blood cell flux was estimated with the blue field entoptic technique. Pulsatile choroidal blood flow was assessed by laser interferometric measurement of fundus pulsation amplitude.. Retinal white blood cell flux ( p=0.0015) and ocular fundus pulsation amplitude ( p<0.001) increased during institution of strict metabolic control. Changes in ocular haemodynamic variables were inversely correlated with concentrations of plasma ET-1, but not with that of insulin or glucose.. These data indicate that institution of improved metabolic status is paralleled by rapid changes in the production of ET-1, which could in turn affect ocular perfusion.

Topics: Adult; Albuminuria; Blood Glucose; Blood Pressure; Cholesterol, HDL; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Dose-Response Relationship, Drug; Endothelin-1; Female; Hemodynamics; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Pulse; Retinal Vessels; Triglycerides

Type I diabetes mellitus is associated with abnormal vascular function, but few studies have documented its effects on human resistance arteries. This study aimed to determine whether endothelial cell and smooth muscle cell function was impaired in resistance arteries isolated from patients with this condition. Biopsies of subcutaneous gluteal fat were taken from 12 patients with Type I diabetes (age 32.3+/-1.9 years; duration of diabetes 13.9+/-2.5 years) and 12 matched controls (age 31.5+/-2.2 years). Levels of glycosylated haemoglobin were higher (P<0.0001) in patients (9.38+/-0.35%) than in controls (5.48+/-0.11%), but most (11 out of 12) patients showed no evidence of microvascular disease. Small resistance arteries were isolated from the biopsies, and isometric responses to vasoconstrictors and vasodilators were measured in a small-vessel myograph. The magnitude and sensitivity of responses to noradrenaline and potassium were not different in diabetic patients compared with controls. In contrast, the sensitivity (pD(2); negative logarithm of the concentration of the vasoconstrictor required to produce 50% of the maximum effect), but not the magnitude, of contraction in response to endothelin-1 in vessels from patients (8.87+/-0.12) was significantly (P=0.02) greater than in those from controls (8.40+/-0.13). Endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (3'-morpholinosydnonimine) relaxation responses were unaltered in patients with Type I diabetes. These results suggest a selective alteration in receptor activity in the endothelium, and contrast strikingly with the considerable evidence of impaired endothelium-dependent relaxation in Type I diabetes. The present study indicates, therefore, that endothelial cell function is largely maintained in resistance arteries from patients with well controlled Type I diabetes. The increased response to endothelin-1 supports the possibility that more significant abnormalities would be evident in patients with severe microvascular complications.

Topics: Adult; Biopsy; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Isometric Contraction; Male; Muscle, Smooth, Vascular; Myography; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Patients with insulin-dependent diabetes mellitus (IDDM) are well known to be at high risk of vascular disease, and dysfunction of vascular endothelium is considered as an early step in the development of diabetic complications. Because of the involvement of autoimmunity in the pathogenesis of IDDM, our aim was to assess, in 45 IDDM patients without clinically evident vascular complications, whether early signs of endothelial cell dysfunction were correlated to alterations of the immune system. IDDM patients were characterized by significantly increased serum levels of C-reactive protein, of polymorphonuclear cells-derived elastase, of endothelin-1 (ET-1) and of thrombomodulin, while plasma concentrations of fibronectin (FNT) were significantly decreased, with a statistically significant inverse correlation between ET-1 and FNT values. The presence of circulating immune complexes (CIC) was investigated in 36 out of our 45 IDDM patients, and values above the cut-off were found in 17 (47.2%) of them. One-third of all patients showed values above the cut-off for IgG-aCL. In IDDM patients, at variance from the control group, the levels of ET-1 were directly correlated to those of von Willebrand factor, of anticardiolipin beta(2)-GPI and of CIC, with an inverse correlation with plasma FNT. An association between antiphospholipid antibodies and endothelial dysfunction and/or activation is therefore suggested, pointing to a synergism, in the early phases of IDDM vascular disease, between generation of autoantibodies and endothelial activation.

