endothelin-1 and Diabetic-Neuropathies

Type 2 diabetes (T2D) accounts for about 90% of all diabetes patients and incurs a heavy global public health burden. Up to 50% of T2D patients will eventually develop neuropathy as T2D progresses. Diabetic peripheral neuropathy (DPN) is a common diabetic complication and one of the main causes of increased morbidity and mortality of T2D patients. Obstructive sleep apnea (OSA) affects over 15% of the general population and is associated with a higher prevalence of T2D. Growing evidence also indicates that OSA is highly prevalent in T2D patients probably due to diabetic peripheral neuropathy. However, the interrelations among diabetic peripheral neuropathy, OSA, and T2D hitherto have not been clearly elucidated. Numerous molecular mechanisms have been documented that underlie diabetic peripheral neuropathy and OSA, including oxidative stress, inflammation, endothelin-1, vascular endothelial growth factor (VEGF), accumulation of advanced glycation end products, protein kinase C (PKC) signaling, poly ADP ribose polymerase (PARP), nitrosative stress, plasminogen activator inhibitor-1, and vitamin D deficiency. In this review, we seek to illuminate the relationships among T2D, diabetic peripheral neuropathy, and OSA and how they interact with one another. In addition, we summarize and explain the shared molecular mechanisms involved in diabetic peripheral neuropathy and OSA for further mechanistic investigations and novel therapeutic strategies for attenuating and preventing the development and progression of diabetic peripheral neuropathy and OSA in T2D.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Progression; Endothelin-1; Glycation End Products, Advanced; Humans; Mice; Neurotransmitter Agents; Oxidative Stress; Plasminogen Activator Inhibitor 1; Poly(ADP-ribose) Polymerases; Prevalence; Protein Kinase C; Rats; Sleep Apnea, Obstructive; Vascular Endothelial Growth Factor A

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET(A) receptor antagonists are discussed.

Topics: Cardiovascular Agents; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Endothelin Receptor Antagonists; Endothelin-1; Humans; Microcirculation; Receptors, Endothelin; Treatment Outcome; Up-Regulation

Erectile dysfunction is a familiar complication of diabetes mellitus, which results from combined factors of impairment to the vascular structure of the penis, the pathological changes in neural system and neural transmitters, and endocrine disorders. There are numerous therapeutic options for the treatment of diabetic erectile dysfunction, including medicines like PDE5 inhibitors, insulin, androgen, surgical therapy and gene therapy.

Topics: Androgens; Diabetes Complications; Diabetic Neuropathies; Endothelin-1; Erectile Dysfunction; Humans; Male; Nitric Oxide

Mineral metabolism is dysregulated within days of acute renal injury in critically ill patients. On univariate analysis, high levels of calcitriol were associated with adverse clinical outcome in AKI. This association was not apparent after adjusting for age and APACHE II. Large controlled studies are needed to confirm these results, and determine if higher 1,25(OH). Los genotipos C/C y C/T en Colombia son tan variables como en otros grupos sanos en otras poblaciones. Los sujetos de nuestra población podrían tener riesgo para el desarrollo de enfermedades asociadas al polimorfismo del genMTHFR y con genotipos de riesgo de presentar toxicidad y efectos adversos del MTX, lo cual sugiere la necesidad de evaluar alternativas terapéuticas con estudios farmacogenéticos.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adult; Advanced Oxidation Protein Products; Aged; Aged, 80 and over; Analgesics, Opioid; Animals; Antibodies, Monoclonal; Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Automation; Benzaldehydes; Bromates; Calcifediol; Calcitriol; Carcinoma, Squamous Cell; Catalase; Chromatography, Liquid; Coloring Agents; Cross-Over Studies; Cross-Sectional Studies; Cytochrome P-450 CYP3A; Cytokines; Diabetic Foot; Diabetic Neuropathies; Diagnostic Self Evaluation; Diosmin; DNA Damage; Double-Blind Method; Drug Combinations; Electrodes; Endothelin-1; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Exercise; Female; Follow-Up Studies; Gene Expression Regulation; Glutathione; Hesperidin; Humans; Illicit Drugs; Indians, North American; Injections, Intravenous; Interferometry; Interleukin-1beta; Interleukin-6; Interviews as Topic; Ions; Jejunum; Kidney; Leukocyte Count; Lipid Peroxidation; Lithium; Liver; Luminescent Measurements; Male; Mice; Middle Aged; Monocytes; Nanostructures; Oklahoma; Organ Specificity; Oxidative Stress; Oxycodone; Photochemistry; Predictive Value of Tests; Pregnane X Receptor; Preoperative Period; Prescription Drugs; Receptors, Steroid; Reference Values; Reproducibility of Results; Retinoid X Receptor alpha; Retrospective Studies; RNA, Messenger; Rumen; Sheep, Domestic; Shoes; Solar Energy; Superoxide Dismutase; Survival Rate; Tandem Mass Spectrometry; Titanium; Treatment Outcome; Tumor Necrosis Factor-alpha; Varicose Veins; Vitamin D; Water Pollutants, Chemical; Weight-Bearing; Young Adult

