neuropeptide-y and Diabetic-Angiopathies

Diabetes-induced atherosclerotic cardiovascular disease is the leading cause of death of diabetic patients. Neuronal regulation plays a critical role in glucose metabolism and cardiovascular function under physiological and pathological conditions, among which, neurotransmitter neuropeptide Y has been shown to be closely involved in these two processes. Elevated central neuropeptide Y level promotes food intake and reduces energy expenditure, thereby increasing adiposity. Neuropeptide Y is co-localized with noradrenaline in central and sympathetic nervous systems. As a major peripheral vascular contractive neurotransmitter, through interactions with its receptors, neuropeptide Y has been implicated in the pathology and progression of diabetes, by promoting the proliferation of endothelial cells and vascular fibrosis, which may contribute to diabetes-induced cardiovascular disease. Neuropeptide Y also participates in the pathogenesis of atherosclerosis, the major form of cardiovascular disease, via aggravating endothelial dysfunction, growth of vascular smooth muscle cells, formation of foam cells and platelets aggregation. This review highlights the causal role of neuropeptide Y and its receptor system in the development of diabetes mellitus and one of its complications: atherosclerotic cardiovascular disease. The information from this review provides both critical insights onto the mechanisms underlying the pathogenesis of atherosclerosis and evidence for the development of therapeutic strategies.

Topics: Animals; Arteries; Atherosclerosis; Diabetic Angiopathies; Humans; Neuropeptide Y; Prognosis; Receptors, Neuropeptide Y; Risk Factors; Signal Transduction

We investigated the associations of inflammatory blood cell activation with vascular parameters in patients with type 2 diabetes to elucidate the possible mechanisms of accelerated atherosclerosis observed in subjects with the Leucine 7 to Proline 7 polymorphism (Leu7Pro) in the neuropeptide Y (NPY).. Our study included 31 Caucasian patients with type 2 diabetes; 12 of them had the Leu7Pro7 (heterozygous), and 19 had the Leu7Leu7 (wild type) genotype. Vascular parameters were determined by ultrasound methods. Leukocyte analyses were performed from blood samples using flow cytometry. NPY concentrations were determined in plasma.. The amount of platelet-granulocyte complexes was positively correlated with NPY concentration (p=0.008) and carotid intima-media thickness (p=0.035) in the Leu7Pro7 group. Interferon gamma (IFN-γ) expression in monocytes correlated negatively with brachial artery flow-mediated dilatation also in the Leu7Pro7 group (p=0.037). The expression of tissue factor on monocytes correlated negatively with brachial artery diameter in the Leu7Pro7 patients as well (p=0.019).. The results indicate significant associations between inflammatory cell activation in blood and vascular atherosclerosis in genetically prone subjects, and provide possible mechanistic information about the role of NPY and the Leu7Pro polymorphism in the development of atherosclerosis.

Topics: Aged; Analysis of Variance; Brachial Artery; Carotid Artery Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Finland; Flow Cytometry; Genotype; Humans; Inflammation; Interferon-gamma; Leukocytes; Linear Models; Male; Middle Aged; Neuropeptide Y; Phenotype; Proline; Risk Assessment; Risk Factors; Ultrasonography; Vasodilation

The Leucine7 to Proline7 (Leu7Pro) polymorphism of the signal peptide of neuropeptide Y (NPY) increases risk for vascular complications in diabetes. Diabetes is associated with low-grade inflammation, which has an important role in the development of atherosclerosis. Currently, we followed diabetes patients to investigate, if the Pro7 allele is associated with the inflammation related to atherosclerosis.. In the 5-year follow-up, the genotyped, pair-matched type 2 diabetes patients (12 with the Pro7 allele and 19 without) were investigated using non-invasive ultrasound based methods to measure the development of atherosclerosis (intima media thickness=IMT) and endothelium-dependent (FMD) and -independent nitrate-mediated (NMD) vasodilatation. The development of diabetic complications was followed annually, and the concentrations of inflammatory markers and NPY in plasma were determined.. Patients with the Pro7 had increased U-albumin/creatinine (p=0.037), E-selectin (p=0.016), fasting insulin (p=0.011) and HOMA index (p=0.013) but decreased serum amyloid P concentrations (p=0.021). Furthermore, men with the Pro7 had increased CRP (p=0.010) and NPY (p=0.026) concentrations. IMT and FMD were similar in all patients, however, NMD decreased more during the follow-up in the patients with the Pro7 (p=0.002). NPY correlated positively with bIMT [r 0.04 (SE 0.02), p=0.007] and E-selectin negatively with FMD [r -0.05 (S.E 0.02), p=0.039].. Diabetes patients with the Pro7 allele display increased levels of inflammatory molecules and NPY in blood, preceding vascular wall thickening and impaired endothelial dilatation, especially in male patients.

Topics: Aged; Albuminuria; Atherosclerosis; Biomarkers; C-Reactive Protein; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; E-Selectin; Female; Finland; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Inflammation Mediators; Insulin Resistance; Linear Models; Logistic Models; Male; Matched-Pair Analysis; Middle Aged; Neuropeptide Y; Phenotype; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Protein Sorting Signals; Risk Assessment; Risk Factors; Serum Amyloid P-Component; Sex Factors; Time Factors; Ultrasonography; Up-Regulation; Vasodilation

We have recently demonstrated that subjects having Pro7 in the signal peptide ofneuropeptide Y (NPY) have higher serum cholesterol and apolipoprotein B levels than individuals with wild-type (Leu7Leu7) signal peptide sequence. We investigated the association of Leu7Pro polymorphism with common carotid intima media thickness (IMT) assessed by ultrasonograph in patients with type 2 diabetes (n = 81; 41 men and 40 women; mean age, 67.1 yr) and nondiabetic subjects (n = 105; 48 men and 57 women; mean age, 65.5 yr) and genotyped for the Leu7Pro polymorphism in prepro-NPY. The frequency of Pro7 in prepro-NPY was 9.9% (8 of 81) in diabetic patients and 14.3% (15 of 105) in control subjects (P = 0.360). The mean common carotid IMT was 1.04 +/- 0.02 mm in nondiabetic subjects without the Leu7Pro polymorphism and 1.14 +/- 0.04 mm in nondiabetic subjects with in (P = 0.156) and 1:18 +/- 0.03 and 1.58 +/- 0.21mm in diabetic patients without and with the Leu7Pro polymorphism (P = 0.004), respectively. In the analysis of covariance of the entire group, the mean common carotid IMT was independently associated with the Leu7Pro polymorphism (F = 5.165; P = 0.024) after adjustment for known risk factors. Thus, the presence of the Pro7 substitution in the prepro-NPY associates with increased carotid atherosclerosis.

Topics: Aged; Amino Acid Substitution; Arteriosclerosis; Autonomic Nervous System; Blood Pressure; Carotid Stenosis; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Genotype; Heart Rate; Humans; Leucine; Male; Neuropeptide Y; Polymorphism, Genetic; Proline; Risk Factors