Topics: Adult; Antibodies, Anticardiolipin; Antigen-Antibody Complex; Autoantibodies; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Fibronectins; Humans; Immunoglobulin G; Immunoglobulin M; Male; Thrombomodulin; von Willebrand Factor

Diabetes is associated with vascular dysfunction, which may be due in part to altered vascular responses to endogenous peptides such as endothelin-1. These altered responses may also contribute to the decreased maternal peripheral resistance in pregnancy. The aim of this study was to examine the effect of diabetes on the vasoconstrictor response to endothelin-1 in pregnant women. Small arteries were isolated from nine healthy pregnant, seven type 1 diabetic pregnant women, and five healthy nonpregnant women. Contraction curves were performed on a wire myograph for noradrenaline (1 nM to 30 microM) and endothelin-1 (1 pM to 0.3 microM). Maximum responses and sensitivity were compared by t test. No differences in maximum response to noradrenaline or potassium were seen among the three groups. The maximum response to endothelin-1 was significantly increased in pregnancy (P < 0.05), whereas endothelin-1 sensitivity was reduced in the diabetic compared with the nondiabetic pregnant women (P < 0.05). Pregnant women have an increased maximum vasoconstriction response to endothelin-1 compared with nonpregnant women, whereas diabetic pregnant women demonstrate reduced sensitivity to endothelin-1. These observations suggest that endothelin-1 may play a role in maintaining peripheral vascular tone in normal pregnancy, and the decreased sensitivity seen in pregnant women with diabetes may reflect abnormal vascular reactivity.

Topics: Adult; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; In Vitro Techniques; Insulin; Pregnancy; Pregnancy in Diabetics; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstriction

Patients with type 1 diabetes, aged 18 to 42 years, were compared to those aged 11 to 22 years. Activities of endothelial vasoactive factors and endothelial and leukocyte adhesion molecules were studied at different stages of development diabetes complications: nephropathy and retinopathy. The findings reveal role of the vasoactive factors in microangiopathy course.

Topics: Adolescent; Adult; Biomarkers; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; E-Selectin; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Intercellular Adhesion Molecule-1; Microcirculation; Nitric Oxide; Thromboxane A2

The alteration of endothelin (ET) levels in diabetic patients with cardiac autonomic neuropathy (CAN) has not been studied extensively and its correlation with cardiac function parameters has not been discussed.. The aim of the present study was to discuss the correlation between the degree of cardiac autonomic neuropathy, plasma big-ET levels, and cardiac functions in diabetic patients who were clinically free of cardiovascular disease.. Twenty subjects (32.1 +/- 7.8 years, 11 men, 9 women) with insulin-dependent diabetes mellitus (IDDM) were studied to evaluate the relationship between circulating big-endothelin (big-ET1) levels, CAN, and cardiac functions. The severity of CAN was scored according to Ewing's criteria. Cardiac functions were assessed using Doppler echocardiography.. Left ventricular systolic function in the patient group was within normal limits and comparable with the values of the control group (n = 10). The mean E/A values of diabetics with CAN (1.15 +/- 0.33, p = 0.004) and without CAN (1.34 +/- 0.17) were significantly lower than those of controls (1.57 +/- 0.27). Diabetics with CAN had significantly higher big-ET1 values (81.1 +/- 94 pg/ml) compared with others (12.4 +/- 5.9 and 21.1 +/- 17.7 pg/ml, p = 0.04). Circulating big-ET1 levels showed a significant correlation with E/A values in the control group (p = 0.01, r = -0.7) and with peak A values (p = 0.003, r = 0.64) in diabetics. The CAN score correlated negatively with E/A values (p = 0.01, r = 0.54).. High big-ET levels might have an important role in the pathogenesis or consequences of diastolic dysfunction in diabetics with CAN. Their role in cardiac autonomic neuropathy and diastolic dysfunction should be investigated further.