To observe clinical therapeutic effect of mild-warm moxibustion on diabetic peripheral neuropathy (DPN) and to probe the mechanism.. Sixty cases of DPN were randomly divided into a mild-warm moxibustion group, an acupuncture group and a medication group, 20 cases in each group. In the mild-warm moxibustion group and the acupuncture group, the same points, Shenshu (BL 23), Pishu (BL 20), Zusanli (ST 36), Yongquan (KI 1), etc. were selected; and the medication group were treated with Mecobalamin tablets. Their therapeutic effects and changes of fasting blood-glucose (FBG), glycosylated hematoglobin (GHB), hemorheological indexes, plasma endothelin (ET), nitric oxide (NO) and malondialdehyde (MDA) before and after treatment were investigated.. The total effective rate was 90.0%, FBG, GHB, hemorheological indexes, plasma ET, NO and MDA significantly improved in the mild-warm moxibustion group (P < 0.01), with no significant difference as compared with those in the acupuncture group (P > 0.05), but with a significant difference as compared with the medication group (P < 0.05).. Mild-warm moxibustion has definite therapeutic effect on diabetic peripheral neuropathy, which is better than that of Mecobalamin.

Topics: Adult; Aged; Diabetic Neuropathies; Endothelin-1; Female; Hemodynamics; Humans; Male; Malondialdehyde; Middle Aged; Moxibustion; Nitric Oxide; Peripheral Nervous System Diseases

A high blood concentration of endothelin (ET)-1 may participate in the onset and progress of diabetic microangiopathy, resulting in neuropathy. We examined the therapeutic effects of prostaglandin E1 (PGE1), which possesses both a peripheral vasodilating action and inhibition of platelet aggregation, on diabetic microangiopathy. Increases in both skin temperature and peripheral never conduction velocity in diabetic patients were recorded four weeks after Lipo PGE1 administration. A quantitative decrease in urinary albumin concentration was also observed, suggesting its efficacy of action was on diabetic nephropathy. Lipo PGE1 administration reduced the elevated circulating plasma ET-1 levels in the diabetic patients. As an increase in ET-1 concentrations is thought to correlate with the onset and progress of diabetic microangiopathy, the reduction of plasma ET-1 concentration by Lipo PGE1 administration may be one reason for the improvement in diabetic neuropathy and nephropathy.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Alprostadil; Angiotensins; Blood Glucose; Collagen Type IV; Cyclic AMP; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electric Conductivity; Electrocardiography; Endothelin-1; Fasting; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Peripheral Nerves; Renin; Skin Temperature

