natriuretic-peptide--c-type and Diabetes-Mellitus--Type-2

In this study, we aimed to demonstrate the effectiveness of serum amino-terminal proCNP (NT-proCNP) levels in predicting coronary heart disease (CHD) and cardiovascular risk in type 2 diabetes mellitus (T2DM) patients.. We recruited 73 patients with T2DM in the study. Additionally, we grouped the patients according to their status of diabetic retinopathy (DR) as no DR, non-proliferative DR, or proliferative DR. Serum NT-proCNP levels of the patients were measured and their atherosclerotic cardiovascular disease (ASCVD) risk scores were calculated.. There was no significant difference in terms of NT-proCNP levels between the groups (p = 0.3) and in terms of CHD and ASCVD risk scores (p = 0.4 and p = 0.4, respectively). In the correlation analysis, a significant correlation was observed between the NT-proCNP levels and the ASCVD risk score (r = 0.373; p = 0.008 among the entire cohort and r = 0.555; p = 0.01 in the non-proliferative-DR group), smoking status (r = 0.280; p = 0.03 among the entire cohort and r = 0.362; p = 0.035 in the non-proliferative-DR group), sBP (r = 0.278; p = 0.038 among the entire cohort), and dBP (r = 0.284; p = 0.034 among the entire cohort and r = 0.482; p = 0.004 in the proliferative-DR group). In the ROC analysis, we found that the NT-proCNP level predicted a high ASCVD risk score with 83.3% sensitivity and 70.8% specificity and a very high ASCVD risk score with 100% sensitivity and 69.2% specificity among the proliferative-DR patients. No cut-off value was calculated for the prediction of high and very-high ASCVD risk scores in patients with non-proliferative DR. Similarly, no cut-off value was revealed for the prediction of established coronary artery disease in all groups.. Our study revealed a significant association between NT-proCNP levels and high ASCVD risk scores in patients with proliferative DR.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Heart Disease Risk Factors; Humans; Natriuretic Peptide, C-Type; Risk Factors

Chronic renal inflammation and fibrosis are common sequelae in diabetes mellitus (DM) and are major causes of premature mortality. Although upregulation of. ProCNP products in urine were characterized with HPLC and a range of antisera directed to specific epitopes of amino-terminal proCNP (NTproCNP). The 5-kDa intact peptide was quantified in spot urine samples from healthy adults and 202 participants with DM selected to provide a broad range of renal function.. The predominant products of proCNP in urine were consistent with the 2-kDa fragment (proCNP 3-20) and a smaller peak of intact (5-kDa) fragment (proCNP 1-50, NTproCNP). No peaks consistent with bioactive forms (proCNP 82-103, 50-103) were identified. The urine NTproCNP to creatinine ratio (NCR) was more reproducible than the albumin to creatinine ratio (ACR) and strongly associated with the presence of chronic kidney disease. In models predicting independence, among 10 variables associated with renal function in DM, including plasma NTproCNP, only 3 (sex, ACR, and plasma creatinine) contributed to NCR.. Characterization of the products of proCNP in urine confirmed the presence of NTproCNP. In spot random urine from study participants with DM, NCR is inversely associated with estimated glomerular filtration rate. In contrast to ACR, NCR reflects nonvascular factors that likely include renal inflammation and fibrosis.

Topics: Adult; Aged; Albuminuria; Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Creatinine; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Natriuretic Peptide, C-Type; Renal Insufficiency, Chronic

Obesity is defined as an abnormal increase in white adipose tissue (WAT) and is a major risk factor for type 2 diabetes and cardiovascular disease. Brown adipose tissue (BAT) dissipates energy and correlates with leanness. Natriuretic peptides have been shown to be beneficial for brown adipocyte differentiation and browning of WAT.. Here, we investigated the effects of an optimized designer natriuretic peptide (CD-NP) on murine adipose tissues. In murine brown and white adipocytes, CD-NP activated cGMP production, promoted adipogenesis, and increased thermogenic markers. Consequently, mice treated for 10 days with CD-NP exhibited increased "browning" of WAT. To study CD-NP effects on diet-induced obesity (DIO), we delivered CD-NP for 12 weeks. Although CD-NP reduced inflammation in WAT, CD-NP treated DIO mice exhibited a significant increase in body mass, worsened glucose tolerance, and hepatic steatosis. Long-term CD-NP treatment resulted in an increased expression of the NP scavenging receptor (NPR-C) and decreased lipolytic activity.. NP effects differed depending on the duration of treatment raising questions about the rational of natriuretic peptide treatment in obese patients.

Topics: Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Diet; Elapid Venoms; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, C-Type; Obesity; Thermogenesis

We aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy.. A systematic data integration approach was used to select biomarkers representing different disease pathways. Twenty-eight biomarkers were measured in 82 patients seen at an outpatient diabetes center in The Netherlands. Median follow-up was 4.0 years. We compared the cross-validated explained variation (R2) of two models to predict eGFR decline, one including only established risk markers, the other adding a novel panel of biomarkers. Least absolute shrinkage and selection operator (LASSO) was used for model estimation. The C-index was calculated to assess improvement in prediction of accelerated eGFR decline defined as <-3.0 mL/min/1.73m2/year.. Patients' average age was 63.5 years and baseline eGFR was 77.9 mL/min/1.73m2. The average rate of eGFR decline was -2.0 ± 4.7 mL/min/1.73m2/year. When modeled on top of established risk markers, the biomarker panel including matrix metallopeptidases, tyrosine kinase, podocin, CTGF, TNF-receptor-1, sclerostin, CCL2, YKL-40, and NT-proCNP improved the explained variability of eGFR decline (R2 increase from 37.7% to 54.6%; p=0.018) and improved prediction of accelerated eGFR decline (C-index increase from 0.835 to 0.896; p=0.008).. A novel panel of biomarkers representing different pathways of renal disease progression including inflammation, fibrosis, angiogenesis, and endothelial function improved prediction of eGFR decline on top of established risk markers in type 2 diabetes. These results need to be confirmed in a large prospective cohort.

Topics: Adaptor Proteins, Signal Transducing; Adipokines; Adult; Aged; Biomarkers; Bone Morphogenetic Proteins; Chemokine CCL2; Chitinase-3-Like Protein 1; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Fibrosis; Genetic Markers; Glomerular Filtration Rate; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Lectins; Male; Matrix Metalloproteinases, Secreted; Membrane Proteins; Middle Aged; Natriuretic Peptide, C-Type; Outpatients; Prognosis; Prospective Studies; Protein-Tyrosine Kinases; Receptors, Tumor Necrosis Factor, Type I; Renal Insufficiency, Chronic; Risk Factors

Topics: Aged; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Natriuretic Peptide, C-Type; Oxidative Stress

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

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Bradykinin; Calcium; Calcium Signaling; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Transfer Techniques; In Vitro Techniques; Muscle, Smooth, Vascular; Natriuretic Peptide, C-Type; Oligopeptides; Penile Erection; Peptide Fragments; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Salivary Proteins and Peptides