Topics: Adult; Autonomic Nervous System Diseases; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Endothelin-1; Endothelins; Female; Heart; Heart Diseases; Humans; Male; Myocardial Contraction; Prognosis; Protein Precursors; Radioimmunoassay; Ventricular Function, Left

The damage of endothelial integrity is an important step in the atherogenic process. To evaluate the role of circulating endothelin-1 (ET-1) in Type 1 diabetes mellitus (T1DM), plasma ET-1 levels were evaluated in T1DM patients either with (n=9) or without hyperlipidaemia (n=11), or with (n=9) and without (n=11) late diabetic complications, in non-diabetic hyperlipidaemic patients (n=17) and in healthy volunteers. Groups were matched for age, sex and body mass index.. Serum total cholesterol and apolipoprotein B were significantly higher in the diabetic group (p<0.05). Plasma ET-1 level was similar in controls and in non-diabetic hyperlipidaemic subjects (5.77+/-1.74 ng/l vs 4.97+/-1.58 ng/l); however, diabetic hyperlipidaemic patients had a significantly higher plasma ET-1 concentration compared to control subjects (6.67+/-2.44 ng/l vs 4.97+/-1.58 ng/l, p<0.05). Diabetic patients with vascular complications had a significantly higher plasma ET-1 concentration than found in diabetic patients without complications (6.99+/-2.17 ng/l vs 4.74+/-1.27 ng/l, p<0.01) and in controls (6.99+/-2.17 ng/l vs 4.97+/ 1.58 ng/l, p<0.01). Patients with diabetic complications also had a significantly higher apolipoprotein B level compared to healthy controls (0.94+/-0.37 g/l vs 0.66+/-0.12 g/l, p<0.005).. The susceptibility of T1DM patients to the development of atherosclerosis might be attributed to the relationship between elevated lipid levels and ET-1.

Topics: Adolescent; Adult; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Triglycerides

Insulin stimulates endothelin-1 (ET-1) expression in a dose-response relationship, and ET-1 effects on vascular wall structure are similar to the long-term complications of diabetes. We therefore determined whether the plasma ET-1 concentration in patients with diabetes is associated with their total insulin exposure to see if plasma ET-1 might be a link between insulin exposure and long-term complications of diabetes. We studied 69 patients with Type I and 40 patients with Type II diabetes mellitus in equally tight glycaemic control for 2 years in a cross-sectional design. We measured basal and glucagon-stimulated plasma C-peptide, abdominal sagittal diameter, skinfold thickness, glomerular filtration rate, albumin excretion rate and standard clinical characteristics. Mean HbA1c was 6.4% in Type I and 6.3% in Type II diabetes. Patients with an albumin excretion rate >300 microg/min were excluded. Adjusted mean plasma ET-1 was 4.11 (S.E.M. 0.39) pg/ml in 21 normal subjects, 3.47 (0.19) pg/ml in Type I diabetes and 4.84 (0.26) pg/ml in Type II diabetes (P=0.0001). In all patients with measurable plasma C-peptide, plasma ET-1 was associated with basal plasma C-peptide (r=0.5018, P<0.0001), with stimulated plasma C-peptide (r=0.5379, P<0.0001), and with total daily insulin dose (r=0.2219, P=0.00851). Abdominal obesity, metabolic abnormalities, blood pressure and glomerular filtration rate were not associated with plasma ET-1, when corrected for C-peptide and daily insulin dose. Our study shows that the plasma concentration of ET-1 is closely associated with insulin secretion and insulin dose in patients with diabetes. Plasma ET-1 is higher in Type II diabetes than in Type I diabetes. Increased insulin exposure in patients with diabetes may have long-term effects on vascular wall structure through its stimulation of ET-1 expression.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Administration Schedule; Endothelin-1; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Multivariate Analysis

Endothelin-1, and constitutive endothelial nitric oxide synthase, have been implicated in the pathogenesis of diabetic retinopathy. We therefore screened polymorphisms within the genes encoding these two vasoactive agents in a sample of individuals with 15 years of diabetes and no retinopathy (ETDRS level 10 or better) and those with severe retinopathy (ETDRS level 50 or worse).. PCR primers for highly polymorphic sites within the EDN1 and NOS3 genes were used to genotype individuals with type 1 or type 2 diabetes with severe or no retinopathy. Allele frequencies were compared between groups using chi-squared analysis and adjusting for multiple comparisons.. No significant differences were observed in allele frequencies for these two markers between the patients who had retinopathy and the patients who did not.. Polymorphic variability in the EDN1 and NOS3 genes does not appear to have a major impact on determining susceptibility or resistance to diabetic retinopathy.

