neuropeptide-y and Diabetes-Mellitus--Type-1

The discovery of leptin has generated an extraordinary interest in the field of obesity but also in the understanding of the relationship between metabolic status and the neuroendocrine system. Following the initial demonstration that leptin administration to fasting mice can 'protect' neuroendocrine secretions and prevent the changes that are associated with fasting, the concept has emerged that a normal leptin secretion is a prerequisite for normal neuroendocrine secretions. Several unfavorable metabolic situations are associated with low plasma leptin, increased secretion of hypothalmic neuropeptide Y (NPY), and hypogonadism, and a causal relationship has been evoked. Severe dietary restriction in juvenile female rats is associated with low plasma leptin and sexual immaturity. Cessation of food restriction leads to immediate increase in plasma leptin followed 4 days later by vaginal opening. If food restriction is maintained, central leptin infusion can induce sexual maturation, thus demonstrating that leptin can act as a signal for the onset of puberty. In untreated type-I diabetic rats, hypogonadism is associated with very low plasma leptin and increased hypothalmic NYP synthesis and oestrous cyclicity. Fasting rapidly inhibits growth hormone (GH) secretion in association with low plasma leptin and elevated hypothalmic NPY. Central infusion of leptin to fasting rats was able to completely prevent the collapse of GH secretion and to maintain a normal low NPY synthesis. In summary, normally elevated plasma levels appear to be a prerequisite for normal GH and gonadotropin secretion in the rat. Degradation of metabolic conditions results in a rapid reduction of circulating leptin that could represent the signal for several alterations of neuroendocrine secretions. At the level of the hypothalamus, leptin could act on NPY neurons to transduce part or all of this 'metabolic' message. The possibility that changing plasma levels for leptin also affect peripheral endocrine targets, such as pituitary, ovary, adrenal or pancreas, is likely since these endocrine organs express functional long-term leptin receptors.

Topics: Animals; Diabetes Mellitus, Type 1; Female; Food Deprivation; Growth Hormone; Leptin; Neuropeptide Y; Proteins; Rats; Sexual Maturation

Neuropeptide Y (NPY), a major brain neurotransmitter, is expressed in neurons of the hypothalamic arcuate nucleus (ARC) that project mainly to the paraventricular nucleus (PVN), an important site of NPY release. NPY synthesis in the ARC is thought to be regulated by several factors, notably insulin, which may exert an inhibitory action. The effects of NPY injected into the PVN and other sites include hyperphagia, reduced energy expenditure and enhanced weight gain, insulin secretion, and stimulation of corticotropin and corticosterone release. The ARC-PVN projection appears to be overactive in insulin-deficient diabetic rats, and could contribute to the compensatory hyperphagia and reduced energy expenditure, and pituitary dysfunction found in these animals; overactivity of these NPY neurons may be due to reduction of insulin's normal inhibitory effect. The ARC-PVN projection is also stimulated in rat models of obesity +/- non-insulin diabetes, possibly because the hypothalamus is resistant to inhibition by insulin; in these animals, enhanced activity of ARC NPY neurons could cause hyperphagia, reduced energy expenditure, and obesity, and perhaps contribute to hyperinsulinemia and altered pituitary secretion. Overall, these findings suggest that NPY released in the hypothalamuss, especially from the ARC-PVN projection, plays a key role in the hypothalamic regulation of energy balance and metabolism. NPY is also found in the human hypothalamus. Its roles (if any) in human homeostasis and glucoregulation remain enigmatic, but the animal studies have identified it as a potential target for new drugs to treat obesity and perhaps NIDDM.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Homeostasis; Humans; Mice; Neural Pathways; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Syndrome

