atrial-natriuretic-factor and Diabetes-Mellitus--Type-2

Midregional pro-atrial natriuretic peptide (MR-proANP), first isolated in 1981, is a novel peptide with multiple biological functions, especially within the cardiovascular system. This peptide plays an important role in many processes, including natriuresis, diuresis, and other physiological and pathophysiological pathways in the human body. Several electronic databases (PubMed, EBSCO, Scopus, and ScienceDirect) were analyzed in the present literature review. The aim of this study was to elucidate the wide roles of MR-proANP, which can be analyzed because of the development of a new sandwich immunoassay, and to determine the possible diagnostic and prognostic implications of MR-proANP on cardiovascular disease and other disorders. The studies discussed in this literature review provide valuable data on the role of ANP in the pathogenesis, diagnostic process, prognosis, and potential therapeutic strategies for disease. Although ANP is mainly associated with cardiovascular disease, it may be used as a biomarker in diabetology, neurology, and metabolic disorders.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Obesity; Prognosis; Renal Insufficiency, Chronic

Atrial and B-type Natriuretic Peptides (NP) are cardiac hormones with potent cardiovascular and metabolic effects. They signal through the NPRA/cGMP system and are inactivated by a clearance receptor NPRC and neutral endopeptidases (NEP). Recombinant ANP and BNP are currently used as drug treatment for acute decompensated congestive heart failure. Recent literature indicate that a defective NP system is linked to obesity and predict the risk of type 2 diabetes (T2D). Areas covered: This article reviews recent epidemiological, clinical and preclinical evidences that NP system deficiency may be causal of obesity and T2D. The molecular mechanisms of the NP pathway in several metabolic target tissues are presented. The therapeutic potential of NP in obesity and T2D is discussed. Expert opinion: Targeting the NP pathway may offer a novel therapeutic avenue for the management of obesity and T2D. The benefit/risk of drugs increasing circulating NP levels by blocking NPRC and NEP, and/or enhancing NPRA signaling should be assessed in obese and type 2 diabetic individuals.

Topics: Animals; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Humans; Molecular Targeted Therapy; Natriuretic Peptide, Brain; Neprilysin; Obesity; Receptors, Atrial Natriuretic Factor

Natriuretic peptides (NPs) play a key role in cardiovascular homeostasis, counteracting the deleterious effects of volume and pressure overload and activating antibrotic and antihypertrophic pathways in the heart. N-terminal B-type NP (NT-proBNP) also is a promising biomarker of global cardiovascular risk in the general population, and there is increasing interest on its potential use in diabetic patients for screening of silent cardiovascular abnormalities, cardiovascular risk stratification, and guided intervention. Recently, both atrial NP (ANP) and B-type NP (BNP) have emerged as key mediators in the control of metabolic processes including the heart in the network of organs that regulate energy usage and metabolism. Epidemiological studies have shown that ANP and BNP are reduced in people with obesity, insulin resistance, and diabetes, and this deficiency may contribute to enhance their global cardiovascular risk. Moreover, ANP and BNP have receptors in the adipose tissue, enhance lipolysis and energy expenditure, and modulate adipokine release and food intake. Therefore, low ANP and BNP levels may be not only a consequence but also a cause of obesity, and recent prospective studies have shown that low levels of NT-proBNP and midregional proANP (MR-proANP) are a strong predictor of type 2 diabetes onset. Whether ANP and BNP supplementation may result in either cardiovascular or metabolic benefits in humans remains, however, to be established.

Topics: Adipose Tissue; Animals; Atrial Natriuretic Factor; Biomarkers; Biomedical Research; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Risk Factors

In normal and obese humans, lipid mobilization and systemic nonesterified fatty acid levels are thought to be acutely controlled by catecholamines (ie, epinephrine and norepinephrine) and insulin. Natriuretic peptides (NPs) are known to play a key role in the regulation of salt and water balance and blood pressure homeostasis. They are involved in the pathophysiology of hypertension and heart failure. NPs have recently been found to exert potent lipolytic effects (ie, activating the breakdown of stored triacylglycerols) in isolated human fat cells and to promote lipid mobilization in vivo. Atrial natriuretic peptide increases the intracellular 3', 5'-cyclic guanosine monophosphate (cGMP) concentration which activates cGMP-dependent protein kinase leading to perilipin and hormone-sensitive lipase phosphorylation and lipolysis. NPs promote lipid mobilization when administered intravenously. NPs are also responsible for the residual lipid-mobilizing action observed under oral beta-blockade in subjects performing physical exercise. NPs are therefore novel factors which may open promising research pathways to explain the control of lipid mobilization in physiological and pathological conditions. The metabolic impact of altered production and circulation of NPs remains to be established. The potential influence of NPs on the development of lipid disorders, obesity-related cardiovascular events, and cardiac cachexia will be discussed in this review.

Topics: Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Lipid Metabolism; Lipolysis; Metabolic Syndrome; Obesity

Genetic polymorphisms of factors regulating the function of endothelium and blood pressure are recently intensively studied also in type 2 diabetes because endothelial dysfunction and arterial hypertension are risk factors of atherosclerosis. The following review deals with relations of polymorphisms in the renin-angiotensin-aldosterone (RAAS) system, polymorphisms of NO-synthase (NOS) as well as the gene for atrial natriuretic peptide (hANP). So far most information was assembled on the influence of polymorphisms of RAAS genes, in particular the gene coding the angiotensin converting enzyme (ACE), on complications of type 2 diabetes. A relationship with the development of coronary disease was described in ACE genes, the receptor for angiotensin II--type 1 (AT1R), angiotensinogen and in several NOS polymorphisms. Also the relationship of polymorphisms of genes ACE, AT1R, NOS and hANP was described in relation to the development of hypertension which is an important risk factor for macrovascular and microvascular complications of diabetes. In some investigations the relationship of polymorphisms of ACE and AT1R genes and the development of diabetic nephropathy was described where a significant acceleration of the process of atherogenesis occurs. As type 2 diabetes mellitus and atherosclerosis are polygenically determinal diseases, it will be in particular necessary to investigate in future the concurrent influence of several gene polymorphisms and their interactions with the diabetic milieu intérieur on the development of macrovascular and microvascular complications of diabetes.

Topics: Angiotensinogen; Arteriosclerosis; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Humans; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors

CGRP (calcitonin gene-related peptide) is a potent vasodilator neuropeptide which acts on peri-arteriolar neurones and is implicated in the pathogenesis of numerous cardiovascular diseases. The synthesis of CGRP antagonists should be useful for the treatment of Raynaud's disease as well as migraine. There exists an homology between the structures of CGRP and pancreatic amylin and therefore an eventual role of CGRP in type II diabetes pathophysiology is currently being studied.

Topics: Aldosterone; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Digestive System Diseases; Humans; Nervous System Diseases; Renin; Vasodilation

Topics: Animals; Atrial Natriuretic Factor; Catecholamines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Humans; Hypertension; Insulin Resistance; Renin-Angiotensin System; Sodium

To assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on urinary sodium excretion as well as on circulating adrenomedullin and copeptin levels in patients with type 2 diabetes (T2D).. In the LIVE study, patients (n = 241) with left ventricular ejection fraction ≤45% were randomized to liraglutide 1.8 mg daily or placebo for 24 weeks, and 30% had a concomitant diagnosis of T2D. Plasma levels of N-terminal brain-natriuretic-peptide (NT-proBNP) (a predefined secondary endpoint), midregional pro-atrial-natriuretic-peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM) and copeptin were measured at baseline and after 24 weeks in this substudy. The potential effect modification of T2D was assessed.. In the eligible subgroup of 231 patients with available biomarkers (115 randomized to liraglutide and 116 to placebo), MR-proANP decreased by 12% (P = .002) and NT-proBNP by 9% (P = .009) during liraglutide treatment compared with placebo at week 24. Interaction with T2D for the treatment effect of change in MR-proANP and NT-proBNP levels was P = .003 and P = .03, respectively. Consequently, in patients with T2D, liraglutide decreased MR-proANP by 27% (P < .001) and NT-proBNP by 25% (P = .02) compared with placebo, whereas no change was observed in patients without T2D. There was no effect of liraglutide on MR-proADM (P = .10) or copeptin (P = .52).. Liraglutide decreased the A- and B-type natriuretic peptides significantly in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant T2D, suggesting a beneficial mechanism of liraglutide in T2D patients with HFrEF.

Topics: Atrial Natriuretic Factor; Biomarkers; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Liraglutide; Natriuretic Peptide, Brain; Peptide Fragments; Stroke Volume; Ventricular Function, Left

The aim of this study was to determine the levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) after treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitor or dipeptidyl peptidase-4 (DPP4) inhibitor in patients with type-2 diabetes inadequately controlled by insulin, and to determine whether variation in ANP levels can explain favorable cardiovascular outcome.. We enrolled 56 patients, aged 18-80years, with type-2 diabetes inadequately controlled by insulin: i.e., HbA1c level 7.5-10.5% despite at least 8weeks' injectable insulin at a stable mean dose of 20-150IU daily, with or without no more than two oral antidiabetic agents.. The 56 patients were randomized between 3 treatment groups: SGLT2 inhibitor (n=18), DPP4 inhibitor (n=19) and placebo (n=19). Patients who received SGLT2 inhibitor or DPP4 inhibitor treatment all showed significantly lower HbA1c levels, fasting blood glucose (FBG) levels and systolic blood pressure at 24weeks than controls. SGLT2 inhibitor treatment decreased ANP levels, BNP levels, systolic blood pressure and weight compared with placebo. Compared to those receiving DPP4 inhibitor, patients receiving SGLT2 inhibitor showed lower HbA1c levels (7.01 vs. 7.58%; P=0.03), ANP levels (28.41 vs. 43.03 pg/mL; P=0.00) and weight (66.14 vs. 71.76 kg; P=0.04) at 24weeks after adjusting for baseline values. The SGLT2 inhibitor group showed higher sodium concentrations than the placebo and DPP4 inhibitor groups (145.89 vs. 143.89 and 144.79 mmol/L, respectively; P=0.00 and P=0.04) at 24 weeks. ANP and BNP levels did not significantly correlate with HbA1c and blood glucose levels.. These results indicated that SGLT2 inhibitors may be superior to DPP4 inhibitors in reducing risk of cardiovascular disease in diabetic patients. The major study limitation was the small number of patients per group, which should be enlarged in further research.

Topics: Adamantane; Adolescent; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Female; Glucosides; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Natriuretic Peptide, Brain; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Young Adult

Reports that sodium glucose cotransporter 2 inhibitors decrease cardiovascular death and events in patients with diabetes have attracted attention in the cardiology field. We conducted a study of canagliflozin in patients with chronic heart failure and type II diabetes.. Thirty-five Japanese patients with chronic heart failure and type II diabetes were treated with canagliflozin for 12 months. The primary endpoints were the changes of subcutaneous, visceral, and total fat areas at 12 months determined by computed tomography. Secondary endpoints included markers of glycemic control, renal function, and oxidative stress, as well as lipid parameters, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), flow-mediated dilation (FMD), and echocardiographic left ventricular function.. All fat areas (subcutaneous, visceral, and total) showed a significant decrease at 12 months. ANP and BNP also decreased significantly, along with improvement of renal function, oxidized LDL, and E/e', FMD increased significantly after canagliflozin treatment.. Canagliflozin demonstrated cardiac and renal protective effects as well as improving oxidative stress, diastolic function, and endothelial function. This drug was effective in patients who had heart failure with preserved ejection fraction and could become first-line therapy for such patients with diabetes. Trial registration UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000021239.

Topics: Adiposity; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Canagliflozin; Chronic Disease; Diabetes Mellitus, Type 2; Female; Heart; Heart Failure; Humans; Japan; Kidney; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; Weight Loss

This study was designed to comparatively assess the effects of add-on pentoxifylline to losartan versus increasing the dose of losartan on serum N-terminal pro-brain natriuretic peptide (NT-proBNP), serum highly sensitive C-reactive protein (hsCRP) and the urinary albumin excretion (UAE) rate in patients with type 2 diabetes and nephropathy.. In an open-label, single-center, parallel-group, randomized clinical trial (NCT03006952), 30 patients received b.i.d. dose of pentoxifylline 400mg plus daily dose of losartan 50mg (pentoxifylline arm) and 29 patients received b.i.d. dose of losartan 50mg (losartan arm) during a 12-week follow-up period.. Serum NT-proBNP, serum hsCRP and UAE levels all significantly decreased from baseline in both trial arms. The pentoxifylline and losartan trial arms were equally effective in reducing serum NT-proBNP levels during the course of trial (multivariable adjusted model P value = 0.864, effect size = 0.2%). There was a greater decrease in UAE and serum hsCRP levels in the pentoxifylline arm (P = 0.034, effect size = 7.8%; P = 0.009, effect size = 11.7%, respectively). Conversely, patients in the losartan arm achieved better systolic and diastolic blood pressure control (P < 0.001, effect size = 25.4%; P = 0.010, effect size = 11.3%, respectively).. Circulating NT-proBNP levels equally and significantly reduced from baseline in the pentoxifylline and losartan treatment arms, in parallel with comparatively superior decreases of UAE and serum hsCRP in the pentoxifylline arm, and larger decreases of systolic and diastolic blood pressures in the losartan arm.

Topics: Atrial Natriuretic Factor; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Losartan; Male; Middle Aged; Pentoxifylline; Protein Precursors; Serum Albumin, Human; Treatment Outcome

In view of the known vasodilatory effects of glucagon-like peptide-1 and exenatide, we investigated the effects of exenatide on vasoactive factors. We analysed blood samples and mononuclear cells (MNCs) from a previous study, collected after a single dose and 12 weeks of exenatide or placebo treatment in a series of 24 patients with type 2 diabetes mellitus. After exenatide treatment, plasma concentrations of atrial natriuretic peptide, cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate increased significantly at 12 weeks. Plasma cGMP and adenylate cyclase expression in MNCs increased significantly after a single dose. Angiotensinogen concentration fell significantly 2 hours after a single dose and at 12 weeks, while renin and angiotensin II levels fell significantly only after a single dose and not after 12 weeks of treatment. Exenatide also suppressed the plasma concentration of transforming growth factor-β and the expression of P311 in MNCs at 12 weeks. Thus, exenatide induces an increase in a series of vasodilators, while suppressing the renin-angiotensin system. These changes may contribute to the overall vasodilatory effect of exenatide.