Diabetic peripheral neuropathy (DPN) is a common microvascular complication in patients with type 2 diabetes (T2D). Apart from hyperglycemia, few modifiable risk factors have been identified. Endothelin-1 is a potent vasoconstrictor peptide, implicated in the causal pathway of microangiopathy. We investigated whether baseline plasma endothelin-1 and other metabolic and vascular risk factors predicted the incidence of DPN.. This is a 3-year observational, cohort study.. In patients with T2D (n = 2057), anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements. Forearm cutaneous endothelial reactivity was assessed by iontophoresis and laser Doppler flowmetry/imaging. Measurements were repeated on follow-up. Incident DPN was considered present if an abnormal finding in monofilament (<8 of 10 points) or neurothesiometer testing was ≥25 volts on either foot at 3-year follow-up, but normal at baseline. Plasma endothelin-1 was assessed by ELISA.. At baseline, mean age of patients was 57.4 ± 10.8 years old and prevalence of DPN was 10.8%. Of the 1767 patients without DPN, 1250 patients returned for follow-up assessment ((2.9 ± 0.7) years), with a 10.7% incidence of DPN. Patients with incident DPN had significantly higher baseline endothelin-1 (1.43 (1.19-1.73) vs 1.30 (1.06-1.63)) pg/mL, P < 0.0001. Multivariable Cox proportional hazards ratio showed a 1-s.d. increase in log endothelin-1 (adjusted HR: 4.345 (1.451-13.009), P = 0.009), systolic blood pressure (per 10-unit) (adjusted HR: 1.107 (1.001-1.223), P = 0.047) and diabetes duration (adjusted HR: 1.025 (1.004-1.047), P = 0.017) predicted incident DPN, after adjustment for glycemic control, eGFR, albuminuria, peripheral arterial disease and retinopathy status.. Higher baseline endothelin-1, blood pressure and diabetes duration were significant and independent predictors for incident DPN. Validation of our findings in independent cohorts and molecular mechanistic studies will help better our understanding on the role of endothelin-1 in DPN.

Topics: Aged; Blood Pressure; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Endothelin-1; Female; Humans; Incidence; Male; Middle Aged; Prevalence; Proportional Hazards Models; Risk Factors

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. There is an increased attention directed towards the role of angiogenic factors including vascular endothelial growth factor (VEGF) and anti-angiogenic factors including soluble endoglin (sEng) as contributors to diabetic microvascular complications including neuropathy. The purposes of this study were to determine the role of these angiogenesis regulators in the prognosis of DPN. The study group included 60 patients with type 2 diabetes mellitus (T2DM) and 20 clinically healthy individuals. The patients were divided into two groups. Group I included 20 T2DM patients without peripheral neuropathy, and Group II consisted of 40 T2DM patients with DPN. In all groups, plasma VEGF, sEng and endothelin-1 (ET-1), nitric oxide and ET-1 mRNA were estimated. Plasma levels of VEGF, sEng, ET-1 and nitric oxide were significantly elevated in diabetic patients (Groups I and II) compared with healthy control subjects, with a higher increase in their levels in patients with DPN compared with diabetic patients without peripheral neuropathy. Measurement of plasma levels of angiogenesis-related biomarkers in high-risk diabetic patients might identify who later develop DPN, thus providing opportunities for early detection and targets for novel treatments.

Topics: Adult; Aged; Antigens, CD; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Endoglin; Endothelin-1; Female; Humans; Male; Middle Aged; Neovascularization, Physiologic; Nitric Oxide; Receptors, Cell Surface; RNA, Messenger; Vascular Endothelial Growth Factor A

To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM).. In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively.. Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure.. Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.

Topics: Aged; Albuminuria; Blood Glucose; Blood Pressure; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Endothelin-1; Female; Glomerular Filtration Rate; Glucuronidase; Glycated Hemoglobin; Humans; Klotho Proteins; Lipids; Male; Middle Aged; Oxidative Stress; Protein Precursors; Superoxide Dismutase