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

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

(1) Autoantibodies to the leucine variant of neuropeptide Y (NPY-LA) have been found in individuals with type 1 diabetes (T1D). We investigated the association between the levels of NPY-LA and single nucleotide polymorphisms (SNP) to better understand the genetic regulatory mechanisms of autoimmunity in T1D and the functional impacts of increased NPY-LA levels. (2) NPY-LA measurements from serum and SNP genotyping were done on 560 newly diagnosed individuals with T1D. SNP imputation with the 1000 Genomes reference panel was followed by an association analysis between the SNPs and measured NPY-LA levels. Additionally, functional enrichment and pathway analyses were done. (3) Three loci (DGKH, DCAF5, and LINC02261) were associated with NPY-LA levels (p-value < 1.5 × 10−6), which indicates an association with neurologic and vascular disorders. SNPs associated with variations in expression levels were found in six genes (including DCAF5). The pathway analysis showed that NPY-LA was associated with changes in gene transcription, protein modification, immunological functions, and the MAPK pathway. (4) Conclusively, we found NPY-LA to be significantly associated with three loci (DGKH, DCAF5, and LINC02261), and based on our findings we hypothesize that the presence of NPY-LA is associated with the regulation of the immune system and possibly neurologic and vascular disorders.

Topics: Autoantibodies; Case-Control Studies; Diabetes Mellitus, Type 1; Humans; Neuropeptide Y; Polymorphism, Single Nucleotide

Neuropeptide Y (NPY) plays a crucial role in many neurobiological functions, such as cognition and memory. Cognitive and memory impairment have been described in diabetic patients. The metabolism of NPY is determined by the activity of proteases, primarily dipeptidyl-peptidase-IV (DPP-IV). Therefore, DPP-IV inhibitors, such as sitagliptin, may modulate the function of NPY. In this study, we investigated the effect of type 1 diabetes and sitagliptin treatment on the regulation of the mRNA encoding for NPY and its receptors (Y1, Y2, and Y5 receptors) in the hippocampus.. Type 1 diabetes was induced in male Wistar rats by i.p. injection of streptozotocin. Starting two weeks after diabetes onset, animals were treated orally with sitagliptin (5mg/kg, daily) for two weeks. The mRNA expression of Npy and its receptors (Npy1r, Npy2r, and Npy5r) in the hippocampus was evaluated using in situ hybridization with. The mRNA expression of Npy, Npy1r and Npy5r was higher in the dentate gyrus, whereas Npy2r highest level was observed in the CA3 subregion. The mRNA expression of Npy, Npy1r and Npy5r in dentate gyrus, CA1 and CA3 was not affected by diabetes and/or by sitagliptin treatment. Type 1 diabetes increased the mRNA expression of Npy2r in the CA3 subregion, which was prevented by sitagliptin treatment.. Our results show that type 1 diabetes, at early stages, induces mild changes in the NPY system in the hippocampus that were counteracted by sitagliptin treatment.

Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Hippocampus; Hypoglycemic Agents; Male; Neuropeptide Y; Oligonucleotide Probes; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sitagliptin Phosphate

Neuropeptide Y (NPY) is a well-established orexigenic peptide and hypothalamic paraventricular nucleus (PVH) is one major brain site that mediates the orexigenic action of NPY. NPY induces abundant expression of C-Fos, an indicator for neuronal activation, in the PVH, which has been used extensively to examine the underlying NPY orexigenic neural pathways. However, PVH C-Fos induction is in discordance with the abundant expression of NPY receptors, a group of inhibitory Gi protein coupled receptors in the PVH, and with the overall role of PVH neurons in feeding inhibition, suggesting a mechanism of indirect action. Here we showed that the ability of NPY on C-Fos induction in the PVH was blunted in conditions of insulin deficiency and fasting, a condition associated with a high level of NPY and a low level of insulin. Moreover, insulin insufficiency blunted C-Fos induction in the PVH by fasting-induced re-feeding, and insulin and NPY induced c-Fos induction in the same group of PVH neurons. Finally, NPY produced normal C-Fos induction in the PVH with disruption of GABA-A receptors. Thus, our results revealed that PVH C-Fos induction by NPY is mediated by an indirect action, which is at least partially mediated by insulin action, but not GABA-A receptors.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fasting; GABAergic Neurons; Gene Expression; Insulin; Male; Mice; Mice, Transgenic; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; Receptors, GABA-A