Topics: Adenylyl Cyclases; Angiotensinogen; Anti-Obesity Agents; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Type 2; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Leukocytes, Mononuclear; Nerve Tissue Proteins; Obesity; Oncogene Proteins; Peptides; Renin-Angiotensin System; Reproducibility of Results; Single-Blind Method; Transforming Growth Factor beta; Venoms

Topics: Adrenomedullin; Aged; Albuminuria; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycopeptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Peptide Fragments; Protein Precursors; Receptors, Urokinase Plasminogen Activator; Risk Factors; Tumor Necrosis Factor-alpha

To investigate the effects of a single dose of 1.2 mg liraglutide, a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist, on key renal variables in patients with type 2 diabetes.. The study was a placebo-controlled, double-blind, crossover trial in 11 male patients with type 2 diabetes. Measurements included (51) Cr-EDTA plasma clearance estimated glomerular filtration rate (GFR) and MRI-based renal blood flow (RBF), tissue perfusion and oxygenation.. Liraglutide had no effect on GFR [95% confidence interval (CI) -6.8 to 3.6 ml/min/1.73 m(2) ] or on RBF (95% CI -39 to 30 ml/min) and did not change local renal blood perfusion or oxygenation. The fractional excretion of lithium increased by 14% (p = 0.01) and sodium clearance tended to increase (p = 0.06). Liraglutide increased diastolic and systolic blood pressure (3 and 6 mm Hg) and heart rate (2 beats per min; all p < 0.05). Angiotensin II (ANG II) concentration decreased by 21% (p = 0.02), but there were no effects on other renin-angiotensin system components, atrial natriuretic peptides (ANPs), methanephrines or excretion of catecholamines.. Short-term liraglutide treatment did not affect renal haemodynamics but decreased the proximal tubular sodium reabsorption. Blood pressure increased with short-term as opposed to long-term treatment. Catecholamine levels were unchanged and the results did not support a GLP-1-ANP axis. ANG II levels decreased, which may contribute to renal protection by GLP-1 receptor agonists.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Heart Rate; Humans; Kidney; Kidney Function Tests; Liraglutide; Male; Middle Aged; Placebos; Renal Circulation; Renin-Angiotensin System

GLP-1 receptor (GLP-1R) agonists induce natriuresis and reduce blood pressure (BP) through incompletely understood mechanisms. We examined the effects of acute and 21-day administration of liraglutide on plasma atrial natriuretic peptide (ANP), urinary sodium excretion, office and 24-h BP, and heart rate (HR).. Liraglutide or placebo was administered for 3 weeks to hypertensive subjects with type 2 diabetes in a double-blinded, randomized, placebo-controlled crossover clinical trial in the ambulatory setting. End points included within-subject change from baseline in plasma ANP, Nt-proBNP, office BP, and HR at baseline and over 4 h following a single dose of liraglutide (0.6 mg) and after 21 days of liraglutide (titrated to 1.8 mg) versus placebo administration. Simultaneous 24-h ambulatory BP and HR monitoring and 24-h urine collections were measured at baseline and following 21 days of treatment.. Plasma ANP levels did not change significantly after acute (+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 h) or chronic (-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 h) liraglutide administration. Liraglutide significantly increased 24-h and nighttime urinary sodium excretion; however, 24-h systolic BP was not significantly different. Small but significant increases in 24-h and nighttime diastolic BP and HR were observed with liraglutide. Body weight, HbA1c, and cholesterol were lower, and office-measured HR was transiently increased (for up to 4 h) with liraglutide administration.. Sustained liraglutide administration for 3 weeks increases urinary sodium excretion independent of changes in ANP or BP in overweight and obese hypertensive patients with type 2 diabetes.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Rate; Humans; Hypertension; Liraglutide; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Receptors, Glucagon; Sodium

Topics: Administration, Intravenous; Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Male; Middle Aged; Overweight

This study shows the ability of sodium-glucose co-transporter-2 inhibitors to lower atrial natriuretic peptide levels and improve glycaemic control, which may benefit the cardiovascular system.. The correlation between SE and AL/CRC is stronger than that between AL or CRC alone. This suggests that in a research setting, when cycloplegic refraction is difficult to perform on 3-year-old children, AL/CRC may be the next best reference for refractive error.. In the research setting, AL/CRC may be the next best reference for refractive error over AL alone when cycloplegic refraction is unavailable in 3-year old children.

Topics: Active Transport, Cell Nucleus; Adolescent; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Benzhydryl Compounds; Benzylamines; Biopsy; Blood Glucose; Blood Transfusion; Cholesterol, LDL; Combined Modality Therapy; Cyclams; Diabetes Mellitus, Type 2; Disease Progression; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Female; Glucosides; Glycated Hemoglobin; Granulocyte Colony-Stimulating Factor; Hamstring Muscles; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Hodgkin Disease; Humans; Hydrazines; Immunohistochemistry; Insulin-Secreting Cells; Leg; Male; Middle Aged; Muscle Strength; Neoplasms; Peripheral Blood Stem Cell Transplantation; Range of Motion, Articular; Recurrence; Remission Induction; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Soccer; Sodium-Glucose Transport Proteins; Sodium-Glucose Transporter 2 Inhibitors; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Triazoles; Young Adult

Statins have beneficial effects on cardiovascular morbidity and mortality independently of reduction of plasma cholesterol.. In patients with type 2 diabetes and nephropathy, chronic kidney disease stage II-III, we tested the hypothesis that atorvastatin increased systemic and renal nitric oxide (NO) availability using L-NMMA as an inhibitor of NO production. We performed a randomized, placebo-controlled, crossover study, using atorvastatin/placebo treatment for five days with a standardized diet and fluid intake. We measured brachial BP (bBP), central BP (cBP), GFR, urinary output (OU), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of albumin (UAER and UACR), AQP2 (u-AQP2) and ENaC (u-ENaCγ) and plasma concentrations of vasoactive hormones: renin, angiotensin II, aldosterone, arginine vasopressin, endothelin-1 and brain natriuretic peptide.. During atorvastatin and placebo treatment, L-NMMA infusion, changed the effect variables significantly, but to the same extent, i.e. an increase in bBP and cBP, and a decrease in GFR, OU, CH2O, FENa, u-AQP2 and u-ENaCγ. In addition, renin and angiotensin II was reduced, aldosterone increased, and vasopressin, endothelin-1 and brain natriuretic hormone unchanged.. During, atorvastatin and placebo treatment, inhibition of nitric oxide synthesis induced the same response in brachial and central blood pressure, GFR, renal tubular function and vasoactive hormones. Thus, atorvastatin did not change nitric oxide availability in type 2 diabetics with nephropathy.

Topics: Aged; Arginine Vasopressin; Atorvastatin; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glomerular Filtration Rate; Heart Rate; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Tubules; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; omega-N-Methylarginine; Pulse Wave Analysis; Pyrroles; Renal Insufficiency, Chronic; Treatment Outcome; Vascular Stiffness; Vasopressins

The relationship between atrial natriuretic peptide (ANP), increased free fatty acid (FFA) and insulin resistance in patients with mitral valve disease (MVD), a group characterised by elevated atrial pressure and increased ANP levels, is not defined. The present study was performed to evaluate, in MVD patients, the relationship between increased ANP and FFA levels and insulin resistance and the role of mitral valve replacement/repair in ameliorating these metabolic alterations. Conversely, coronary heart disease (CHD) patients were evaluated before and after coronary artery bypass grafting (CABG), since they are known to be insulin resistant in the presence of chronic FFA increase.. Fifty MVD patients and 55 CHD patients were studied before and 2 months after surgery and compared with 166 normal subjects. Before surgery, 56% of MVD patients had impaired glucose tolerance or newly diagnosed type 2 diabetes after a standard oral glucose load and this percentage decreased to 46% after surgery. In CHD, impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetic patients were 67% of patients before and after CABG. In MVD, left atrial (LA) volume, ANP, FFA incremental area and insulin levels were higher and Insulin Sensitivity (IS) index significantly reduced while after surgery, LA volume, ANP and FFA significantly decreased and IS index significantly improved. In CHD, insulin resistance and hyperinsulinaemia were present both before and after surgery with increased tumour necrosis factor (TNF)-α and interleukin (IL)-6 levels.. In MVD, a higher degree of abnormal glucose tolerance and insulin resistance are associated to increased levels of ANP and FFA, while these metabolic alterations are improved by mitral valve replacement/repair surgery. Clinical Trial.gov registration number NCT 00520962.

Topics: Aged; Atrial Natriuretic Factor; Coronary Artery Bypass; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Heart Valve Diseases; Humans; Insulin Resistance; Interleukin-6; Male; Middle Aged; Mitral Valve; Regression Analysis; Tumor Necrosis Factor-alpha

Topics: Acarbose; Atrial Natriuretic Factor; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Postprandial Period; Protein Precursors

Topics: Aldosterone; Amine Oxidase (Copper-Containing); Atrial Natriuretic Factor; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelins; Humans; Hypoglycemic Agents; Pioglitazone; PPAR gamma; Renin; Thiazolidinediones

Thiazolidinediones cause sodium retention and edema by a direct effect on the kidneys. The aim of this study was to use the technique of head-out water immersion to investigate the effects of rosiglitazone on sodium and volume homeostasis in subjects with type 2 diabetes mellitus. The volume expansion response to water immersion was compared with the response on a non-immersion control day in 12 nondiabetic male subjects and 8 diet-controlled male type 2 diabetic subjects with hourly blood and urine sampling over a 4-h period. This was repeated after both groups had taken 4 mg of rosiglitazone daily for 7 days. Immersion produced a natriuresis in both groups (P < 0.001). An impairment of this natriuresis was seen in the diabetic subjects (P = 0.006). However, when rosiglitazone was taken, there was no significant difference in immersion-induced natriuresis compared with nondiabetic controls (P = 0.2). There was an immersion-induced rise in atrial natriuretic peptide (ANP) and urinary cyclic guanosine monophosphate (cGMP), in the healthy subjects (ANP P = 0.001, cGMP P = 0.043), which was not seen in the diabetic subjects (ANP P = 0.51, cGMP P = 0.74). Rosiglitazone restored the immersion-induced increase in cGMP excretion and rise of ANP in the diabetic group (ANP P = 0.048, cGMP P = 0.009). This study confirms that type 2 diabetic subjects have an impaired natriuretic response to acute volume expansion, which appears to be enhanced rather than diminished by rosiglitazone. This may be related to its effects in increasing natriuretic peptides and restoring the impaired cGMP excretion to volume expansion.

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Diabetes Mellitus, Type 2; Homeostasis; Humans; Hypoglycemic Agents; Immersion; Kidney; Male; Middle Aged; Natriuresis; Renin; Rosiglitazone; Thiazolidinediones; Water-Electrolyte Imbalance

We monitored the change in plasma ANP and BNP levels (as markers for left ventricular dysfunction (LVD)) in DM2 patients treated with pioglitazone (Pio) for 4 weeks. Thirty DM2 patients with no sign of heart failure were treated with Pio (15 mg/day), and their plasma ANP (normal levels

Topics: Aged; Atrial Natriuretic Factor; Body Mass Index; Buformin; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Heart Failure; Humans; Hypoglycemic Agents; Male; Middle Aged; Natriuretic Peptide, Brain; Pioglitazone; Stroke Volume; Thiazoles; Thiazolidinediones

Atrial natriuretic peptide (ANP) increases urine albumin excretion (UAER) in humans with Type 1 diabetes. The aim of this study was to establish if ANP increases UAER in microalbuminuric subjects with Type 2 diabetes and to examine whether the albuminuric action of ANP was inhibited by pre-treatment with the ACE-inhibitor perindopril.. Seven microalbuminuric, normotensive males with Type 2 diabetes were entered into a randomised, double-blind, three-armed study of (i) intravenous infusion of ANP (0.25 microg/kg/min in 0.9% NaCl) after 3 weeks' pre-treatment with placebo, (ii) intravenous infusion of vehicle (0.9% NaCl only) after 3 weeks' pre-treatment with placebo, or (3) intravenous infusion of ANP (0.25 microg/kg/min in 0.9% NaCl) after 3 weeks' pre-treatment with perindopril, 4 mg daily.. Baseline parameters were similar on all three study days. During the placebo/vehicle arm there was no change in urine flow rate (UFR, P=0.61), urine cyclic guanosine monophosphate (UcGMP P=0.48) or UAER (P=0.99). During the placebo/ANP arm there was a rise in UFR [13.7+/-2.8 (mean+/-sd) to 25.7+/-7.7 mL/min, P<0.001], UcGMP (60.0+/-36.6 to 160.8+/-118.5 micromol/mmolCr, P=0.045) and UAER [5.13 [2.4-11.6][median (range)] to 71.6 [21.6-175.1] mg/mmolCr, P<0.001]. Pre-treatment with perindopril did not alter the changes in UFR (P=0.63), UcGMP (P=0.46) or UAER (P=0.99) to infusion of ANP, compared with the placebo/ANP arm.. ANP increases UAER in microalbuminuric patients with Type 2 diabetes and the albuminuric action of ANP is not inhibited by pre-treatment with the ACE inhibitor perindopril.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Male; Middle Aged; Perindopril

Increased plasma atrial natriuretic peptide (ANP) levels and impaired ANP action have been reported in patients with diabetes or insulin resistance. The aim of this study was to assess the interaction between insulin and ANP in type 2 diabetes. In 12 normotensive, normoalbuminuric type 2 diabetics, we infused insulin at a high (6.6 pmol/min/kg) or, on a different day, at a low rate (0.6 pmol/min/kg) during 4 hours of isoglycemia under isovolumic, isoosmolar conditions. The normal response was established in 12 healthy volunteers using an identical protocol. Despite higher baseline ANP levels (17.7 +/- 2.8 vs. 10.8 +/- 1.8 pg/ml, p = 0.04), urinary sodium excretion was similar in diabetics and controls (113 +/- 8.5 vs. 102 +/- 8.8 mEq/24 hours, p = ns). In both groups, hyperinsulinemia caused a decrease in blood volume (0.33 +/- 0.10 l, p < 0.01), diastolic blood pressure (6 %, p < 0.02), and natriuresis. However, plasma ANP decreased in controls (from 12.7 +/- 1.9 to 8.6 +/- 1.4 pg/ml, p = 0.01) but not in type 2 diabetics (15.1 +/- 2.7 vs. 17.2 +/- 3.8 pg/ml, p = ns). We conclude that ANP release is resistant to volume stimulation in type 2 diabetic patients, and natriuresis is resistant to ANP action. This dual disruption of ANP control may play a role in blood pressure regulation in diabetes.

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Blood Glucose; Blood Volume; Body Mass Index; Diabetes Mellitus, Type 2; Electrolytes; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Natriuresis; Renin

This study sought to determine if the severity of autonomic perturbations in patients with heart failure are affected by the presence of diabetes. Decreased HRV is frequent in diabetic patients free of clinically apparent heart disease and has been invoked as a risk factor for sudden cardiac death. However, reduced HRV is also commonly present in patients with left ventricular dysfunction. The effect of diabetes on autonomic dysfunction in this setting is not known. Holter ECGs from 69 diabetic patients and 85 nondiabetic control subjects with heart failure were analyzed. The severity of autonomic dysfunction was assessed using 24-hour time- and frequency-domain HRV analysis. Prognostically important time- and frequency-domain HRV measures (SDNN, SDANN5, total power, and ultra-low frequency power) were not different between the two groups. Time- and frequency-domain parameters modulated by parasympathetic tone (pNN50, RMSSD, and HF power) were depressed to a similar degree in the diabetic and the nondiabetic groups. The low frequency power was significantly lower in diabetic patients (5.8 +/- 0.7 vs 5.3 +/- 1.0, P = 0.02). The ratio of low to high frequency power was substantially lower in the diabetic group (2.2 +/- 0.2 vs 1.4 +/- 0.2, P < 0.0001). These differences were more apparent in insulin-treated diabetics. In the presence of heart failure, HRV parameters that are most predictive of adverse outcome are similar in diabetic and nondiabetic patients. Furthermore, during increased sympathetic stimulation in the setting of heart failure, diabetes does not worsen parasympathetic withdrawal but may mitigate sympathetic activation.

Topics: Atrial Natriuretic Factor; Cardiotonic Agents; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dobutamine; Electrocardiography, Ambulatory; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Signal Processing, Computer-Assisted

Relatively few data exist on atrial natriuretic peptide (ANP) characteristics in Type 2 diabetes mellitus (DM). Therefore, plasma immunoreactive ANP concentrations were measured before and for 4 h following the ingestion of a physiological mixed meal in 8 newly diagnosed, normotensive, normoalbuminuric, patients with Type 2 DM and 6 normotensive, non-diabetic controls. In patients with Type 2 DM, basal plasma ANP concentrations were 4.0 +/- 2.0 and not significantly changed following ingestion of the meal, with peak levels of 4.9 +/- 2.8 pmol l(-1). Non-diabetic controls had higher basal plasma ANP concentrations, 8.7 +/- 3.4 pmol l(-1) (p < 0.05), significantly increasing to a peak of 11.9 +/- 6.3 pmol l(-1) at 30 min post meal. Extracellular fluid volume (ECV) was not different between diabetic patients and controls (15877 +/- 2679 vs 13668 +/- 1792 ml3). Glomerular filtration rate (GFR) (isotopic clearance corrected for body surface area) was elevated in diabetic patients (mean +/- SD) 130 +/- 39 vs 98 +/- 10 ml min(-1), p < 0.05). For the DM subjects, basal ANP levels were negatively correlated with GFR (rs - 0.74, p < 0.05) and effective renal plasma flow (ERPF) (rs - 0.8, p < 0.05). We conclude that patients with Type 2 DM demonstrate reduced basal plasma ANP concentrations which are inversely correlated to renal function. In contrast to non-diabetic controls, ANP in Type 2 DM does not rise in response to feeding.