Topics: Adult; Alleles; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dinucleotide Repeats; Endothelin-1; Genetic Predisposition to Disease; Humans; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Polymerase Chain Reaction; Polymorphism, Genetic

Raised circulating levels of the potent vasoconstrictor endothelin-1 (ET-1) have been demonstrated in diabetes and pregnancy-induced hypertension. Pregnant women with diabetic retinopathy are known to be at a higher risk of developing pregnancy-induced hypertension than those without retinopathy. To examine the association between ET-1, pregnancy, diabetes and diabetic retinopathy, circulating ET-1 levels were measured in each trimester in a cohort of women with and without diabetes during pregnancy.. A cohort of women with diabetes (n = 13) and normal controls (n = 8) were followed throughout pregnancy. Detailed clinical and fundoscopic examinations were carried out according to ETDRS protocols. Plasma ET-1 levels were measured in each trimester using a sensitive radioimmunoassay. Those with diabetes were further divided into those with retinopathy (n = 7) and those without (n = 6).. Plasma levels of ET-1 increased progressively during normal pregnancy and peaked in the third trimester. Women with diabetes had significantly higher levels of plasma ET-1 (14.0 vs 4.6 pg/ml in the first trimester, 14.0 vs 4.8 pg/ml in the second trimester and 15.8 vs 7.2 pg/ml in the third trimester) compared with those without diabetes. These were no significant differences in plasma ET-1 levels between women with diabetes who had pre-existing diabetic retinopathy and those without.. This study has shown that ET-1 levels rise during normal pregnancy, and are higher in women with diabetes, which may reflect pre-existing endothelial damage. Although no association could be demonstrated between diabetic retinopathy and serum ET-1 levels, this may reflect the small sample size in this study.

Topics: Adult; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Endothelin-1; Female; Humans; Pregnancy; Pregnancy in Diabetics; Radioimmunoassay

Endothelins (ETs) belong to a family of vasoactive peptides implicated in several disorders of the microvasculature. In the present study, we investigated ET-1 and ET-3 peptide mRNAs and ETA, ETB receptor mRNAs in the retina of diabetic BB/W rats and age-matched, non-diabetic control animals, following six months of diabetes.. Total mRNA was extracted from each retina and was subjected to reverse transcriptase polymerase chain reaction for ET-1, ET-3, ETA and ETB. Simultaneously, beta-globin was amplified and used as a housekeeping gene. The products were analyzed on agarose gels and the specificity of the amplification was established by hybridization with amplification-specific biotinylated oligoprobes. For quantification, the products from the linear phase of amplification were subjected to serial dilution slot-blot hybridization and densitometry.. ETs and their receptor mRNA expressions were present in the retina. Retinas from the diabetic animals showed significant increases in ET-1, ET-3 ET(A), ET(B) mRNA expressions compared to those from control rats.. These findings indicate that retinal ET-1, ET-3, ET(A) and ET(B) mRNA expression in increased in the chronically diabetic BB/W rat. Augmented gene expression of ETs and their receptors potentially may be of importance in the pathogenesis of retinal microangiopathy in diabetes.

Topics: Animals; Blotting, Southern; Chronic Disease; Diabetes Mellitus, Type 1; Diabetic Retinopathy; DNA Primers; DNA, Antisense; Endothelin-1; Endothelin-3; Endothelins; Gene Expression; Male; Polymerase Chain Reaction; Rats; Rats, Inbred BB; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Retina; RNA; RNA, Messenger

The existence of a hyperactive hypothalamic pituitary adrenal (HPA) axis in diabetics and its relevance to diabetic complications has been controversial. In this study we determined the 24 hour urinary excretion of free cortisol (UFC), its nyctohemeral variation and its relation to indices of diabetic angiopathy. In 130 subjects with IDDM, aged 15.2+/-4.8 years and diabetes duration 7.3+/-5 years, and in 48 controls of comparable age, UFC, urinary endothelin (UET1), urinary albumin, HbA1c, and plasma renin were determined. The total 24-hour UFC excretion was greater in diabetics than in controls (p=0.002) and also greater in diabetic males than in females (p=0.006), while no sex difference was detected in the controls. Day UFC excretion was greater than night UFC excretion (p<0.001) in all subjects. UFC correlated to carotid intimal plus medial thickness (r=0.48, p=0.002), urinary albumin (r=0.50, p<0.001), UET1 (r=0.56, p<0.001), diastolic, systolic and mean blood pressure (r=0.27, p=0.003; r=0.41, p<0.001; r=0.34, p<0.001), BMI (r=0.50, p<0.001), serum creatinine (r=0.35, p<0.001), total cholesterol (r= -0.19, p=0.036), HDL (r= -0.22, p=0.038), LDL (r= -0.23, p=0.032), age (r=0.61, p<0.001) and diabetes duration (r=0.37, p<0.001). These results suggest that hyperactivity of the HPA axis or of the adrenals, due to chronic stress, hypoglycemic episodes or other factors, possibly contributes to the establishment or progression of diabetic micro- or macroangiopathy.