Indices of cardiovascular autonomic neuropathy (CAN) in experimental models of Type 1 diabetes mellitus (T1DM) are often contrary to clinical data. Here, we investigated whether a relatable insulin-treated model of T1DM would induce deficits in cardiovascular (CV) autonomic function more reflective of clinical results and if exercise training could prevent those deficits. Sixty-four rats were divided into four groups: sedentary control (C), sedentary T1DM (D), control exercise (CX), or T1DM exercise (DX). Diabetes was induced via multiple low-dose injections of streptozotocin and blood glucose was maintained at moderate hyperglycemia (9-17 mM) through insulin supplementation. Exercise training consisted of daily treadmill running for 10 weeks. Compared to C, D had blunted baroreflex sensitivity, increased vascular sympathetic tone, increased serum neuropeptide Y (NPY), and decreased intrinsic heart rate. In contrast, DX differed from D in all measures of CAN (except NPY), including heart rate variability. These findings demonstrate that this T1DM model elicits deficits and exercise-mediated improvements to CV autonomic function which are reflective of clinical T1DM.

Topics: Animals; Autonomic Nervous System; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular System; Diabetes Complications; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Heart Rate; Hyperglycemia; Insulin; Male; Neuropeptide Y; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

Autoantibodies (A) against Neuropeptide Y (NPY), was reported in 9% newly diagnosed type 1 diabetes (T1D) patients. A single nucleotide polymorphism (SNP) at rs16139 (T1128C) within the NPY-gene identified an amino acid substitution from leucine (L) to proline (P) (L7P) associated with both glucose tolerance and type 2 diabetes. We aimed to determine: (i) the influence of autoantibodies to leucine neuropeptide Y (NPY-LA) and autoantibodies to proline neuropeptide Y (NPY-PA) on the diagnostic sensitivity of type 1 diabetes (T1D), (ii) the association of NPYA with major islet autoantibodies, and (iii) the association of NPYA with HLA-DQ genotypes in newly diagnosed T1D patients.. Serum from the HLA-DQ typed T1D patients (n = 673; median age 10 yr) from Skåne, Sweden, were analyzed for autoantibodies against NPY-L and NPY-P in a radioligand binding assay, and against glutamic acid decarboxylase 65 (GAD65), insulin, insulinoma associated protein-2 (IA-2), and zinc transporter 8 (ZnT8) in addition to islet cell antibodies (ICA). A total of 1006 subjects (median age 9 yr) were used as controls.. A total of 9.2% (n = 62) of the T1D patients were positive for NPY-LA (p < 0.001) and 7.6% (n = 51) for NPY-PA (p < 0.001) compared to 1.1% (n = 11) in controls. The NPY-LA and NPY-PA appeared together (κ = 0.63; p < 0.001) and the median levels correlated (R² = 0.603; p < 0.001). T1D patients diagnosed after 10 yr of age were at an increased risk for NPYA at diagnosis [odds ratio (OR = 2.46; 95% CI 1.46-4.16; p = 0.001)] adjusted for age at diagnosis, gender, autoantibody positivity, and HLA.. NPY is a minor autoantigen in children with newly diagnosed T1D. Therefore, NPY autoantibodies may be investigated in T1D autoimmunity.

Topics: Adolescent; Autoantibodies; Case-Control Studies; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Infant; Male; Neuropeptide Y; Young Adult

Neuropeptide Y (NPY) inhibits insulin secretion. Increased numbers of pancreatic islet cells expressing NPY have been observed in type 1 diabetic rats. To understand the functional significance of NPY expression in islet cells, we investigated the effects of high fat feeding and diabetic conditions on the expression and location of NPY expressing cells in normal and diabetic rats. Twenty rats were maintained on either normal chow (ND) or a high fat dietary regimen (HFD) for 4 weeks. In half of each group, type 1 or type 2 diabetes (groups T1DM and T2DM, respectively) was induced by injection of streptozotocin. At 8 weeks rats were euthanized and the pancreases were processed for immunofluorescence labeling (NPY/insulin, NPY/glucagon, NPY/somatostatin, and NPY/pancreatic polypeptide). Compared with the ND group, HFD rats had significantly fewer alpha cells, but beta cells were similar, while T1DM and T2DM rats showed significant increases in the proportions of alpha, delta, and PP cells. Robust increases in NPY-positive islet cells were found in the HFD, T1DM, and T2DM rats compared with ND controls. In ND rats, 99.7% of the NPY-positive cells were PP cells. However, high fat feeding and diabetes resulted in significant increases in NPY-positive delta cells, with concomitant decreases in NPY-positive PP cells. In summary, high-fat feeding and diabetes resulted in changes in the hormonal composition of pancreatic islet and increased number of NPY-expressing islet cells. Under diabetic conditions NPY expression switched from predominantly a characteristic of PP cells to predominantly that of delta cells. This may be a factor in reduced pancreatic hormone secretion during diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucose Tolerance Test; Islets of Langerhans; Male; Neuropeptide Y; Rats, Sprague-Dawley