Topics: Adult; Aged; Analysis of Variance; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Fasting; Food, Formulated; Glomerular Filtration Rate; Glycated Hemoglobin; Hematocrit; Humans; Insulin; Kidney; Kidney Function Tests; Male; Middle Aged; Renal Plasma Flow, Effective; Urea

To examine the factors that determine the blood pressure response to enalapril and nifedipine monotherapy in the treatment of hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM).. After a 6-week placebo baseline period, 102 hypertensive NIDDM patients were randomly assigned, double-blindly, to treatment with nifedipine retard (slow release) (n = 52) or enalapril (n = 50). The daily dosage of enalapril was increased, if required, from 10 to 20 to 40 mg and that of nifedipine from 40 to 60 to 80 mg at 4-week intervals during the 12-week titration period. Blood pressure, 24-h urinary albumin excretion (UAE), biochemical data, and serum angiotensin-converting enzyme (ACE) activity were measured at weeks -6, -4, 0, 4, 8, and 12. At week 0, venous blood was also sampled for baseline plasma atrial natriuretic peptide, renin, aldosterone, and serum insulin concentrations.. At week 12, the mean daily dose of enalapril was 35 +/- 11.4 mg, and 27 (57%) patients were receiving the maximum daily dose of 40 mg. In the nifedipine group, the mean daily drug dose was 50 +/- 12.9 mg, and 4 (8%) were receiving the maximum daily dose of 80 mg. Despite a dose-dependent fall in the serum ACE activity in the enalapril group, the mean arterial pressure (MAP) was reduced by only 8 mmHg throughout the 12-week titration period compared to a decline of 15, 18, and 19 mmHg at weeks 0, 4, and 12, respectively, in the nifedipine group (P = 0.01 between groups). In the enalapril group, changes in MAP between weeks 0 and 12 correlated significantly with baseline plasma glucose (r = 0.45, P = 0.001) and aldosterone concentrations (r = -0.32, P = 0.02) and UAE (r = 0.3, P = 0.04). There was no statistically significant correlation between the changes in MAP and baseline plasma renin concentration. On multivariate analysis, the baseline renal function, glycemic control, and plasma aldosterone and serum insulin concentrations were all independently related to the changes in blood pressure in the enalapril-treated patients. No such statistical associations were observed in the nifedipine group.. In hypertensive NIDDM patients, the activity of the renin-angiotensin-aldosterone system, the level of serum insulin, glycemic control, renal function, and proteinuria may be important determinants of the blood pressure response to ACE inhibition. Good glycemic control may optimize the antihypertensive efficacy of concomitant ACE inhibitor therapy.

Topics: Albuminuria; Aldosterone; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Furosemide; Glycated Hemoglobin; Humans; Hypertension; Indapamide; Nifedipine; Placebos; Potassium; Regression Analysis; Renin; Sodium; Time Factors

The effects of a short-time insulin suppression on Na+ excretion were evaluated in 9 type II diabetic hypertensive males. All patients had a body mass index < 26 and normal plasma lipid levels. After 2 weeks under constant NaCl intake (120 mEq of NaCl daily) either octreotide, a somatostatin analogue, or its vehicle were infused in a forearm vein during acute volume expansion (0.20 ml/kg/min isotonic saline given intravenously over a period of 30 min). A double blind randomized cross-over design was followed, and each patient was given both infusions at one week interval. Blood and urine samples for the evaluation of plasma insulin and serum and urine Na+ were taken at time-30, 0, 30, 60, 90, 120, and 240 min. Our data showed that octreotide completely suppressed insulin levels (from time 0 to 60 min). During acute volume expansion+octreotide, Na+ excretion was 0.20 +/- 0.15 mEq/min at time 0, 0.23 +/- 0.21 mEq/min at time 30, 0.64 +/- 0.24 mEq/min at 60 (p < 0.05 vs time 0), 0.71 +/- 0.35 mEq/min at 90 (p < 0.05 vs time 0), 0.78 +/- 0.10 mEq/min at 120 (p < 0.01 vs time 0) and 0.71 +/- 0.12 mEq/min at 240 min (p < 0.05 vs time 0). As compared to acute volume expansion alone, octreotide induced a significant increase of Na+ excretion at 60 and 90 min (p < 0.05). In conclusion, a short-time insulin suppression, as obtained by the somatostatin analogue octreotide, enhances the natriuretic response to intravenous saline load in lean type II diabetic hypertensives.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 2; Diastole; Double-Blind Method; Humans; Insulin; Insulin Secretion; Isotonic Solutions; Kidney; Male; Middle Aged; Natriuresis; Octreotide; Renin; Sodium; Sodium Chloride; Systole

Eighteen patients with non-insulin dependent diabetes mellitus and hypertension were treated during two 4 week periods with the calcium antagonist felodipine or placebo in a double-blind, randomised, cross-over study. Mean systemic blood pressure was significantly lower on felodipine, without producing a deleterious effect on diabetic control. Felodipine was associated with an increment in plasma renin concentration but plasma aldosterone and the renal outputs of sodium and dopamine were similar on both treatments. Plasma atrial natriuretic peptide levels were significantly reduced following felodipine treatment.

Topics: Aged; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Renin

Measurement of natriuretic peptides (NPs) has proven its clinical value as biomarker, especially in the context of heart failure (HF). In contrast, a state of partial NP deficiency appears integral to several conditions in which lower NP concentrations in plasma presage overt cardiometabolic disease. Here, obesity and type 2 diabetes have attracted considerable attention. Other factors-including age, sex, race, genetics, and diurnal regulation-affect the NP "armory" and may leave some individuals more prone to development of cardiovascular disease. The molecular maturation of NPs has also proven complex, with highly variable O-glycosylation within the biosynthetic precursors. The relevance of this regulatory step in post-translational propeptide maturation has recently become recognized in biomarker measurement/interpretation and cardiovascular pathophysiology. An important proportion of people appear to have reduced effective net NP bioactivity in terms of receptor activation and physiological effects. The state of NP deficiency both entails a potential for further biomarker development and could also offer novel pharmacological possibilities. Alleviating the state of NP deficiency before development of overt cardiometabolic disease in selected patients could be a future path for improving precision medicine.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Natriuretic Peptide, Brain; Natriuretic Peptides

Low concentrations of natriuretic peptides (NPs) have been associated with greater risk for Type 2 diabetes (T2D). African American individuals (AA) have lower NP levels and are disproportionately burdened by T2D. The purpose of this study was to test the hypothesis that higher post-challenge insulin in AA adults is associated with lower plasma N-terminal pro-atrial natriuretic peptide (NT-proANP). A secondary purpose was to explore associations between NT-proANP and adipose depots. Participants were 112 AA and European American (EA) adult men and women. Measures of insulin were obtained from an oral glucose tolerance test and hyperinsulinemic-euglycemic glucose clamp. Total and regional adipose depots were measured from DXA and MRI. Multiple linear regression analysis was used to assess associations of NT-proANP with measures of insulin and adipose depots. Lower NT-proANP concentrations in AA participants was not independent of 30-min insulin area under the curve (AUC). NT-proANP was inversely associated with 30-min insulin AUC in AA participants, and with fasting insulin and HOMA-IR in EA participants. Thigh subcutaneous adipose tissue and perimuscular adipose tissue were positively associated with NT-proANP in EA participants. Higher post-challenge insulin may contribute to lower ANP concentrations in AA adults.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Male; Natriuretic Peptides; Obesity; Peptide Fragments

Low-density lipoprotein receptor-related protein 1 (LRP1) negatively modulates circulating atrial natriuretic peptide (ANP) levels. Both molecules are involved in the regulation of cardiometabolism.. To evaluate soluble LRP1 (sLRP1) and ANP levels in people with newly diagnosed type 2 diabetes mellitus (T2DM) and determine the effects of metabolic optimization.. This single-center longitudinal observational study recruited patients with newly diagnosed T2DM (. T2DM had higher sLRP1 levels than the control group (p = 0.014) and lower ANP levels (p =0.002). At 12 months, 23 T2DM patients reached the target of HbA1c ≤ 6.5%. These patients significantly reduced sLRP1 and increased ANP levels. Patients who did not achieve HbA1c < 6.5% failed to normalize sLRP1 and ANP levels. There was an inverse correlation in the changes in sLRP1 and ANP (p = 0.031). The extent of sLRP1 changes over 12 months of metabolic control positively correlated with those of total cholesterol, LDL cholesterol, TG, TG/HDLc, and apolipoprotein B.. Newly diagnosed T2DM patients have an increased sLRP1/ANP ratio, and increased sLRP1 and decreased ANP levels are normalized in the T2DM patients that reached an strict glycemic and metabolic control. sLRP1/ANP ratio could be a reliable marker of cardiometabolic function.

Topics: Apolipoproteins B; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Glycemic Control; Humans

Breast cancer is one of the most common cancers worldwide among women, and angiogenesis has an important effect on its growth and metastasis. Glipizide, which is a widely used drug for type 2 diabetes mellitus, has been reported to inhibit tumor growth and metastasis by upregulating the expression of natriuretic peptide receptor A (NPRA). Atrial natriuretic peptide (ANP), the receptor of NPRA, plays an important role in angiogenesis. The purpose of this study was to explore the effect of glipizide combined with ANP on breast cancer growth and metastasis.. This study aimed at investigating the effect of glipizide combined with ANP on breast cancer. Glipizide, ANP, or glipizide combined with ANP was intraperitoneally injected into MMTV-PyMT mice. To explore whether the anticancer efficacy of glipizide combined with ANP was correlated with angiogenesis, a tube formation assay was performed.. Glipizide combined with ANP was found to inhibit breast cancer growth and metastasis in MMTV-PyMT mice, which spontaneously develop breast cancer. Furthermore, the inhibitory effect of ANP combined with glipizide was better than that of glipizide alone. ANP combined with glipizide significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by suppressing vascular endothelial growth factor (VEGF)/VEGFR2 (vascular endothelial growth factor receptor 2) signaling.. These results demonstrate that glipizide combined with ANP has a greater potential than glipizide alone to be repurposed as an effective agent for the treatment of breast cancer by targeting tumor-induced angiogenesis.

Topics: Angiogenesis Inhibitors; Animals; Atrial Natriuretic Factor; Breast Neoplasms; Cell Movement; Cell Proliferation; Diabetes Mellitus, Type 2; Female; Glipizide; Human Umbilical Vein Endothelial Cells; Humans; Mice; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 μL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cardiomyopathies; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Fibrosis; Hyperglycemia; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinase 10; Natriuretic Peptide, Brain; Receptors, Leptin; RNA, Messenger; Signal Transduction; Sirtuin 1

Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD.. Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models.. Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19];. NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.

Topics: Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Natriuretic Peptide, Brain; Natriuretic Peptides; Peptide Fragments; Risk Assessment; Risk Factors

The aim of this study was to investigate the association between plasma MR-proANP and cardiovascular disease (CVD) in a middle-aged population with type 2 diabetes.. MR-proANP was measured in 690 patients with type 2 diabetes participating in the epidemiological study CARDIPP (Cardiovascular Risk Factors in Patients with Diabetes-a Prospective Study in Primary Care). The outcome variables were incident major adverse cardiovascular events (MACE) and all-cause mortality. Patients were followed using the national Swedish Cause of Death Registry and the Inpatient Register.. During the mean follow-up period of 10.8 years, MACE occurred in 111 patients and 102 patients died. The hazard ratio for an increment of MR-proANP of 1 pmol/l adjusted for sex, age, current smoking, previous CVD, HbA1c, serum cholesterol, eGFR, systolic blood pressure, C-reactive protein, aortic pulse wave velocity, left ventricular mass and intima media thickness in the carotid arteries was 1.007 (95% CI 1.000-1.013, P = 0.042) for MACE and 1.008 (95% CI 1.001-1.014, P = 0.017) for all-cause mortality.. Elevated MR-proANP levels predict an increased risk for MACE and all-cause mortality in patients with type 2 diabetes independently of CVD risk factors and markers for subclinical organ damage.

Topics: Atrial Natriuretic Factor; Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Humans; Middle Aged; Prospective Studies; Pulse Wave Analysis

Atrial natriuretic peptide (ANP) is a cardiovascular and metabolic hormone that has been identified recently as being associated with chronic kidney disease (CKD) without diabetes. Cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and adiponectin (ADP) contribute to the development of type 2 diabetes (T2DM). The aim here was to investigate the relationships of ANP with cytokine levels and clinical variables in T2DM nephropathy patients.. A total of 81 participants with T2DM were recruited, including 37 patients with normoalbuminuria, 23 patients with microalbuminuria and 21 patients with macroalbuminuria. Serum concentrations of ANP and cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANP and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANP and the severity and presence of albuminuria.. The macroalbuminuria patients exhibited higher plasma levels of ANP, TNF-α, IL-6, and ADP; higher serum creatinine (Cr) and blood urea nitrogen (BUN); and longer duration of diabetes mellitus (DM) than the patients with normoalbuminuria and microalbuminuria. Plasma ANP level was significantly associated with TNF-α (r = 0.876, p < 0.001), IL-6 (r = 0.816, p < 0.001) and ADP (r = 0.772, p < 0.001), independent of the duration of DM or the BUN concentration.. ANP is higher in type 2 diabetes mellitus nephropathy subjects, especially those who have macroalbuminuria, which is associated with compensatory responses to inflammation.