Topics: Adolescent; Adult; Carotid Arteries; Child; Child, Preschool; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Humans; Hydrocortisone; Male; Reference Values; Sex Characteristics; Tunica Intima; Tunica Media; Ultrasonography

Plasma endothelin-1 was measured around the clock in 72 subjects. Cosinor methods were used to assess circadian and other recurrent variation and trends, that is, the time structure (chronome) of this peptide. Multifactorial analyses of variance and linear regressions assessed chronome alterations associated with different risk factors: diabetes, obesity, high cholesterol, high blood pressure, vascular disease, smoking, and age. The rhythm-adjusted mean (MESOR) of endothelin-1 is elevated in diabetes and vascular disease. Diabetes is also associated with a larger circadian amplitude. A circadian variation in a subgroup of low-risk subjects is modulated by components with both lower and higher frequency.

Topics: Adult; Aged; Circadian Rhythm; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Periodicity; Regression Analysis; Risk Factors; Time Factors; Vascular Diseases

Endothelins (ETs) are a family of vasoactive peptides implicated in several disorders of the microvasculature. In the present study, the distribution of immunoreactive ET-1 and ET-3 was investigated in eyes from 8 month spontaneously diabetic BB/W rats and in age matched control animals. Both peptides showed similar immunoreactivity. In non-diabetic animals, corneal epithelium and endothelium, ciliary epithelium, lens epithelium, iris and the microvasculature of the sclera and choroid showed positive immunoreactivity. In the retina, photoreceptor inner segments showed positivity. In the inner nuclear layer, cells of both neuronal and glial origins showed positive immunoreactivity. Both the nuclei and the cytoplasm of the ganglion cells were positively stained. Retinal pigment epithelium showed patchy but consistent immunoreactivity. Capillary endothelial cells showed inconsistent positive staining. The pericytes were uniformly negative. In diabetic animals although overall intensity was increased, retinal pigment epithelium and ciliary epithelium showed no immunoreactivity. The corneal epithelium showed increased but patchy immunoreactivity. The altered intensity and distribution of ETs in diabetes suggest that ETs may be of importance in the pathogenesis of chronic occular complications in the diabetic BB/W rat.

Topics: Animals; Ciliary Body; Cornea; Diabetes Mellitus, Type 1; Endothelin-1; Endothelin-3; Endothelium; Epithelial Cells; Epithelium; Eye; Immunohistochemistry; Lens, Crystalline; Male; Microcirculation; Photoreceptor Cells; Rats; Rats, Inbred BB; Retina; Retinal Vessels

Plasma ET-1 was measured around the clock on different calendar dates in healthy subjects and in subjects with diabetes and/or with high blood pressure and/or a history of vascular complications (HVDR). A transverse approach, with each subject contributing a single 24-h mean, assessed any about-weekly or half-weekly variation in ET-1. A circasemiseptan component resolved by single cosinor for nondiabetic (but not for diabetic) HVDR subjects (p = 0.010) differs in its timing of overall high values (p < 0.050) from that found in healthy subjects (p = 0.006). The results are aligned with circasemiseptan patterns in other circulatory variables and morbidity/mortality statistics.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Cardiovascular Diseases; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Longitudinal Studies; Male; Middle Aged; Periodicity; Risk Factors; Vascular Diseases

Topics: Diabetes Mellitus, Type 1; Endothelin-1; Female; Humans; Pregnancy; Pregnancy in Diabetics