Imidazoline I1-receptors (I1R) are known to regulate blood pressure and rilmenidine, an agonist, is widely used as antihypertensive agent in clinic. However, the role of I1R in feeding behavior is still unclear. In the present study, we used the agonist of I1R to investigate the effect on hyperphagia in streptozotocin (STZ)-induced diabetic mice. Rilmenidine decreased the food intake of STZ-diabetic mice in a dose-dependent manner. The reduction of food intake was abolished by pretreatment with efaroxan at the dose sufficient to block I1R. Intracerebroventricular (icv) administration of rilmenidine into STZ-diabetic mice also significantly reduced hyperphagia, which was reversed by icv administration of efaroxan. In addition, similar results were observed in STZ-diabetic mice, which received chronic treatment with rilmenidine 3 times daily (t.i.d.) for 7 days. Moreover, the hypothalamic neuropeptide Y (NPY) level was reduced by rilmenidine that was also reversed by pretreatment with efaroxan. In conclusion, the obtained results suggest that rilmenidine can decrease food intake in STZ-diabetic mice through an activation of I1R to lower hypothalamic NPY level.

Topics: Animals; Benzofurans; Cerebrum; Diabetes Mellitus, Type 1; Disease Models, Animal; Eating; Female; Humans; Hyperphagia; Hypothalamus; Imidazoles; Imidazoline Receptors; Male; Mice; Mice, Inbred BALB C; Neuropeptide Y; Oxazoles; Rilmenidine; Streptozocin

The changes in concentrations of two neuropeptides, neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) in different segments of the rat tail artery have been investigated (a) after 12 and 16 weeks of streptozotocin (STZ)-induced hyperglycemia that has been induced at the age of 10 weeks, and (b) in 52-week-old Goto-Kakizaki (GK) rats that were intolerant of glucose, and age-matched Wistar controls. In the control animals at 22, 26 and 52 weeks of age, the concentration of CGRP was significantly greater in distal, relative to proximal, segments of normal arteries, and this contrasted with the pattern of distribution of NPY, which was consistently greater in the proximal than the distal segments. STZ-induced diabetes caused significant reductions in the concentrations of NPY and CGRP in the middle and distal segments of the vessel after 12 and 16 weeks of hyperglycemia. In the glucose-intolerant Goto-Kakizaki (GK) rats, the noradrenalin and adrenalin levels increased significantly in the distal segment of the artery relative to controls; in contrast there was a significant fall in dopamine concentration. The only significant change in the level of NPY in 52-week-old GK rats was an increase in the proximal segment, suggesting that in Type II pre-diabetes, noradrenalin and its co-transmitter NPY are affected independently. The concentration of CGRP increased significantly in all segments of the artery of the 12-month-old GK rats relative to controls. The similarities and differences between these measurements in Type I and Type II diabetic models are discussed.