Topics: Aged; Aged, 80 and over; Albuminuria; Atrial Natriuretic Factor; China; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis

Type 2 diabetes mellitus (T2DM) increases cardiac inflammation which promotes the development of cardiac fibrosis. We sought to determine the impact of circadian disruption on the induction of hyperglycaemia, inflammation and cardiac fibrosis.. Psammomys obesus (P. obesus) were exposed to neutral (12 h light:12 h dark) or short (5 h light:19 h dark) photoperiods and fed a low energy (LE) or high energy (HE) diet for 8 or 20 weeks. To determine daily rhythmicity, P. obesus were euthanised at 2, 8, 14, and 20 h after 'lights on'.. P. obesus exposed to a short photoperiod for 8 and 20 weeks had impaired glucose tolerance following oral glucose tolerance testing, compared to a neutral photoperiod exposure. This occurred with both LE and HE diets but was more pronounced with the HE diet. Short photoperiod exposure also increased myocardial perivascular fibrosis after 20 weeks on LE (51%, P < 0.05) and HE (44%, P < 0.05) diets, when compared to groups with neutral photoperiod exposure. Short photoperiod exposure caused elevations in mRNA levels of hypertrophy gene Nppa (atrial natriuretic peptide) and hypertrophy transcription factors Gata4 and Mef2c in myocardial tissue after 8 weeks.. Exposure to a short photoperiod causes impaired glucose tolerance in P. obesus that is exacerbated with HE diet and is accompanied by an induction in myocardial perivascular fibrosis.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 2; Diet; Energy Intake; Fibrosis; Gene Expression Regulation; Gerbillinae; Glucose Tolerance Test; Heart Diseases; Light; Photoperiod; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases

The prevalence of heart failure (HF) in patients with type 2 diabetes (T2DM) is debatable and no data exist concerning the diagnostic value of mid-regional pro-atrial natriuretic peptide (MR-proANP). We aimed to identify HF prevalence and evaluate the diagnostic value of MR-proANP in outpatients followed in two specialized diabetes clinics. HF was pre-defined as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The prevalence of HFrEF and HFpEF was 2.4% and 17.5%, respectively. An MR-proANP <60 pmol/L ruled out HFrEF in the total population (n = 806) and in patients reporting dyspnea (n = 311) with a sensitivity of 94.7% and 87.5%, a negative predictive value of 99.7% and 99.0%, a specificity of 39.5% and 33.0%, and a positive predictive value of 3.6% and 3.3%, respectively. In a multivariable model including age, sex, T2DM duration, albuminuria, uncontrolled systolic blood pressure, abnormal electrocardiogram and ischaemic heart disease for diagnosis of HF in patients reporting dyspnea, adding MR-proANP increased the area under the curve from 0.69 to 0.78 (P < 0.001). In conclusion, HFrEF was rare among outpatients with T2DM. MR-proANP rules out HFrEF and contributes independent information relevant to diagnosis of HF in patients reporting dyspnea.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Echocardiography; Female; Heart Failure; Humans; Male; Middle Aged; Outpatients; Predictive Value of Tests; Prevalence; Prognosis; Sensitivity and Specificity; Stroke Volume

A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such as NPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of the DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J, and the decrease of cardioprotective EETs.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Cell Line; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Eicosanoids; Epoxide Hydrolases; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Natriuretic Peptide, Brain; Obesity; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Signal Transduction; Streptozocin

The sodium-sparing effect of insulin leads to increase in total sodium pool of the body which is a chronic stimulus for atrial natriuretic peptide (ANP). In our study we aimed to determine the relationship between ANP and microvascular complications of diabetes.. 60 patients, 30-70 years old, with the diagnosis of type 2 diabetes mellitus (DM) are enrolled into the study. Patients with a chronic disease other than DM are excluded. Blood samples for routine biochemical tests are taken after at least 12 h fasting at 8-9 am. Blood samples for glucose and insulin levels are taken 2 h after a standard meal. Blood tubes with EDTA are used for ANP levels. The microvascular complications of the patients are evaluated.. 32 of the patients had microvascular complications. Age, BMI, waist and hip circumferences, and ANP levels were significantly higher in the group with microvascular complications. There were no significant differences in waist-to-hip ratio, blood glucose, HbA1c, fasting insulin, postprandial insulin, fasting HOMA, postprandial HOMA as well as sodium, potassium, magnesium, calcium and lipid levels between the two groups. When the relationship between ANP and obesity, retinopathy, neuropathy, nephropathy, diabetes time, HbA1c, or sex are evaluated separately, the only significant parameters related to ANP were obesity and retinopathy.. In our study we have found that there was a significant relationship between ANP levels and microvascular complications of diabetes. Future studies are needed to show if ANP is the stimulus of microvascular complication development/progression or only an epiphenomenon.

Topics: Adult; Aged; Aryldialkylphosphatase; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Brachial Artery; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Insulin; Male; Middle Aged; Obesity; Organ Size; Tunica Intima

Topics: Adult; Aged; Atrial Natriuretic Factor; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Male; Meals; Middle Aged; Postprandial Period; Protein Precursors

Catecholamines and atrial natriuretic peptide (ANP) are major regulators of adipocyte lipolysis. Although obesity is characterized by catecholamine resistance in subcutaneous adipose tissue (SCAT), data on ANP lipolytic response and sensitivity in different adipose tissue (AT) depots of metabolically distinct humans are scarce. Ex vivo catecholamine- and ANP-induced lipolysis was investigated in adipocytes derived from SCAT and visceral AT (VAT) depot of lean (n=13) and obese men, with (n=11) or without (n=18) type 2 diabetes (HbA1c < or ≥ 6.5%). Underlying molecular mechanisms were examined by looking at functional receptors in the NP signalling pathway at the mRNA and protein level. Maximal ANP- and catecholamine-induced lipolysis in SCAT was blunted in obese type 2 diabetics compared with age-matched lean men whereas non-diabetic obese subjects showed intermediate responses. This blunted ANP-mediated lipolytic response was accompanied by lower mRNA and protein expression of the type-A natriuretic peptide (NP) receptor and higher mRNA but reduced protein expression of the scavenging type-C receptor. Maximal ANP-induced lipolysis was lower in VAT compared with SCAT but not different between groups. Collectively, our data show that both ANP- and catecholamine-mediated lipolysis is attenuated in SCAT of obese men with type 2 diabetes, and might be partially explained by NP receptor defects. Therefore, improving maximal ANP responsiveness in adipose tissue might be a potential novel strategy to improve obesity-associated metabolic complications.

Topics: Adipocytes; Adult; Atrial Natriuretic Factor; Catecholamines; Diabetes Mellitus, Type 2; Humans; Lipolysis; Male; Middle Aged; Obesity; Subcutaneous Fat

Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about the ANP relevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms of ANP to discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently. Method. ANP gene polymorphisms (I/D and A191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls. Result. This case-control study discovered a significant association between I/D polymorphisms of ANP gene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms of ANP in EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P < 0.05). Conclusion. As a risk factor, ANP gene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing the ANP gene polymorphisms in both EH and T2DM patients among Malaysian population.

Topics: Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Essential Hypertension; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Malaysia; Male; Middle Aged; Polymorphism, Single Nucleotide

The Goto-Kakizaki (GK) rat, a non-obese model of type 2 diabetes mellitus (T2DM), was generated by the selective inbreeding of glucose-intolerant Wistar rats. This is a convenient model for studying diabetes-induced cardiomyopathy independently from the effects of the metabolic syndrome. We investigated the myocardial functional and structural changes and underlying molecular pathomechanisms of short-term and mild T2DM. The presence of DM was confirmed by an impaired oral glucose tolerance in the GK rats compared with the age-matched nondiabetic Wistar rats. Data from cardiac catheterization showed that in GK rats, although the systolic indexes were not altered, the diastolic stiffness was increased compared with nondiabetics (end-diastolic-pressure-volume-relationship: 0.12 ± 0.04 vs. 0.05 ± 0.01 mmHg/μl, P < 0.05). Additionally, DM was associated with left-ventricular hypertrophy and histological evidence of increased myocardial fibrosis. The plasma pro-B-type natriuretic peptide, the cardiac troponin-T, glucose, and the urinary glucose concentrations were significantly higher in GK rats. Among the 125 genes surveyed using PCR arrays, DM significantly altered the expression of five genes [upregulation of natriuretic peptide precursor-A and connective tissue growth factor, downregulation of c-reactive protein, interleukin-1β, and tumor necrosis factor (TNF)-α mRNA-level]. Of the altered genes, which were evaluated by Western blot, only TNF-α protein expression was significantly decreased. The ECG recordings revealed no significant differences. In conclusion, while systolic dysfunction, myocardial inflammation, and abnormal electrical conduction remain absent, short-term and mild T2DM induce the alteration of cardiac TNF-α at both the mRNA and protein levels. Further assessments are required to reveal if TNF-α plays a role in the early stage of diabetic cardiomyopathy development.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Blood Glucose; C-Reactive Protein; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2; Down-Regulation; Echocardiography; Electrocardiography; Fibrosis; Glucose Tolerance Test; Glycosuria; Hypertrophy, Left Ventricular; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Interleukin-1beta; Male; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Troponin T; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

Liraglutide treatment can improve glycemic control with a concomitant weight loss, but the underlying mechanism on weight loss is not completely understood. Cardiac natriuretic peptides (NPs) can resist body fat accumulation through increasing adipocytes lypolysis. In this study, we tested the hypothesis that liraglutide-induced weight loss was associated with increased plasma NPs concentrations.. Thirty-one outpatients with type 2 diabetes (T2D) treated with metformin and other oral antidiabetic drugs except for thiazolidinediones (TZDs) were subcutaneously administered with liraglutide for 12 weeks. Body composition, abdominal visceral adipose tissue areas (VAT) and subcutaneous adipose tissue areas (SAT) were assessed at pre- and post-treatment by dual-energy X-ray absorptiometry (DXA) scanning and abdominal computerized tomography (CT). Plasma atrial natriuretic peptides (ANP) and B-type ventricular natriuretic peptides (BNP) concentrations were tested by commercial ELISA Kit quantitatively.. Following 12-week liraglutide treatment, body weight, waist circumference, total fat and lean mass, fat percentage, SAT and VAT areas were significantly reduced from baseline. Concurrently, plasma ANP and BNP levels were significantly increased following 12-week liraglutide treatment. There were significant correlations between the reductions in body compositions and the increases in both plasma ANP and BNP levels.. There were significant correlations between increases in both plasma ANP and BNP levels and changes in liraglutide-induced body composition. Our data implied that increases in plasma NPs may add a novel dimension to explain how liraglutide induces weight loss.

Topics: Adult; Atrial Natriuretic Factor; Biomarkers; Body Composition; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptides; Obesity; Prospective Studies

We have recently shown that low plasma levels of mid-regional atrial natriuretic peptide (MR-ANP) predict development of diabetes and glucose progression over time, independently of known risk factors for diabetes development. However, since MR-ANP levels might be influenced by unknown factors causing diabetes, we cannot rule out that such relationship might be confounded. Previous studies have shown an association of a single nucleotide polymorphism rs5068 on the natriuretic peptide precursor A (NPPA) locus gene with higher levels of circulating ANP. Since gene variants are inherited randomly and not subject to confounding, we aimed to investigate whether the variant rs5068 within the NPPA locus is associated with incident type 2 diabetes.. We genotyped the variant rs5068 within the NPPA locus in 27,307 individuals without known diabetes from the Malmö Diet Cancer Study. Incident diabetes was retrieved through national and regional registers (median follow-up time of 14 years, 2,823 incident diabetes cases).. In Cox regression analysis adjusted for age, sex and BMI, we found that the carriers of at least one copy of the G allele of rs5068 had lower likelihood of incident diabetes within 14 years (HR = 0.88, 95% CI 0.78-0.99, p = 0.037).. Our results indicate a role of the ANP system in the etiology of type 2 diabetes and might help provide insight in the metabolic actions of natriuretic peptides and the pathophysiology of type 2 diabetes.

Topics: Age Factors; Atrial Natriuretic Factor; Body Mass Index; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Male; Polymorphism, Single Nucleotide; Proportional Hazards Models; Regression Analysis; Sex Factors; Sweden

Glucagon-like peptide-1 receptor (GLP-1R) agonists exert antihypertensive actions through incompletely understood mechanisms. Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that GLP-1R activation promotes the secretion of atrial natriuretic peptide (ANP) and a reduction of blood pressure. Consistent with an indirect ANP-dependent mechanism for the antihypertensive effects of GLP-1R activation, the GLP-1R agonist liraglutide did not directly increase the amount of cyclic GMP (cGMP) or relax preconstricted aortic rings; however, conditioned medium from liraglutide-treated hearts relaxed aortic rings in an endothelium-independent, GLP-1R-dependent manner. Liraglutide did not induce ANP secretion, vasorelaxation or lower blood pressure in Glp1r(-/-) or Nppa(-/-) mice. Cardiomyocyte GLP-1R activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4) to the membrane, whereas Epac2 deficiency eliminated GLP-1R-dependent stimulation of ANP secretion. Plasma ANP concentrations were increased after refeeding in wild-type but not Glp1r(-/-) mice, and liraglutide increased urine sodium excretion in wild-type but not Nppa(-/-) mice. These findings define a gut-heart GLP-1R-dependent and ANP-dependent axis that regulates blood pressure.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Diabetes Mellitus, Type 2; Endothelium, Vascular; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Guanine Nucleotide Exchange Factors; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptide, C-Type; Perfusion; Protein Precursors; Receptors, Glucagon; Vasodilation

Subjects with metabolic syndrome (MetS) and individuals with type 2 diabetes are at high risk for vascular complications. Hormones acting on vascular endothelium may be involved in the atherogenic process associated with metabolic disorders. The objective of this study was to determine the correlation of pro-atrial natriuretic hormone (proANP) with the presence of subclinical atherosclerosis.. In 1272 subjects participating in the KORA F4 study, we determined plasma levels of mid-regional proANP (MR-proANP) and the intima-media thickness (IMT) of the carotid artery. We used logistic regression models to investigate the relation of MR-proANP with components of MetS and IMT.. In multiple adjusted regression models, MR-proANP levels were inversely associated with MetS (OR = 0.66, 95% CI 0.47-0.93), central obesity (OR = 0.67, 95% CI 0.46-0.96), raised triglyceride levels (OR = 0.53, 95% CI 0.37-0.77), prediabetes (OR = 0.62, 95%, CI 0.44-0.87) and type 2 diabetes (OR = 0.55, 95% CI 0.35-0.88) when comparing the top quartile vs. the lower three quartiles. Furthermore, there was an inverse relationship between MR-proANP and IMT. After adjustment for traditional cardiovascular risk markers, individuals with high MR-proANP plasma levels in the top quartile (Q4) had significantly lower IMT values (Q4 vs. Q1-Q3: β -0.0178, 95% CI -0.0344; -0.0013).. In this population-based study, high plasma concentrations of MR-proANP were significantly associated with a lower incidence of MetS components and lower measures of early atherosclerosis. The data suggest a link between MR-proANP levels and the development of vascular complications.

Topics: Atherosclerosis; Atrial Natriuretic Factor; Automation; Carotid Arteries; Carotid Intima-Media Thickness; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucose Tolerance Test; Hormones; Humans; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Peptide Fragments; Regression Analysis; Risk Factors; Triglycerides

Ginseng (Araliaceae) has multiple pharmacological actions because of its diverse phytochemical constituents. The aims of the present study are to evaluate the preventive effects of North American ginseng on diabetic retinopathy and cardiomyopathy and to delineate the underlying mechanisms of such effects. Models of both type 1 (C57BL/6 mice with streptozotocin-induced diabetes) and type 2 diabetes (db/db mice) and age-matched and sex-matched controls were examined. Alcoholic ginseng root (200 mg/kg body weight, daily oral gavage) extract was administered to groups of both type 1 and type 2 diabetic mice for 2 or 4 months. Dysmetabolic state in the diabetic mice was significantly improved by ginseng treatment. In both the heart and retina of diabetic animals, ginseng treatment significantly prevented oxidative stress and diabetes-induced upregulations of extracellular matrix proteins and vasoactive factors. Ginseng treatment in the diabetic animals resulted in enhancement of stroke volume, ejection fraction, cardiac output, and left ventricle pressure during systole and diastole and diminution of stroke work. In addition, mRNA expressions of atrial natriuretic factor and brain natriuretic factor (molecular markers for cardiac hypertrophy) were significantly diminished in ginseng-treated diabetic mice. These data indicate that North American ginseng prevents the diabetes-induced retinal and cardiac biochemical and functional changes probably through inhibition of oxidative stress.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Retinopathy; Extracellular Matrix Proteins; Heart; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Oxidative Stress; Panax; Phytotherapy; Plant Extracts; Plant Roots; Retina

Evidence that midregional fragment of pro-A-type natriuretic peptide (MR-proANP) is a marker of mortality in patients with type 2 diabetes is limited. Therefore, we aimed to investigate the capabilities of MR-proANP in predicting mortality. We also investigated whether MR-proANP influences the relationship between blood pressure and mortality in old age.. In 1998, 1,143 primary care patients with type 2 diabetes participated in the ZODIAC study. Because blood was drawn for 867 patients (76%) and confounders were missing for 19 patients, the final study sample comprised 848 patients. After a follow-up time of 10 years, we used Cox proportional hazard models to evaluate the relationship between MR-proANP and (cardiovascular) mortality. Harrell C statistic was used to compare models with and without MR-proANP. The regression analyses were repeated without MR-proANP for patients aged older than 75 years.. Median MR-proANP in the total study sample was 75 pmol/L (interquartile range, 48-124 pmol/L). During follow-up, 354 (42%) out of 848 patients had died, of whom 152 (43%) deaths were attributable to cardiovascular factors. MR-proANP was independently associated with all-cause and cardiovascular mortality, irrespective of age. During old age, there was a significant inverse relationship between blood pressure and mortality. This relationship did not change after adjustment for MR-proANP.. MR-proANP is independently associated with mortality in patients with type 2 diabetes. MR-proANP did not influence the inverse relationship between blood pressure and mortality in elderly patients.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prospective Studies

Animal data suggest that natriuretic peptides play an important role in energy metabolism, but prospective studies evaluating a relationship between these peptides and type 2 diabetes mellitus (T2DM) in humans are few and results are conflicting.. We used a prospective case-cohort approach (n = 491 T2DM cases, n = 561 reference subcohort) within the Women's Health Study to evaluate baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and the risk of incident T2DM. We also tested for associations between 4 common variants in the natriuretic peptide A and B genes (NPPA and NPPB) and NT-proBNP concentrations (n = 458) and incident T2DM (n = 1372 cases among 22 607 women).. Case subjects had higher median baseline body mass index (29.4 vs 25.0 kg/m(2), P < 0.001) and lower baseline median (interquartile range) NT-proBNP concentrations [46.8 ng/L (26.1-83.2) vs 66.7 ng/L (39.3-124.7), P < 0.001]. In proportional hazards models adjusting for established diabetes risk factors, women in the highest quartile of baseline NT-proBNP concentration (≥ 117.4 ng/L) had a 49% reduction in risk of T2DM [hazard ratio (HR) 0.51, 0.30-0.86, P = 0.01] relative to those in the lowest quartile. Two of the 4 tested variants in NPPA and NPPB (rs632793, rs198389) were associated with increased NT-proBNP concentrations and reduced risk of T2DM. For example, each copy of the minor allele of rs632793 was associated with increased NT-proBNP [β (SE) = 0.201 (0.063), P < 0.01] and decreased T2DM risk (HR 0.91, 0.84-0.989, P = 0.026).. NT-proBNP concentrations that are high, but still within the reference interval, associate with reduced risk of incident diabetes in women and support a favorable role for natriuretic peptides in the prevention of T2DM.