The roles of endothelin-1 (ET-1) and oxidative stress causing vascular injury in the pathogenesis of diabetic neuropathy are debatable. The present study was undertaken to clarify the possible effects of oxidative stress and ET-1 in diabetic patients with and without peripheric neuropathy.. We studied plasma ET-1, nitric oxide (NO), catalase, glutathione (GSH) levels of fifty (22 females, 28 males) patients with Type 2 diabetes in order to evaluate endothelial dysfunction and oxidative stress. The neuropathy types (motor, sensorial and sensorimotor), comorbid diseases, antidiabetic treatments, smoking, diabetes duration were also considered. Short McGill Pain Questionnaire (SF-MPQ) was also performed for patients with neuropathy.. There were no significant differences between patients with (n=23) and without (n=27) neuropathy with regards to demographic features except diabetic disease duration. The statistical analysis was done considering this difference. Although NO and ET-1 levels were higher, and catalase and GSH levels were decreased in neuropathic patients, no statistical significancy was found. We also couldn't find any correlations between the parameters and SF-MPQ scores.. Although there were no relationships between neuropathy and the studied parameters, we found lower levels of catalase and GSH as intracelluler antioxidants and higher NO and ET-1 as markers of endothelial injury in patients with neuropathy. Our data suggest that there is a need of further studies with larger study groups in order to clear out the role of endothelial injury and oxidative status in the pathogenesis of diabetic neuropathy.

Topics: Adult; Aged; Catalase; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Endothelin-1; Endothelium; Female; Glutathione; Humans; Male; Middle Aged; Neuralgia; Nitric Oxide; Oxidative Stress; Surveys and Questionnaires

Understanding the causes of diabetic vascular complications has become an increasingly important issue because of the rapidly rising prevalence of diabetes. Recently discovered vasoconstrictors and angiogenesis regulators, such as endothelin (ET) and vascular endothelial growth factor (VEGF), have been intensely studied for possible pathogenic roles in diabetic vascular complications. The present study was undertaken to clarify the effect of glycemic control on serum VEGF and plasma ET-1 concentrations in diabetic patients, and to identify other factors that may cause fluctuations of these substances. Plasma VEGF and ET-1 concentrations of 45 hospitalized diabetic patients and 54 control subjects were measured by enzyme immunoassay (EIA) and radioimmunoassay (RIA), respectively. Plasma VEGF was elevated in poorly controlled diabetic patients compared with healthy subjects and plasma VEGF concentrations declined after hospitalized treatment with either insulin or oral hypoglycemic agents in combination with diet. There was a significant correlation between plasma VEGF concentration and both fasting plasma glucose (FPG) and hemoglobin A(1c) (HbA(1c)). Plasma ET-1 in poorly controlled diabetic patients was higher than in healthy controls, but improved glycemic control did not affect plasma ET-1 concentrations. Thus, poor glycemic control causes increased levels of plasma VEGF, which may result in hypertension and vascular complications in diabetes. Short-term treatment resulting in good glycemic control can improve levels of VEGF and may provide beneficial effects on diabetic vascular complications.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Diabetic Retinopathy; Endothelin-1; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Proteinuria; Regression Analysis; Vascular Endothelial Growth Factor A

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

Experimental diabetes is associated with susceptibility to ischemic fiber damage. In a model of ischemia previously studied in our laboratory and induced by topical endothelin-1 (ET-1), diabetic nerves had selective conduction block that progressed to motor fiber inexcitability, associated with prolonged vasoconstrictive ischemia. In this work, we report our analysis of histological consequences of ET-1 ischemia. Our hypothesis was that intense epineurial vasoconstriction would be associated with centrofascicular fiber loss, confined to diabetic nerves. By quantitating the sectorial and fascicular distribution of fibers undergoing axonal degeneration we determined the degree and geographical distribution of axonal damage induced by topical ET-1 in the sciatic nerve trunk two weeks after ischemia. Axonal damage induced by ET-1 in diabetics exceeded that of non-diabetics by a factor greater than 5. The pattern of axonal degeneration was multifocal but not centrofascicular and did not vary with fascicular area. Some small fascicles had rates of axonal degeneration that far exceeded those of large adjacent fascicles. In other instances, sectors with intense axonal degeneration were subperineurial crescentic areas, similar to those originally described by Nukada following microsphere embolization. We conclude that diabetic nerves are highly susceptible to ischemic injury, but that multifocal and not centrofascicular fiber degeneration may be encountered.

Topics: Analysis of Variance; Animals; Diabetic Neuropathies; Disease Susceptibility; Endothelin-1; Ischemia; Male; Peripheral Nerves; Rats; Rats, Sprague-Dawley