Topics: Animals; Arteries; Blood Glucose; Calcitonin Gene-Related Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Male; Neuropeptide Y; Rats; Rats, Wistar; Streptozocin; Tail

To observe the development of neuropathic changes in two types of experimental diabetes using changes in concentrations of NPY, CGRP and amines in the corpora cavernosa and seminal vesicles. Type I diabetes was studied in Wistar rats after 12 and 16 weeks of STZ-induced hyperglycaemia, and Type II diabetes was studied in prediabetic GK rats aged 52 weeks. Both were compared with age-matched normal Wistar rats.. NPY and CGRP were estimated using radioimmunoassay, and amines using HPLC.. There were significant changes in [CGRP] in the normal corpus cavernosum and in [NPY] in the normal seminal vesicle with age. STZ-diabetes, induced at 10 weeks of age, resulted in significant elevation of [NPY] and [CGRP] in the corpora cavernosa and seminal vesicles after 12 and 16 weeks of hyperglycaemia, relative to age-matched control rats. The GK rats were intolerant of glucose at 52 weeks of age, but did not have raised fasting blood glucose levels. [NPY], [CGRP] and [noradrenaline] in corpora cavernosa were significantly increased in the prediabetic GK animals relative to age-matched Wistar control rats. The seminal vesicles of GK rats showed a significant increase in [NPY], a non-significant increase in [CGRP], and a fall in [noradrenaline] relative to the age-matched Wistar controls.. The results indicate increased levels of NPY and noradrenaline in autonomic nerves, and of CGRP in sensory nerves, innervating the corpus cavernosum in Type I and in prediabetic Type II GK rats.

Topics: Aging; Animals; Blood Glucose; Calcitonin Gene-Related Peptide; Catecholamines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Erectile Dysfunction; Glucose Tolerance Test; Male; Neuropeptide Y; Penis; Prediabetic State; Rats; Rats, Mutant Strains; Rats, Wistar; Seminal Vesicles; Streptozocin; Sympathetic Fibers, Postganglionic

The four major autoantigens (IA-2, IA-2 beta, GAD65 and insulin) of type 1 diabetes are all associated with dense core or synaptic vesicles. This raised the possibility that other secretory vesicle-associated proteins might be targets of the autoimmune response in type 1 diabetes. To test this hypothesis 56 proteins, two-thirds of which are associated with secretory vesicles, were prepared by in vitro transcription/translation and screened for autoantibodies by liquid phase radioimmunoprecipitation. Two secretory vesicle-associated proteins, VAMP2 and NPY, were identified as new minor autoantigens with 21% and 9%, respectively, of 200 type 1 diabetes sera reacting positively. These findings add support to the hypothesis that secretory vesicle-associated proteins are particularly important, but not the exclusive, targets of the autoimmune response in type 1 diabetes. Selective screening of the human proteome offers a useful approach for identifying new autoantigens in autoimmune diseases.

Topics: Adolescent; Adult; Autoantibodies; Autoantigens; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Male; Neuropeptide Y; Secretory Vesicles; Vesicle-Associated Membrane Protein 2

The distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations.. One sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study.. Genotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization.. The C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249-5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD.. The present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leucine; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Proline; Sweden; United States

Neuropeptide Y is a potent vasoconstrictor thought to enhance the development of atherosclerosis. The leucine 7 to proline 7 (Leu7Pro) polymorphism, located in the signal peptide part of the human preproneuropeptide Y, has been associated with serum lipid levels, intima-media thickness of the common carotid arteries, and diabetic retinopathy in type 2 diabetic patients. Therefore, we investigated the impact of the Leu7Pro polymorphism on diabetic nephropathy, cardiovascular risk factors, and cardiovascular disease in type 1 diabetic patients.. A total of 996 patients from the Finnish Diabetic Nephropathy study were studied in a case-control, cross-sectional study. The carrier frequency of the Pro7 substitution was 13% in the entire study population.. The Pro7 substitution was more common in patients with proteinuria than in those with a normal albumin excretion rate (16 vs. 11%, P < 0.05). Patients with the Pro7 allele had worse glycemic control (HbA(1c) 8.8 vs. 8.5%, P < 0.005), more coronary heart disease (CHD) (14 vs. 8%, P < 0.05), and higher serum triglycerides (1.65 vs. 1.35 mmol/l, P < 0.005) than patients with the wild-type genotype. There were no differences in the plasma neuropeptide Y levels between the patients with Pro7 compared with those with the wild-type genotype. The Leu7Pro polymorphism was independently associated with HbA(1c) (P < 0.001), proteinuria (P < 0.01), and CHD (P < 0.01) in multiple regression analyses.. We conclude that the Leu7Pro polymorphism may contribute to the genetic susceptibility to diabetic nephropathy and CHD in type 1 diabetic patients, possibly by influencing glycemic control and triglycerides.