Topics: Atrial Natriuretic Factor; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Polymorphism, Single Nucleotide; Prospective Studies; Risk

To examine concentrations of three cardiovascular propeptides in umbilical cord plasma of neonates born to mothers with Type 1, Type 2 and gestational diabetes. Measurement of cardiovascular markers in umbilical cord plasma may potentially help identify neonates at risk of postnatal complications. Neonates born to mothers with diabetes have an increased risk of neonatal morbidity and mortality, and measurement of these new biomarkers may potentially help identify neonates at risk of these complications.. Copeptin, midregional proadrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) were measured in cord plasma of neonates (n = 63) born to mothers with the three types of diabetes. Associations with maternal glycemic control, mode of delivery and neonatal metabolic acidosis were examined.. Umbilical cord plasma copeptin concentrations were lowest in neonates after elective cesarean sections (6.1 pmol/l; interquartile range [IQR]: 4.5-9.1) compared with emergency cesarean sections (156 pmol/l; IQR: 9.6-311; p = 0.019) and vaginal delivery (831 pmol/l; IQR: 107-2407; p < 0.0001). MR-proADM was also affected by mode of delivery; however, this seemed more likely to be caused by an inverse association with the acid-base balance. In this population, only MR-proANP plasma concentrations were related to type of diabetes. Neonates born to mothers with Type 1 diabetes had higher concentrations (median 260 pmol/l; IQR: 222-318) compared with Type 2 diabetes (175 pmol/l; IQR: 169-200; p = 0.003) and gestational diabetes (200 pmol/l; IQR: 149-276; p = 0.009).. Umbilical cord plasma copeptin and MR-proADM concentrations primarily reflect perinatal stress associated with mode of delivery and the degree of fetal acidosis, whereas MR-proANP concentrations are higher in neonates born to mothers with Type 1 diabetes.

Topics: Acidosis; Adrenomedullin; Adult; Atrial Natriuretic Factor; Biomarkers; Delivery, Obstetric; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Blood; Glycopeptides; Humans; Infant, Newborn; Maternal-Fetal Relations; Pregnancy; Protein Precursors; Stress, Psychological

The atrial natriuretic peptide (ANP) is known mainly for its effects on kidney function and blood pressure homeostasis. We investigated the association between two ANP polymorphisms and pre-existing coronary artery disease (CAD) in patients of African descent with type 2 diabetes (T2D).. We conducted a cross-sectional and retrospective study of 218 volunteer Afro-Caribbean patients with T2D. Two polymorphisms (rs5064, 708C>T; and rs5065, 2238T>C) of ANP were genotyped using PCR-restriction fragment length polymorphism analysis. ANCOVA, χ2-test, and logistic regression were used for statistical analysis.. Among these patients (92 men; 128 women), 67 (30.7%) had CAD, of whom 75% had had myocardial infarction. The frequency of rs5065-C carriers (TC/CC) was significantly lower in patients with CAD than in those without CAD (24 vs. 41%, P = 0.01). The frequency of hypertension did not differ significantly according to genotype. Univariate logistic regression revealed that male sex, age, dyslipidemia, hypertension, and rs5065-C carrier status were associated significantly with CAD. After adjustment for the variables of interest, the odds ratio (ORs) of CAD for rs5065-C carriers (TC/CC) was 0.50 (0.26-0.96; P = 0.038). No association was found between the rs5064 (708C>T) single-nucleotide polymorphisms (SNPs) and pre-existing CAD or cardiovascular risk factors.. The ANP rs5065 (2238T>C) C allele seems to exert a protective effect against CAD in T2D patients of African descent. The relevance of ANP polymorphisms for CAD should be determined in different populations.

Topics: Aged; Atrial Natriuretic Factor; Black People; Cardiovascular Diseases; Comorbidity; Coronary Artery Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Regression Analysis; Retrospective Studies; Risk Factors; West Indies

Urotensin II (UII) exerts multiple effects on the cardiovascular system, acts as a diabetogenic agent, and may also contribute to the development of the metabolic syndrome (MetS). The aim of this study was to determine circulating UII in patients with type 2 diabetes mellitus (T2DM) and its relationship with MetS. A total of 360 consecutive patients with T2DM were included. MetS presence/absence (MetS [+]/[-]) was defined according to American Heart Association/National Heart, Lung and Blood Institute criteria. Plasma concentrations of UII were determined by radioimmunoassay. UII levels were significantly higher in MetS (+) than in MetS (-) T2DM patients (0.97 pg/mL [0.93-1.01], n=294 vs 0.82 pg/mL [0.75-0.88] pg/mL, n=66, respectively; P<.001). Multiple logistic regression analysis showed that UII was significantly associated with MetS (+) (odds ratio, 6.41 [95% confidence interval, 1.21-16.04]; P=.02). UII plasma concentrations are significantly higher in T2DM patients presenting with MetS. Therefore, circulating UII may participate in the worsening course of some T2DM patients and may provide novel therapeutic perspectives.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Natriuretic Peptide, Brain; Phenotype; Protein Precursors; Retrospective Studies; Urotensins

The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes.. This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively.. MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 +/- 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l).. The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Endothelin-1; Female; Glycopeptides; Humans; Kidney; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Protein Precursors

Urate, a naturally-occurring antioxidant, is a marker/factor for cardiovascular disease. Hyperuricaemia is associated with IR, MetS and endothelial dysfunction. We characterised the associations between neurohormones, uricaemia, and glucose homeostasis in type 2 diabetes mellitus (T2DM) males. Cross-sectional; 705 T2DM males divided into two groups: uric acid < 7.0 mg/dl (normouricaemic; n=476) versus uric acid >or= 7.0 mg/dl (hyperuricaemic; n=229). HOMA beta-cell function (B), insulin sensitivity (S), hyperbolic product (BxS), and (BxS) loss rate were determined alongside neurohormones (Nt-proANP, BNP, Big ET-1 and UII). Mean age and diabetes duration were not different between groups. Hyperuricaemics had more macroangiopathy, total/central adiposity, IR, hypertension, dyslipidemia and MetS prevalence. Nt-proANP and BNP levels were more than twice as high in hyperuricaemics, whereas Big ET-1 and UII were higher by 46% and 14%, respectively. HOMA (BxS) was higher in hyperuricaemics: 31 (16)% vs. 26 (18)% (p=0.0004). BxS loss rate was faster in normouricaemics: 1.36 (0.54)% vs. 1.20 (0.43)%/year(-1) (p<0.0001 ). The proportion with HbA(1C) < 7.0% was 39% (normouricaemics) vs. 49% (hyperuricaemics; p=0.0091). In T2DM males, hyperuricaemia is associated with raised neurohormones together with better beta-cell indices. Urate's dual properties may translate into beneficial (glucose homeostasis) and detrimental (raised neurohormones) effects.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelin-1; Glycated Hemoglobin; Humans; Hyperuricemia; Insulin; Insulin-Secreting Cells; Male; Metabolic Syndrome; Middle Aged; Natriuretic Peptide, Brain; Up-Regulation; Uric Acid

Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients, and following an infarction, diabetes is associated with an increased risk for the development of left ventricular (LV) dysfunction and heart failure. The goal of this study was to determine if the progression of heart failure following myocardial infarction in type 2 diabetic (T2D) rats is accelerated compared with nondiabetic rats. Male nondiabetic Wistar-Kyoto (WKY) and T2D Goto-Kakizaki (GK) rats underwent coronary artery ligation or sham surgery to induce heart failure. Postligation (8 and 20 wk), two-dimensional echocardiography and LV pressure measurements were made. Heart failure progression, as assessed by enhanced LV remodeling and contractile dysfunction, was accelerated 8 wk postligation in the T2D animals. LV remodeling was evident from increased end-diastolic and end-systolic diameters and areas in the GK compared with the WKY infarcted group. Furthermore, enhanced LV contractile dysfunction was evident from a greater deterioration in fractional shortening and enhanced myocardial performance index (an index of global LV dysfunction) in the GK infarcted group. This accelerated progression was accompanied by greater increases in atrial natriuretic factor and skeletal alpha-actin (gene markers of heart failure and hypertrophy) mRNA levels in GK infarcted hearts. Despite similar decreases in metabolic gene expression (i.e., peroxisome proliferator-activated receptor-alpha-regulated genes associated with fatty acid oxidation) between infarcted WKY and GK rat hearts, myocardial triglyceride levels were elevated in the GK hearts only. These results, demonstrating enhanced remodeling and LV dysfunction 8 wk postligation provide evidence of an accelerated progression of heart failure in T2D rats.

Topics: Actins; Animals; Atrial Natriuretic Factor; Blood Glucose; Cardiac Output, Low; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Fatty Acids, Nonesterified; Heart Rate; Male; Myocardial Infarction; Rats; Rats, Inbred Strains; Rats, Inbred WKY; RNA, Messenger; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Adult; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Nephrotic Syndrome; Treatment Outcome

We recently showed that plasma concentration of N-terminal atrial natriuretic peptide (Nt-proANP) is strongly directly related to salt sensitivity. The aims of the present study were to test (i) whether plasma concentration of N-terminal brain natriuretic peptide (Nt-proBNP) is related to salt sensitivity and (ii) whether Nt-proANP, as a marker of salt sensitivity, differs between type 2 diabetes patients and nondiabetic subjects without a history of coronary heart disease.. Nt-proBNP was determined in 30 Swedish normal subjects with heredity for primary hypertension and salt sensitivity was defined as the difference between mean arterial blood pressure after 1 week on a high-salt diet (240 mmol day(-1)) and 1 week on a low-salt diet (10 mmol day(-1)). Nt-proANP was measured in 253 patients with type 2 diabetes and in 230 nondiabetic subjects aged 40-70 years, all without a history of coronary heart disease.. Amongst the 30 subjects, in whom salt sensitivity was directly measured, Nt-proBNP was not correlated with salt sensitivity (R=-0.18, P=0.35). Nt-proANP (median, interquartile range) was lower in patients with type 2 diabetes (505, 387-661 pmol L(-1)) than in nondiabetic subjects (536, 421-696 pmol L(-1)) (P=0.02). In a multiple regression analysis heart rate (P <0.00001), diastolic blood pressure (P=0.02) and diabetes status (P=0.02) were inversely related whereas age (P <0.00001), cystatin C (P=0.0006), hypertension treatment (P=0.002) and female sex (P=0.006) were directly related to ln(Nt-proANP).. In contrast to Nt-proANP, Nt-proBNP is not related to salt sensitivity. Salt sensitivity, as estimated by Nt-proANP, seems to be reduced in type 2 diabetes.

Topics: Atrial Natriuretic Factor; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Protein Precursors; Sodium Chloride, Dietary

Combination of diabetes and chronic heart failure is a frequently occurring syndrome. We studied interrelationship between state of carbohydrate metabolism, diabetic nephropathy and level of natriuretic peptide in patients with type 2 diabetes and concomitant chronic heart failure. The study confirmed high diagnostic value of natriuretic peptide as quantitative criterion of the presence of heart failure and revealed association of decompensation of carbohydrate metabolism and presence of diabetic nephropathy with more severe heart failure and left ventricular dysfunction. Among patients with renal failure those with more severe heart failure had low values of glycosylated hemoglobin.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Female; Glycated Hemoglobin; Heart Failure; Humans; Male; Middle Aged; Myocardial Contraction; Prognosis; Severity of Illness Index

Pioglitazone is an insulin-sensitizer with a thiazolidinedione structure. It is used to reduce hyperglycemia and is frequently prescribed to type 2 diabetic patients. However, it causes edema as an adverse effect in some patients. Although the mechanism of edema is unclear, it may bring an increased risk of congestive heart failure. We investigated whether pioglitazone correlates with the level of plasma human atrial natriuretic peptide (hANP), a marker for congestive heart failure. We administered 15 mg/day of pioglitazone for 3 months to 49 patients (34 men and 15 women; mean age: 64+/-12 years) with type 2 diabetes and no history of pretibial edema. Three of the patients complained of pretibial edema during the 3-month period, and their plasma hANP levels were higher than those of the other 46 before and during the treatment. We therefore suspect that pretibial edema appearing after administration of low-doses of pioglitazone coincides with the level of plasma hANP, and that the appearance of pretibial edema may reflect an increase in circulating blood volume induced by pioglitazone.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Edema; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Thiazolidinediones; Tibia

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Diabetes Mellitus, Type 2; Echocardiography; Enalapril; Fibrosis; Heart; Insulin; Male; Metalloendopeptidases; Myocardium; Natriuretic Peptide, Brain; Organ Size; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary; Thiazepines

Atrial natriuretic peptide (ANP) has been recently described as an endogenous inhibitor of the synthesis and angiogenic action of vascular endothelial growth factor (VEGF). Given VEGF's key role in promoting neovascularization in proliferative diabetic retinopathy (PDR), this study was designed to evaluate the possibility that ANP could be involved in the neovascular and fibrotic complications of PDR.. We determined ANP by radioimmunoassay in plasma and vitreous humor samples collected from diabetic patients with and without PDR and from non-diabetic subjects. ANP was also immunohistochemically localized in the epiretinal membranes of patients with PDR.. Vitreous ANP concentrations were significantly higher in patients with active PDR compared to patients with quiescent PDR, diabetes without PDR or controls <0.05. Significant differences were also observed between vitreous ANP levels in diabetic patients without PDR and control subjects. There was no significant correlation between serum and vitreous ANP levels in any of the patient groups. ANP was detected in the fibrovascular epiretinal tissue of patients with PDR.. Diabetic patients with active neovascularization have significantly higher levels of ANP in the vitreous humor than those without active PDR. Diabetic patients without PDR were also found to have significantly higher vitreous ANP levels than non-diabetic patients. Since plasma and vitreous ANP concentrations were found to be unrelated, we suggest intraocular ANP synthesis and/or an increase in the release of ANP into the vitreous, as opposed to diffusion from the blood, as the main factors contributing to the high vitreous ANP levels observed in diabetic patients. In the fibrovascular epiretinal tissue of these patients, ANP was found to be localized in vascular, glial, fibroblast-like and retinal pigment epithelium cells. Our findings suggest a role for ANP in PDR.