Topics: Adult; Amino Acid Substitution; Blood Glucose; Body Mass Index; Cholesterol; Coronary Disease; Diabetes Mellitus, Type 1; Female; Genotype; Glycated Hemoglobin; Humans; Leucine; Male; Mutation, Missense; Neuropeptide Y; Proline; Protein Precursors; Proteinuria; Risk Factors; Triglycerides

Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina.. Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide.. The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide.. NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.

Topics: Adult; Aged; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Humans; Male; Mice; Middle Aged; Neuropeptide Y; Rats; Receptors, Neuropeptide Y; Retinal Neovascularization

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Heart Rate; Humans; Hypoglycemia; Insulin; Male; Neuropeptide Y; Pancreatic Polypeptide; Respiratory Mechanics

Within the brain, subgroups of neurons respond differently to altered glucose concentrations. Identification of neuropeptide Y in hypothalamic neurons that sense glucose suggests a role for neuropeptide Y in glucose sensing. Using in vitro and in vivo techniques to monitor transmitter release, we investigated whether lowering glucose concentration affects the release of neuropeptide Y from the brain, and whether this process is altered in Type I (insulin-dependent) diabetes mellitus.. Male Sprague-Dawley rats were treated with 48 mg/kg streptozotocin or vehicle intravenously. The effect of reduced glucose on endogenous neuropeptide Y overflow from slices of hypothalamus and medulla incubated in Krebs solution was examined 4 weeks later. The hypothalamus was separated into a dorsal region containing the paraventricular nucleus and a ventral region containing the arcuate nucleus.. Streptozotocin-induced diabetes increased basal neuropeptide Y overflow in the dorsal and ventral hypothalamus ( p<0.05) but not the medulla. In vitro neuropeptide Y overflow was reduced by low glucose in the dorsal hypothalamus in diabetic, but not in control rats. No effect of reduced glucose was observed in the ventral hypothalamus or medulla. In vivo push-pull studies in the paraventricular nucleus also showed greater neuropeptide Y overflow in diabetic rats relative to control rats ( p<0.05). Insulin-induced hypoglycaemia induced a decrease in neuropeptide Y overflow in diabetic rats, while an increase was observed in control rats ( p<0.05).. These region-specific effects of low glucose on neuropeptide Y overflow in diabetic rats support a part for neuropeptide Y in altered glucose sensing in Type I diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drinking Behavior; Feeding Behavior; Glycosuria; Hypothalamus; Male; Medulla Oblongata; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley

Recent findings suggest that proinsulin C-peptide improves renal and nerve function as well as microcirculation in patients with insulin-dependent diabetes possibly by stimulating Na-K+-ATPase activity. Furthermore, in vitro studies on proximal rat renal tubule cells show that the effect of C-peptide on Na+, K+-ATPase activity is potentiated in the presence of the vasoconstrictor peptide neuropeptide Y. The aim of the present study was to examine whether the effects of neuropeptide Y on resting forearm blood flow in insulin-dependent patients is altered in the presence of C-peptide. Forearm blood flow was measured by a plethysmographic method in eight insulin-dependent patients and six healthy control subjects. Neuropeptide Y (20, 200 and 2000 pmol min(-1)) was infused into the brachial artery before and during an i.v. infusion of C-peptide (5 pmol kg(-1) min(-1)). Basal blood flow was 36.7 +/- 2.2 mL min(-1) L(-1) tissue. It decreased in a dose dependent manner by 11 +/- 2, 18 +/- 3 and 25 +/- 3%, respectively, during infusion of neuropeptide Y. Administration of C-peptide increased basal blood flow by 25 +/- 6%, to 46.3 +/- 3.5 mL min(-1) L(-1) tissue (P < 0.01) and forearm glucose uptake by 76 +/- 34% (P < 0.05). Infusion of the three doses of neuropeptide Y during administration of C-peptide decreased forearm blood flow by 14 +/- 4, 22 +/- 3 and 42 +/- 4%. There was a significant difference (43%, P < 0.001) between the reduction in blood flow evoked by the high dose (2000 pmol min(-1)) of neuropeptide Y before and during C-peptide infusion. Similar differences were also obtained when data were calculated as changes in vascular resistance. C-peptide did not affect resting forearm blood flow or the response to neuropeptide Y in healthy controls. In conclusion, the present data demonstrate that C-peptide increases resting forearm blood flow and augments the vasoconstrictor effects of neuropeptide Y in insulin-dependent patients.