Topics: Adult; Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Epiretinal Membrane; Female; Glial Fibrillary Acidic Protein; Humans; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Radioimmunoassay; Retinal Neovascularization; Vitrectomy; Vitreous Body

Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the ScaI and BstXI polymorphisms of the human ANP (hANP) gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively (P<0.0001). Genotype distributions were in Hardy-Weinberg equilibrium in all 4 patient subgroups. The frequency of the ScaI mutated allele (A(1)) was significantly lower in hypertensive than in control subjects (11% versus 19%, P=0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%; P<0.0001). In a nominal logistic model adjusting for gender, age, obesity, diabetes, micro/macroalbuminuria, and hypertension, the A(1) allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59; P=0.003) but not with hypertension. In the same model, the frequency of the BstXI mutated allele (T(708)) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59; P<0.001). We conclude that the mutated genotypes of the ScaI polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of BstXI polymorphism are positively associated with microalbuminuria. hANP gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.

Topics: Adult; Aged; Albuminuria; Atrial Natriuretic Factor; Cohort Studies; Deoxyribonucleases, Type II Site-Specific; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genes; Genetic Predisposition to Disease; Humans; Hypertension, Renal; Male; Middle Aged; Polymorphism, Genetic

We investigated plasma brain natriuretic polypeptide (BNP) in Type 2 NIDDM patients with albuminuria. This study involved normal control subjects (Controls), hypertensive patients without diabetes mellitus (HT) and Type 2 NIDDM patients. Diabetic patients were divided into 4 groups by urinary albumin index (Alb-I): group I <30; group II 30-149; group III 150-300; group IV >300 mg/g creatinine. BNP levels in group III or IV were significantly higher than in Controls. The diabetic patients were re-divided into 4 groups (DM: with neither diabetic retinopathy (which was one of indicators of microangiopathy) nor hypertension, DM+HT: without diabetic retinopathy and with hypertension, DM+R: with diabetic retinopathy and without hypertension and DM+R+HT: with both diabetic retinopathy and hypertension). The Alb-I levels in DM+HT and DM+R+HT were significantly higher than the Controls, indicating the development of diabetic nephropathy in those groups. BNP levels in DM+HT, DM+R or DM+R+HT were significantly higher than in Controls. This indicates that BNP levels elevate in diabetic patients with increased albuminuria due to hypertension or microangiopathy deteriorating diabetic nephropathy. Elevated plasm BNP may play a pathophysiological role in the development of diabetic nephropathy.

Topics: Albuminuria; Atrial Natriuretic Factor; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycated Hemoglobin; Humans; Middle Aged; Natriuretic Peptide, Brain

To clarify the association between the actions of insulin on the vascular wall and on the muscles in diabetes, we evaluated insulin-mediated vasodilation and muscle glucose uptake simultaneously using the euglycemic hyperinsulinemic glucose clamp technique and the calculation of total peripheral vascular resistance (TPR) from arterial pulse wave analysis in 19 Japanese patients with type 2 diabetes who had no signs of atherosclerosis. During the clamp study, the plasma norepinephrine (NE) level and plasma renin activity (PRA) increased without showing any significant correlation to the glucose infusion rate (GIR); a marker of muscle insulin sensitivity, and no changes of other plasma vasoactive hormone levels were observed. TPR decreased over time during the clamp study. The decrease of TPR from baseline was 0.88 +/- 0.02 at 1 h (mean +/- S.E.M., P < 0.01) and 0.79 +/- 0.03 at 2 h (P < 0.01), and the relative change in TPR from baseline was negatively correlated with GIR (r = -0.48 at 1 and 2 h; both P < 0.05). Our results suggest that there is also insulin resistance in the vascular wall, and this phenomenon may be associated with muscle insulin resistance in type 2 diabetes.

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Type 2; Endothelin-1; Female; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Norepinephrine; Regression Analysis; Renin; Sodium; Vascular Resistance; Vasodilation

Topics: Aldosterone; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Renin

The present investigation was designed to determine if atrial natriuretic peptides (ANPs) are increased in a spontaneous model of non-obese type 2 diabetes, the Goto-Kakizaki (GK) rat. Four peptide hormones originating from the ANP prohormone were increased twofold (P < .05) to sixfold (P < .01) in the circulation of GK rats compared with nondiabetic Wistar rats from which the GK colony was originally derived. Thus, ANP, long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide were (mean +/- SE) 497 +/- 78, 1,285 +/- 105, 457 +/- 45, and 385 +/- 87 pg/mL in GK rats, versus 78 +/- 23, 542 +/- 77, 137 +/- 26, and 134 +/- 33 pg/mL, respectively, in Wistar rats. In evaluating the cause of the increased ANPs, the blood volume of GK rats (16.2 +/- 0.4 mL) was significantly (P < .01) increased compared with Wistar rats (9.5 +/- 0.3 mL). The ventricles of GK rats were not dilated when examined by transthoracic echocardiography, but the venous system was markedly distended. GK rats had a 48% to 79% decrease in renal function (ie, increased serum creatinine and blood urea nitrogen [BUN]) compared with Wistar rats. These results indicate that circulating ANPs are increased in the GK spontaneously diabetic rat secondary to (1) increased blood volume, which leads to increased synthesis and release of ANPs, and (2) renal failure, which results in a delayed metabolic processing of these peptides. The early combined increases of the four atrial peptides collectively may contribute to the hyperfiltration that occurs in early diabetes mellitus.

Topics: Animals; Atrial Natriuretic Factor; Blood Urea Nitrogen; Blood Volume; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Echocardiography; Hematocrit; Mice; Rats; Rats, Inbred Strains; Rats, Wistar; Renal Insufficiency; Time Factors

This study was undertaken to measure urinary atrial natriuretic peptide-like immunoreactivity (ANP-LI) and plasma ANP concentration in patients with hyperosmolar-hyperglycemic nonketotic syndrome (HHNS) to investigate the change of renal ANP-LI and cardiac ANP synthesis in volume-depleted diabetic patients.. The urine ANP-LI:creatinine ratio, plasma ANP level, and plasma renin activity (PRA) were measured in 12 patients with HHNS during the acute stage and after recovery, in 28 oral hypoglycemic agent (OHA)-treated type 2 diabetic patients, and in 23 normal subjects. ANP and PRA were measured by radioimmunoassay.. These HHNS patients had severe hyperglycemia and hyperosmolality as well as increased blood urea nitrogen, creatinine, and PRA levels, as compared with normal subjects and OHA-treated type 2 diabetic patients. In these patients, the urinary ANP-LI:creatinine ratio (11.69 +/- 2.11 pmol/mmol) was significantly increased in comparison with the normal group (1.78 +/- 0.11 pmol/mmol) and OHA-treated diabetic patients (2.43 +/- 0.45 pmol/mmol), whereas plasma ANP concentration (5.12 +/- 0.72 pmol/l) was significantly lower than the corresponding values of the normal group (7.39 +/- 0.85 pmol/l) and OHA-treated diabetic patients (8.43 +/- 1.05 pmol/l). All of these abnormalities were significantly ameliorated after insulin, fluid, and electrolyte replacement.. Our data show that urinary ANP-LI was significantly increased, whereas plasma ANP concentration was decreased, in the face of raised PRA in HHNS patients. This study indicates that renal ANP-LI substances and cardiac ANP may exhibit different responsiveness in diabetic patients with HHNS.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Blood Urea Nitrogen; Creatinine; Diabetes Mellitus, Type 2; Humans; Hyperglycemic Hyperosmolar Nonketotic Coma; Hypoglycemic Agents; Middle Aged; Radioimmunoassay; Reference Values; Renin

Brain natriuretic peptide (BNP), a member of the natriuretic peptide family, is produced and released from cardiac ventricles. BNP regulates the body fluid volume, blood pressure, and vascular tones through the A-type guanylate cyclase-coupled receptor. The presence of renal dysfunction in patients with diabetes affects the plasma levels of atrial natriuretic peptide (ANP). In the present study, we investigated the plasma levels of BNP and ANP and their relationship in normotensive diabetic patients with normoalbuminuria and microalbuminuria. Forty-seven normotensive lean noninsulin-dependent diabetic patients (31 with normoalbuminuria, 16 with microalbuminuria), with normal cardiac function, and 30 age-matched control subjects were enrolled in this study. The plasma levels of BNP in diabetic patients with microalbuminuria were significantly higher than those in diabetic patients with normoalbuminuria (16.7+/-2.4 vs. 9.6+/-1.3 pg/mL, P<0.01) or normal subjects (16.7+/-2.4 vs. 7.0+/-0.6 pg/mL, P<0.01). There was a significant positive correlation between plasma BNP levels and urinary albumin excretion rate in all diabetic patients (r = 0.58, P<0.0001). There was also a significantly positive correlation between plasma BNP and ANP levels in diabetic patients (r = 0.62, P<0.0001). The increased plasma level of BNP in patients with microalbuminuria and its significant correlation with urinary albumin excretion rate suggest that the elevated circulating levels of BNP are caused by the presence of diabetic nephropathy. Down-regulation of A-type guanylate cyclase-coupled receptor of renal tubules may explain the increased plasma levels of both BNP and ANP in normotensive diabetic patients with microalbuminuria.

Topics: Albuminuria; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Natriuretic Peptide, Brain; Reference Values

Thickening of the basement membrane and other structural alterations of the vascular walls occur frequently in patients with diabetes. The vascular response to atrial natriuretic peptide (ANP) is also altered in these patients. Abnormal vascular response in diabetes may be due to alteration of vascular physicochemical properties induced by accumulation of components of vascular basement membrane. The aim of this study was to evaluate the relationship between circulating levels of the 7 S domain of type IV collagen (7 S-collagen), and ANP in normotensive type 2 diabetic patients with or without retinopathy. Forty-one normotensive type 2 diabetic patients (n = 19 with and n = 22 without retinopathy) and 18 age-matched control subjects participated in the study. Serum 7 S-collagen and plasma ANP levels were measured by radioimmunoassays. Serum 7 S-collagen (4.4 +/- 0.1 vs 3.5 +/- 0.1 ng/ml; p < 0.01) levels and plasma ANP (20.8 +/- 1.0 vs 15.5 +/- 1.0 pg/ml; p < 0.01) were significantly higher in diabetic patients than in normal subjects. Serum 7 S-collagen increased significantly in diabetic patients without retinopathy compared with normal subjects (4.1 +/- 0.1 vs 3.5 +/- 0.1 ng/ml; p < 0.01). Diabetic patients with retinopathy showed significantly higher circulating concentrations of 7 S-collagen (4.6 +/- 0.1 vs 4.1 +/- 0.1 ng/ml; p < 0.01) and ANP (22.9 +/- 1.4 vs 18.9 +/- 1.3 pg/ml; p < 0.05) than those without retinopathy. There was a significant and positive correlation (r = 0.51, p < 0.01) between the circulating levels of 7 S-collagen and ANP in all patients. The results of this investigation showed that increased circulating levels of ANP correlate with the abnormal metabolism of the vascular basement membrane observed in diabetic patients with microangiopathy.

Topics: Atrial Natriuretic Factor; Blood Glucose; Collagen; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Middle Aged

Atrial natriuretic peptide is involved in blood pressure regulation via its vasodilating and natriuretic actions. Since diabetic nephropathy and hypertension are closely related, ANP is a reasonable candidate gene for diabetic nephropathy (DN).. We genotyped 410 patients with type I diabetes (without DN n = 307; with DN n = 103) and 658 patients with type II diabetes (without DN n = 464; with DN n = 194). In the patients the duration of diabetes was at least 10 years. Diabetic nephropathy was defined as urinary albumin excretion of > or = 30 mg/24 h. The HpaII polymorphism in intron 2 of the ANP gene was determined using PCR amplification followed by restriction digest. Alleles were separated on agarose gels stained with ethidium bromide.. We compared genotype distribution and allele frequencies between patients with and without nephropathy. No significant difference was observed either in type I (allele frequency without DN H1, 0.02/H2, 0.98 vs with DN H1, 0.05/H2, 0.95; P = 0.132) or in type II diabetes (allele frequency without DN H1, 0.04/H2, 0.96 vs with DN H1, 0.05/H2, 0.95; P = 0.551).. The polymorphism in the gene for the atrial natriuretic peptide does not seem to play a major role in the development of diabetic nephropathy in either type I or in type II diabetes.

Topics: Adult; Alleles; Atrial Natriuretic Factor; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA Primers; Female; Gene Frequency; Genotype; Humans; Introns; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors

To investigate the relationship between circadian changes in urinary microalbumin excretion (UAE), blood pressure (BP) and physical activity in patients with essential hypertension.. The subjects were 45 patients with essential hypertension (EH group: 26 male and 19 female, age 56+/-12 years (mean +/- SD)) and 25 patients with diabetes mellitus (DM group: 14 male and 11 female, age 61+/-10 years). Their BP and physical activity (acceleration) were measured at 30-min intervals for 24 h by means of a multi-biomedical recorder (TM2425). Urine samples were collected during each of four 4-h daytime periods and one 8-h night-time period. From these samples, per-h UAE (UAE/h) was measured. Mean values for mean blood pressure (MBP) and acceleration were calculated for corresponding time periods. Plasma hormones were measured during an early morning rest period.. In the EH group, a significant positive correlation was observed between circadian variation of UAE/h and MBP in 35 (78%) subjects, and the mean coefficient of correlation (r) was 0.86+/-0.12. A significant positive correlation was observed between circadian variation of UAE/h and mean acceleration value (Gh) in 25 (56%) subjects, and the mean r value was 0.70+/-0.26. Multivariate linear regression analysis showed that MBP exerted a greater influence on UAE/h than Gh. Significant positive correlations were observed between UAE/day and plasma human atrial natriuretic peptide and plasma aldosterone concentration (r = 0.50, P < 0.01; r = 0.36, P< 0.05). None of these relations, however, was observed in the DM group.. In patients with essential hypertension, circadian changes in activity and variation of BP influence UAE/h, but no definite relationship of this kind was observed in patients with diabetes mellitus. Measurement of circadian changes in UAE or UAE/day may be useful in estimating the degree of daily stress in non-diabetic patients with essential hypertension.

Topics: Adult; Aged; Albuminuria; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Male; Middle Aged; Motor Activity

Topics: Adult; Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Endothelins; Female; Humans; Male; Middle Aged

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance hyperinsulinaemia and a high frequency of hypertension. It has recently been shown that insulin exerts a sodium-retaining effect, which is preserved in NIDDM: We sought to determine whether insulin affected renal sodium handling differently in hypertensive and normotensive NIDDM patients.. After a baseline period of 2 h, eight normotensive (N-) NIDDM patients and eight NIDDM patients with hypertension (H-) underwent a euglycaemic clamp with infusion of two sequential doses of insulin (50 and 500 mU/kg/h) or vehicle (time control) during 2-h periods each. Fractional clearances of sodium and lithium were determined according to standard methods. Fractional lithium clearance was used to assess segmental tubular sodium handling.. Insulin induced similar decrements in fractional sodium excretion (N-NIDDM: 43+/-5.9 and 57+/-9.1%,H-N IDDM: 48+/-16.4 and 62+/-12.5%, low and high insulin dose respectively). Distal tubular sodium absorption increased simultaneously. A fall in fractional proximal sodium reabsorption was observed in N-NIDDM (4.4+/-2.7 and 29.8+/-5.1%, low and high insulin dose respectively), which was attenuated in H-NIDDM (-5.0+/-7.3 and -2.1+/-13.9% respectively). The latter appeared to be related to a defective atrial natriuretic factor (ANF) and renal cyclic GMP response. A modest decrease in blood pressure occurred during insulin infusion that was not related to changes in ANF or FeLi.. The findings suggest that insulin-induced sodium retention may contribute to hypertension in NIDDM if the homeostatic response to offset this effect fails.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cardiovascular System; Case-Control Studies; Cyclic GMP; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Insulin; Insulin Resistance; Kidney; Male; Middle Aged; Natriuresis; Renin

In diabetic patients, several factors contribute to volume expansion and have to be counteracted by humoral and neuronal feedback control systems. We investigated N-terminal proatrial natriuretic factor (ANF1-98) and digoxin-like immunoreactive factor (DLIF), which are two counteracting hormones, and their interrelationship, with additional consideration given to autonomic nervous function in diabetic patients. ANF1-98 and DLIF were measured in 64 diabetic patients. Autonomic nervous function was assessed using nine autonomic nervous function tests. The patients were subdivided into two groups, one with four or more (group 1) and one with less than four abnormal results in autonomic function tests (group 2). Compared with group 2, group 1 demonstrated detectable DLIF levels less often (17.2 vs. 45.7, P = 0.0195) and increased levels of ANF1-98 (mean +/- SEM: 850.0 +/- 108.8 vs. 554.8 +/- 45.9 pmol/L, P = 0.0099). However, the groups did not differ in blood pressure, daily sodium, and daily potassium excretion. The number of abnormal autonomic function tests correlated significantly with ANF1-98 (P = 0.0002). In patients with detectable DLIF, DLIF correlated with ANF1-98 (P = 0.0080). These results demonstrate close interactions between the autonomic nervous system and the two natriuretic hormones. In patients with autonomic nervous dysfunction, higher levels of ANF may possibly compensate for the lack of the natriuretic DLIF to counteract hypertension and chronic volume expansion.

Topics: Adult; Aged; Atrial Natriuretic Factor; Autonomic Nervous System; Cardenolides; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Digoxin; Female; Humans; Male; Middle Aged; Peptide Fragments; Protein Precursors; Saponins

The objective of this study was to determine the role of atrial natriuretic peptide (ANP) in autonomic neuropathy and to learn the effect of saline solution infusion on ANP. Twenty one subjects were distributed in three groups: 1) control group, 2) diabetic patients with autonomic neuropathy, and 3) diabetic patients without autonomic neuropathy. The levels of ANP, renin, aldosterone and cortisol were determined at baseline and 30, 60, and 75 min after saline infusion. At baseline ANP was lower in diabetic patients with autonomic neuropathy (32.9 +/- 13) than control group (34 +/- 15). ANP increased statistically significantly at 30 min after solution administration in control group (60 +/- 35, F = 4, p < 0.05), but it did not change in diabetic patients (Group II: 34.3 +/- 9.3 and Group III 34.6 +/- 10.7). Sixty and 75 min after saline infusion ANP returned to basal levels in control group, but they did not change in diabetic patients. A delayed response of renin, aldosterone and cortisol to saline solution administration was observed in diabetic patients. There was no correlation between ANP levels and alteration of autonomic tests. It is concluded that independent of autonomic neuropathy, the levels of ANP did not increase with saline infusion in diabetic patients.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Hydrocortisone; Middle Aged; Plasma Volume; Renin; Sodium Chloride

Impaired renal sodium excretion and increased plasma atrial natriuretic peptide (ANP) levels have been reported in patients with hypertension associated with insulin resistance and hyperinsulinemia. To clarify the interrelationship between hyperinsulinemia and plasma natriuretic peptides, we investigated the effects of physiological and non-physiological hyperinsulinemia on the plasma ANP and brain natriuretic peptide (BNP) levels. Plasma immunoreactive insulin (IRI), ANP and BNP levels were determined by a euglycemic-hyperinsulinemic glucose clamp in 20 patients with non-insulin-dependent diabetes mellitus, by a glucose challenge test in 22 normal subjects and by an insulin challenge test in six normal subjects. Both in the glucose clamp and the glucose challenge test, plasma ANP showed a significant increase in association with increased plasma IRI and plasma volume. However, there was no significant correlation between the changes in plasma ANP levels and plasma IRI levels in view of the peak values and the area under the curve of their responses. In addition, the plasma ANP did not show any significant change despite the marked elevation of plasma IRI in the insulin challenge test. There was no significant change in plasma BNP under any of the hyperinsulinemic conditions. These findings provide in vivo evidence for the lack of a direct effect of acute hyperinsulinemia on natriuretic peptides, although the chronic effects of hyperinsulinemia remain to be elucidated.

Topics: Acute Disease; Adult; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins

Topics: Adult; Animals; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA, Complementary; Gene Expression; Humans; Kidney; Polymerase Chain Reaction; Rats; Rats, Mutant Strains; RNA, Messenger

Plasma levels of endothelin (ET) and atrial natriuretic peptide (ANP) are known to be elevated in patients on chronic hemodialysis. Since ET and ANP plasma levels are found to be raised in nonuremic diabetic versus nondiabetic subjects, we wanted to detect a possible difference in plasma levels of these hormones in diabetic versus nondiabetic patients who were on chronic renal replacement therapy. ET is a possible marker of increased vascular atherogenic activity. We measured plasma levels of ET and ANP pre- and posthemodialysis in 23 non-insulin-dependent (NIDDM) diabetic versus 23 nondiabetic patients who were matched according to age and time of day of hemodialysis, and who did not show clinical signs of overt cardiac decompensation. Mean plasma levels of ET and ANP did not differ in diabetic from nondiabetic patients, neither pre- nor postdialysis. In both patient groups, mean ET levels were twice the upper normal limit, did not change significantly pre- versus postdialysis, and did not correlate with blood pressure or with volume ultrafiltration during dialysis. Calcium channel blocker therapy was accompanied by a significant rise of ET pre- and postdialysis in nondiabetic patients but not in diabetic patients. In diabetic patients, ET plasma levels correlated positively with fructosamine levels as an indicator of short-term blood glucose control. Mean ANP plasma levels were about three times the upper normal limit and decreased significantly during dialysis, but this decrease correlated neither with volume ultrafiltration nor with blood pressure. In conclusion, we could not find a difference in plasma levels of ET and ANP for diabetic versus nondiabetic dialysis patients, but impaired short-term blood glucose control in diabetic and calcium channel blocker therapy in only nondiabetic dialysis patients showed concomitant increases in plasma ET levels and thus possibly different mechanisms of ET regulating pathways.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Endothelins; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Diurnal changes in plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and plasma aldosterone as related to those in blood pressure (BP) were studied under hospital conditions in 18 diabetic subjects without proteinuria and 8 age-matched control subjects. Of 18 diabetic subjects, 10 had a normal diurnal BP rhythm with the peak value in the afternoon (group 1) and 8 had a reversed BP rhythm with the peak value during the night (group 2). Autonomic dysfunction estimated by measuring orthostatic BP and heart-rate changes and beat-to-beat heart-rate variations was more pronounced in group 2 than in group 1. Fasting plasma glucose and HbA1c were similarly high in both diabetic groups. Group 1 showed modestly elevated mean 24-h MBP and plasma ANP levels, modestly low mean 24-h PRA and plasma aldosterone levels, and a lack of diurnal ANP changes similar to that in controls. Group 2 showed markedly elevated mean 24-h BP and plasma ANP levels, markedly low mean 24-h PRA and plasma aldosterone levels, and nocturnal rises in plasma ANP and BP. PRA and plasma aldosterone exhibited circadian rhythms with their peak values found in the early morning in all three groups. The daytime/overnight excretion ratios of sodium and water were normal in group 1 and low in group 2. These results indicate that diurnal changes in plasma ANP, PRA and plasma aldosterone are altered in diabetic subjects with normal and reversed diurnal BP rhythms, predominantly in the latter.

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Circadian Rhythm; Diabetes Mellitus, Type 2; Diuresis; Electrolytes; Female; Hormones; Hospitalization; Humans; Male; Middle Aged; Reference Values

A total of 78 Chinese patients with clinically uncomplicated non-insulin-dependent diabetes (NIDDM) who had plasma creatinine concentrations of < 150 mumol/l were studied. Antihypertensive treatment was discontinued for at least six weeks prior to measurements of routine biochemistry, proteinuria, plasma atrial natriuretic peptide (ANP) concentrations and components of the renin-angiotensin-aldosterone system (RAAS). BP was measured on three occasions during the six weeks period prior to these measurements. At the end of the six week period, a total of 33 patients had definite hypertension (supine BP > or = 160/95 mmHg). The hypertensive patients had significantly higher plasma sodium (mean +/- SD): 140.3 +/- 1.9 vs. 138.5 +/- 2.0 mmol/l, P < 0.001) and lower plasma potassium (3.8 +/- 0.5 vs. 4.2 +/- 0.5 mmol/l, P < 0.01) concentrations. These were associated with reduced plasma aldosterone (median (range): 297 (98-1145) vs. 448.5 (93-1330) pmol/l, P < 0.01) and renin concentrations (16.8 (7.4-71.8) vs. 23.5 (7.4-83.7) ng/l, P = 0.06). The hypertensive patients also had significantly higher plasma ANP concentrations (36.5 (20.5-125.1) vs. 23.2 (11.7-63.0) pg/ml, P < 0.001), serum angiotensin converting enzyme (ACE) activity (65 (26-140.9) vs. 47 (22-106) units/l, P < 0.001) and urinary albumin excretion (UAE) (35.4 (1.6-4800) vs. 7.8 (1.8-310.4) mg/day, P < 0.001). Glycaemic control and renal function were similar between the two groups. Mean arterial pressure (MAP) correlated positively with plasma ANP concentration (r = 0.53, P < 0.001) and serum ACE activity (r = 0.37, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Electrolytes; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System

1. Diabetes mellitus is associated with high body sodium, but the pathogenetic mechanism is still unknown. The possibility that an abnormal renal handling of sodium, an abnormal responsiveness of sodium-modulating factors or a shift in the set point for sodium metabolism may contribute to or be associated with sodium retention was tested with an acute saline infusion. 2. A consecutive sample of 33 patients with stable non-azotaemic diabetes mellitus (24 insulin-dependent patients) and 30 normal control subjects was studied. Two litres of a 0.9% NaCl infusion were infused over 4 h. The urinary sodium excretion during the infusion and the next 18 h was analysed in relation to blood pressure, creatinine and lithium clearances, Na(+)-K+ co-transport, Na(+)-Li+ countertransport, plasma levels of renin, angiotensin II, aldosterone, noradrenaline, adrenaline, atrial natriuretic factor and digoxin-like factor. 3. Diabetic patients and control subjects did not differ in blood pressure, body mass index, clearances of creatinine, sodium or lithium, intracellular sodium Na(+)-K+ co-transport and Na(+)-Li+ countertransport, urinary and plasma levels of digoxin-like factor, plasma renin activity, angiotensin II, aldosterone, noradrenaline, adrenaline and atrial natriuretic factor. The intravenous saline infusion caused a similar natriuresis in diabetic patients and normal subjects; the renin-angiotensin-aldosterone system was suppressed to a higher degree in diabetic patients than in normal subjects, whereas atrial natriuretic factor was stimulated to a similar extent; plasma digoxin-like activity was unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aldosterone; Angiotensin II; Atrial Natriuretic Factor; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Norepinephrine; Peptides; Renin; Renin-Angiotensin System; Sodium

To evaluate plasma atrial natriuretic factor (ANF) behavior in hypertensive patients with either insulin-dependent (type I) or non-insulin-dependent (type II) diabetes.. Plasma ANF levels were measured in euglycemic normotensive patients (n = 18) and hypertensive patients (n = 18), in diabetic normotensive patients (type I diabetes, n = 12; type II diabetes, n = 12), and in diabetic hypertensive patients (type I diabetes, n = 12; type II diabetes, n = 22). In all groups, plasma ANF levels were determined at the end of a normal NaCl diet period (120 mmol NaCl per day for 10 days) in both the supine and the upright positions.. Plasma ANF levels were significantly higher (P < 0.05) in hypertensive euglycemic patients (supine vs. upright: 13.4 +/- 6.7 vs. 8.5 +/- 4.3 fmol/ml) than in normotensive type I diabetic patients (supine vs. upright: 8.6 +/- 2.2 vs. 5.9 +/- 2.9 fmol/ml) but not in euglycemic normotensive subjects (supine vs. upright: 11.4 +/- 5.1 vs. 7.6 +/- 5.8 fmol/ml) and normotensive type II diabetic patients (supine vs. upright: 10.1 +/- 4.1 vs. 7.9 +/- 4.1 fmol/ml). Moreover, in the normotensive groups plasma ANF levels did not significantly differ among euglycemic type I and type II diabetic patients. However, the highest levels of plasma ANF were observed in hypertensive type II diabetic patients (supine vs. upright: 16.9 +/- 7.4 fmol/ml [P < 0.01 vs. euglycemic normotensive subjects, P < 0.0001 vs. normotensive type I diabetic patients, P < 0.01 vs. hypertensive type I diabetic patients and normotensive type II diabetic patients] vs. 11.6 +/- 2.9 fmol/ml [P < 0.005 vs. normotensive type I diabetic patients, P < 0.01 vs. hypertensive type I diabetic patients]). On the contrary, plasma ANF levels were higher (P < 0.05) in hypertensive type I diabetic patients (supine vs. upright: 10.8 +/- 1.9 vs. 6.4 +/- 2.2 fmol/ml) compared with normotensive type I diabetic patients, but not with any other patient group. A significant correlation between supine ANF and insulin levels was found in both type II diabetic (r = 0.457; P < 0.05) and nondiabetic hypertensive patients (r = 0.716; P < 0.0001).. These findings indicate that circulating ANF levels are markedly elevated in type II diabetic patients affected by essential hypertension. On the contrary, plasma ANF levels are in the range of normality in normotensive type I and type II diabetic patients.

Topics: Adult; Analysis of Variance; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Fructosamine; Hexosamines; Humans; Hypertension; Insulin; Male; Middle Aged; Posture; Potassium; Reference Values; Sodium

Aim of this study was to verify the existence of a correlation between the insular hormones and the atrial natriuretic factor (ANF). We studied 70 subjects (20 control, 20 obese, 20 non insulin-dependent diabetic obese, 10 insulin-dependent diabetic subjects) submitted to a glucagon test (1 mg i.v.). Blood samples were collected at -15, 0, 3, 6, 12, 15, 30, 60, 120, 150 minutes to assay insulin, C-peptide, serum electrolytes and ANF levels. The results to point out are: the ANF basal values are significantly higher (p < 0.01) in non insulin-dependent obese patients than in controls; the obese subjects also present a significant difference (p < 0.05). After glucagon injection no variations have been found in the ANF values until the 15th minute; then the controls, the obese and, above all, the non insulin-dependent diabetic obese subjects showed a significant increase of the ANF values between 60' and 90' (basal values 38 +/- 4 ng/ml; 90' values 85 +/- 7 ng ml). As these high values appear only after the induction of hyperinsulinism in our experiment and are not present in the type-1 diabetic subjects, it's probable that insulin, rather than glucagon, stimulates, directly or indirectly, the ANF secretion. If this hypothesis is confirmed, the correlation between insulin and ANF should deserve attention from a therapeutic point of view in subjects with glycometabolic imbalance.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Potassium; Secretory Rate; Sodium

Evidence that an increase in plasma atrial natriuretic peptide (ANP) concentrations mediates, at least in part, glomerular hyperfiltration in diabetic rats prompted us to study the relationship between ANP and renal haemodynamics in hyperfiltering type 2 diabetic patients in association with other hormones implicated in the control of glomerular filtration rate (GFR) (catecholamines, vasopressin, renin) and in sodium tubular transport (aldosterone, ouabain-displacing factor, ODF). Since hyperglycaemia is also associated to hyperfiltration, diabetic patients who presented with secondary drug failure were studied both in hyperglycaemic and in normoglycaemic condition. For this purpose, 11 normotensive non-macroproteinuric hyperfiltering patients with type 2 diabetes were treated with an 8-day continuous insulin infusion (days 0-7). Dehydration was prevented or corrected and natriuresis was on day 0 above 100 mmol/day. The following parameters were determined on days 0 and 7: GFR and renal plasma flow (RPF) by 99mTc-DTPA and 131I-hippuran clearances; the extracellular volume, assimilated to the DTPA diffusion volume; urinary ODF by receptor-binding assay and urinary as well as plasma catecholamines by HPLC after extraction on alumin. Plasma ANP and antidiuretic hormone (ADH) were measured by radioimmunoassay after extraction on phenyl-silylsilica (ANP) and with ether (ADH). Unextracted plasma was used for radioimmunological measurement of plasma renin activity and aldosterone. When correcting hyperglycaemia to normoglycaemia GFR decreased from high to normal mean value (138 +/- 27 and 115 +/- 6 ml/min, p < 0.001), RPF followed the same trend, and the DTPA diffusion volume did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Hormones; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Renal Circulation; Vasopressins

Physical training has been generally recommended for patients with diabetes mellitus as a basic therapeutic tool. In the present study the metabolic and endocrinological effects during the training program were examined in patients with non insulin dependent diabetes mellitus (NIDDM). Moreover the significance of continuous blood lactate monitoring and that of the determination of plasma atrial natriuretic polypeptide (ANP) during exercise loading in diabetics was also studied. (1) The glucose metabolic clearance rate (MCR) during euglycemic insulin clamp was higher in athletes than in patients with NIDDM and control subjects. (2) MCR increased significantly in the training group after the eight weeks program and a significant relationship between the changes of MCR and those of HbAIc observed. Moreover a decrease in the triglyceride level and increase in the HDL cholesterol level in plasma were significantly related with the improvement of MCR. (3) A continuous blood lactate monitoring system was newly developed. This system was simple and showed good reproducibility. The anaerobic threshold (AT) determined using this system corresponded to that obtained by respiratory gas analysis. It was useful for the determination of the exercise intensity without overloading in patients with diabetes mellitus. (4) The increase of plasma ANP during exercise loading was higher in diabetics than healthy controls, and a significant relationship was found between the increment of ANP during exercise and the diastolic function judged from the echocardiogram in diabetics. In conclusion clinical laboratory examinations and medical checkups are important in the practice of physical exercise therapy in patients with diabetes mellitus.

Topics: Adult; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Exercise Therapy; Humans; Insulin; Lactates; Male; Middle Aged

1. Disturbances of sodium and water homoeostasis may contribute to the close association between diabetes, hypertension and proteinuria. We therefore studied the patterns of two natriuretic hormones, plasma atrial natriuretic peptide and urinary dopamine, in 165 Chinese patients with non-insulin-dependent diabetes mellitus controlled by diet or oral hypoglycaemic agents on two occasions over a 6-week period. Patients were divided into three groups based on the mean value of two 24h urinary albumin excretion measurements. In group 1, 88 patients had normoalbuminuria (urinary albumin excretion < or = 30 mg/day), in group 2, 48 patients had microalbuminuria (urinary albumin excretion between 30 and 300 mg/day), and in group 3, 29 patients had macroalbuminuria (urinary albumin excretion > or = 300 mg/day). 2. The supine systolic blood pressure (mean +/- SD) was higher in patients with abnormal albuminuria (group 1: 140.9 +/- 27.4 mmHg; group 2: 158.1 +/- 26.4 mmHg; group 3: 166.7 +/- 23.9 mmHg; F = 13.1, P < 0.001, analysis of variance). Urinary sodium output was similar in these three groups of patients. The geometric means (anti-logarithm of 95% confidence interval logarithm) of plasma atrial natriuretic peptide concentrations increased with increasing proteinuria [group 1: 33.3 (29.9-37.1) pg/ml; group 2: 39.1 (34.2-44.6) pg/ml; group 3: 50 (38.6-54.7) pg/ml; F = 4.24, P < 0.01; analysis of variance], whereas those of urinary dopamine output were related inversely to proteinuria [group 1: 1291.7 (1167.2-1437.0) nmol/day; group 2: 1142.3 (975.9-1337.2) nmol/day; group 3: 982.7 (775.7-1245) nmol/day; F = 3.10, P < 0.05, analysis of variance].(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dopamine; Humans; Hypertension; Middle Aged; Proteinuria

Diabetes mellitus (DM) is frequently associated with hypertension for which an independent pathomechanism has been suggested. We studied 26 patients with insulin-dependent (IDDM) and 18 patients with non-insulin-dependent (NIDDM) uncomplicated DM; all patients were in metabolic balance and none of them had hypertension. Exchangeable body sodium (NaE was estimated by isotope dilution, using appr. 1.1 Mbq 24NA. In a subset of 8 IDDM and 8 NIDDM patients atrial natriuretic peptide (ANP) plasma concentration was determined prior to and after the infusion of 2000 ml physiological saline over 2 hr. NaE was significantly increased both in IDDM and NIDDM patients (104.4 +/- 11.4% and 109.9 +/- 8.0% of the normal value for healthy subjects of identical body surface area; p < 0.05 and < 0.001 resp.). Mean blood pressure (MBP) correlated significantly with NaE in both groups (r = 0.364 and r = 0.520; p < 0.05 and < 0.025, resp.) but not in healthy control subjects (r = 0.112; N.S.). Resting ANP levels were not significantly different in IDDM (34.9 +/- 11.3 pg/ml), NIDDM (42.6 +/- 11.7 pg/ml) or control subjects (40.9 +/- 17.2 pg/ml) however the infusion of saline resulted in a significantly greater increase of plasma ANP in the NIDDM patients (to 82.9 +/- 43.2 pg/ml; P < 0.01) than in the controls (55.6 +/- 23.7 pg/ml; P < 0.01) which was associated with a significantly less increase in sodium excretion (UNAV) in the NIDDM patients (+86% vs. 3170%; P < 0.02) indicating down-regulation of ANP receptors in the kidney of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Sodium

To clarify a possible mechanism whereby the perception of thirst may be associated with diabetes mellitus, we measured plasma levels of vasopressin (AVP), angiotensin II (ANG II), atrial natriuretic peptide (ANP) and plasma renin activity (PRA) in non-insulin-dependent (NIDDM) diabetic patients with or without thirst. Thirteen male NIDDM patients complaining of thirst had a significantly high blood hematocrit, plasma urea nitrogen and creatinine concentrations and plasma osmolality, indicating a reduction in plasma volume. In addition, the patients had a significantly high mean plasma concentrations of AVP (3.20 +/- 1.27 pmol/l) ANG II (33.8 +/- 31.4 pmol/l) and PRA, but a low mean plasma ANP concentration (8.9 +/- 4.5 pmol/l). After treatment with diet and/or sulfonylurea, plasma levels of AVP, ANG II and PRA decreased with a concomitant increase in plasma volume and disappearance of thirst. In contrast, 13 NIDDM patients (9 females and 4 males) without thirst had normal plasma urea nitrogen and creatinine concentrations, and the hematocrit did not change significantly after treatment. Plasma AVP (0.95 +/- 0.34 pmol/l), ANG II (14.7 +/- 8.8 pmol/l) and ANP (10.7 +/- 4.9 pmol/l) concentrations, and PRA were normal in this group of patients. There was no significant difference between the two groups of patients, however, in fasting glucose concentration and HbA1c. We conclude from these results that a reduction in plasma volume may be the major factor responsible for the induction of thirst sensation and for increased AVP secretion in NIDDM patients. The mechanism underlying a reduction in plasma volume remains unclear.

Topics: Adult; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 2; Female; Heart Rate; Humans; Male; Middle Aged; Reference Values; Renin; Thirst

The effect of postural changes on plasma atrial natriuretic factor (ANF) levels was investigated in 16 diabetic hypertensives (eight with and eight without mild autonomic neuropathy) and in 10 hypertensives. The presence of renal damage or secondary hypertension was excluded. All diabetic patients were in good metabolic control. In upright position, the mean levels of plasma ANF were of 23.1 +/- 7.6 pg/mL in neuropathic diabetic hypertensives, 24.2 +/- 8.3 pg/mL in diabetic hypertensives, and 21.6 +/- 6.7 in essential hypertensives. Percentage decrease observed after the assumption of supine position was 47 +/- 18, 50 +/- 10, and 46 +/- 13, respectively. No significant difference was found between hypertensives and diabetic hypertensives, even in the presence of mild autonomic neuropathy. Plasma ANF response to postural changes was similar in all groups.

Topics: Adult; Angiotensin II; Atrial Natriuretic Factor; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Hypertension; Male; Middle Aged; Posture; Renin

Subjects with Type 2 diabetes have been reported to have elevated total exchangeable sodium when compared with normal subjects. Sodium retention may contribute to the development of hypertension in these subjects. Atrial natriuretic factor may play a role in sodium and blood pressure homeostasis in Type 2 diabetes. We have studied plasma atrial natriuretic factor in 17 subjects with Type 2 diabetes (9M:8F; aged 49 +/- 2 years) (mean +/- SE) and in 17 age- (49 +/- 2 years) and sex-matched controls. Mean fasting blood sugar was 8.3 +/- 0.6 mmol l-1 in the diabetic subjects. After fasting from 2200h, subjects remained upright from 0745h until 0945h when blood was taken for plasma atrial natriuretic factor, plasma renin activity and serum aldosterone. Two litres of 0.15 mmol l-1 NaCl was infused intravenously between 1000h and 1400h while the subjects remained supine. Blood was taken hourly. At 0945h plasma atrial natriuretic factor was 3.8 +/- 0.4 pmol l-1 in diabetic subjects and 6.1 +/- 1.6 pmol l-1 in controls (NS), at 1000h after 15 mins supine 3.5 +/- 0.3 and 7.9 +/- 2.3 pmol l-1 respectively (p < 0.05) and increased to 9.4 +/- 1.5 and 9.4 +/- 1.2 pmol l-1 in diabetic subjects and controls at 1400h (NS; both p < 0.01 vs basal values). Serum aldosterone, plasma renin activity, blood pressure and urinary sodium output for 12h before, 4h during and 8h after the NaCl infusion were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Posture; Renin; Sodium Chloride; Supine Position

Plasma atrial natriuretic peptide (ANP) levels were examined in 66 patients with non-insulin-dependent diabetes mellitus (NIDDM), and in 9 age-matched normal controls and 18 hypertensive controls. The diabetic patients were classified into three groups according to random urine albumin/creatinine ratio (ACR, mg/g or mg/88.4 nM); group 1 (normo-albuminuria, ACR less than 20, n = 34), group 2 (borderline microcalbuminuria, 20 less than or equal to ACR less than 100, n = 17) and group 3 (manifest microalbuminuria and macroalbuminuria, 100 less than or equal to ACR less than 2000, n = 15). Plasma ANP levels (pg per ml) were significantly elevated in group 2 (46.0 +/- 19.0 SD) when compared with either normal controls (23.8 +/- 14.2), group 1 (28.9 +/- 15.6) or group 3 (26.0 +/- 12.9). This increase in plasma ANP levels was not related to hypertension. Furthermore, plasma ANP levels correlated positively with log(ACR) among the patients with ACR under 100 (groups 1 and 2 combined, r = 0.4701, p less than 0.01). These results suggest that an elevated plasma ANP level in the early phase of microalbuminuria possibly plays a pathophysiological role in the development of nephropathy in NIDDM patients.

Topics: Albuminuria; Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Middle Aged; Radioimmunoassay

To evaluate the effects of acute protein loading on the glomerular filtration rate, albumin excretion rate and concentration of plasma amino acids, ten healthy volunteers and six type 2 diabetic patients with normoalbuminuria were studied before and after eating 0.7 g/kg body weight of tuna fish, boiled egg white, cheese or tofu (bean curd) on separate days. Furthermore, to study the possible role of glucagon, growth hormone, atrial natriuretic peptide and kallikrein in the responses of glomerular filtration rate to protein, these substances were measured before and after ingestion of tuna fish or egg white in six healthy volunteers. In healthy subjects, glomerular filtration rate increased significantly (p less than 0.01) from 98.1 +/- 4.2 ml/min during the baseline period to 129.9 +/- 6.6 ml/min after ingestion of tuna fish. No significant differences were seen between glomerular filtration rate before and after ingestion of egg white, cheese or bean curd. No significant differences were observed between the baseline albumin excretion rate and that after loading with any of the four kinds of protein. Plasma concentrations of alanine, glycine and arginine (amino acids known to induce glomerular hyperfiltration) increased to a greater degree after ingestion of tuna fish than after administration of the other meals. Diabetic subjects and healthy volunteers had similar responses. Plasma glucagon and growth hormone concentrations increased after ingestion of the tuna fish meal or egg white. Plasma atrial natriuretic peptide concentration and urinary kallikrein excretion were unaffected by ingestion of these two kinds of protein. These findings suggest that responses of glomerular filtration rate to acute protein loading may differ depending on the protein ingested, and that these responses may not be directly induced by glucagon, growth hormone, atrial natriuretic peptide or kallikrein.

Topics: Adult; Albumins; Amino Acids; Atrial Natriuretic Factor; Creatinine; Diabetes Mellitus, Type 2; Dietary Proteins; Female; Glomerular Filtration Rate; Glucagon; Growth Hormone; Humans; Kallikreins; Male; Middle Aged

In order to clarify the mode of atrial natriuretic peptide (ANP) release and the effect of autonomic nerve function on ANP release, we measured plasma ANP concentrations in response to hypertonic saline infusion in patients with non-insulin-dependent diabetes mellitus (NIDDM) having or not having autonomic neuropathy (AN). Studies were made on 72 normal subjects (male 44, female 28; 53.0 +/- 0.9 yr.), and 63 patients with NIDDM (male 36, female 27; 56.9 +/- 2.1 yr.). The patients with NIDDM were divided into two groups: Group A was 48 diabetics without AN, and Group B was 15 diabetics with AN. Six patients selected randomly from each group and 6 normal subjects were given an infusion of hypertonic saline (2.5% NaCl) at a rate of 0.25 ml/min/kg over 45 min. Autonomic nerve function was estimated by clinical symptoms, coefficient of variation of R-R intervals (CVR-R), Valsalva test and Schellong test. Plasma ANP concentration was measured by a sensitive and specific radioimmunoassay (RIA) after extraction using SEP-PAK C18 cartridge reported previously. The mean plasma concentration of ANP was 20.7 +/- 1.8 pg/ml (mean +/- SEM) in normal subjects, 24.3 +/- 2.4 pg/ml in NIDDM patients without AN, and 26.4 +/- 3.6 pg/ml in NIDDM patients with AN. There was no significant difference in these levels among the 3 groups. The fasting plasma concentration of ANP in diabetics as well as in normal subjects increased parallel with age. In 12 diabetics, plasma concentrations of ANP significantly elevated from 27.6 +/- 2.0 pg/ml to 149.4 +/- 29.8 pg/ml at 60 min after start of hypertonic saline infusion as compared with 6 normal subjects in whom the levels increased from 15.6 +/- 2.9 pg/ml to 34.1 +/- 5.7 pg/ml at 75 min. On the other hand, the plasma ANP concentration in response to hypertonic saline infusion in NIDDM patients with AN (71.8 +/- 14.4 pg/ml, at 60 min) was lower than that in NIDDM patients without AN (224.2 +/- 38.2 pg/ml, at 60 min). Area under the curve (AUC) of plasma ANP of NIDDM patients with AN after hypertonic saline infusion was 6560 +/- 879.6 pg.min/ml (normal subjects, 2575.6 +/- 444.6 pg.min/ml), which was significantly lower than that of NIDDM patients without AN (13757.8 +/- 1148.4 pg.min/ml). Moreover, there was a positive correlation between AUC and CVR-R in patients with NIDDM. These results indicate that the response of plasma ANP to hypertonic saline infusion in NIDDM patients is significantly higher than in normal subjects.(ABSTRACT TRU

Topics: Adult; Age Factors; Atrial Natriuretic Factor; Autonomic Nervous System; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Saline Solution, Hypertonic

Topics: Adult; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Immersion; Male; Middle Aged; Reference Values; Renin