Topics: Adult; Blood Flow Velocity; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Synergism; Female; Forearm; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Male; Neuropeptide Y; Plethysmography; Vasoconstriction

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of beta-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.

Topics: Animals; Antimetabolites; Bromodeoxyuridine; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Glucagon; Guinea Pigs; Homeodomain Proteins; Immune Sera; Immunohistochemistry; Insulin; Male; Mice; Mice, Inbred NOD; Neuropeptide Y; Pancreatic Ducts; Rabbits; Rats; Regeneration; Trans-Activators; Tyrosine 3-Monooxygenase

Topics: Animals; Base Sequence; Chromosome Mapping; Crosses, Genetic; Diabetes Mellitus, Type 1; Genes, Recessive; Haplotypes; Lymphopenia; Molecular Sequence Data; Neuropeptide Y; Rats; Rats, Inbred BB; Rats, Inbred BN; Rats, Inbred Strains; T-Lymphocytes

To clarify the impact of autonomic neuropathy in diabetic patients, we have conducted a prospective study of 58 Type 1 and 51 Type 2 diabetic patients (investigated at baseline, after 4, and after 7 years). In Type 1 diabetic patients, the sympathetic nerve function (orthostatic acceleration and brake indices) and in Type 2 patients, parasympathetic nerve function (R-R interval variation; E/l ratio) deteriorated during 7 years of prospective observation. Symptoms of autonomic neuropathy were associated with signs of autonomic neuropathy (low brake indices) in Type 1 but not in Type 2 diabetic patients. In the latest assessment 24 h ECG recording was performed and blood samples assayed for neuropeptide Y (NPY) and motilin were obtained. Type 1 diabetic patients with parasympathetic neuropathy (abnormal E/l ratio) showed significantly lower SD value (less variation in the R-R intervals; 29 [17] vs 50 [16], [mean (interquartile range)]; p = 0.001) and higher postprandial plasma motilin values (70 [20] pmol l-1 vs 50 [15] pmol l-1; p < 0.01) than patients with normal parasympathetic nerve function. In Type 2 diabetic patients, sympathetic neuropathy (low brake indices) was associated with an increased frequency of ventricular extra systolic beats during 24 h ECG recording (rs = 0.65; p < 0.01). Postprandial plasma NPY levels were not associated with disturbed autonomic nerve function.

Topics: Adolescent; Adult; Autonomic Pathways; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Electrocardiography, Ambulatory; Female; Heart Rate; Humans; Male; Middle Aged; Motilin; Neuropeptide Y; Prospective Studies

The changes in plasma gastrin-releasing peptide (GRP), arginine vasopressin (AVP), neuropeptide Y (NPY), corticotropin releasing hormone (CRH), galanin, ACTH, cortisol, delta sleep-inducing peptide (DSIP), adrenaline, noradrenaline and pancreatic polypeptide (PP) were measured after 5 and 15 minutes of acute insulin-induced moderate hypoglycaemia (2.0 mmol/l) in 10 patients with Type 1 diabetes mellitus with no autonomic neuropathy and in 10 healthy subjects. Plasma catecholamine and PP levels rose in both groups in response to hypoglycemia and the secretory response of ACTH was lower in the diabetic subjects (p < 0.01). GRP concentrations increased during hypoglycaemia (p < 0.01) while a reduction in AVP occurred at the start of hypoglycaemia (p < 0.001). The plasma AVP concentrations were higher in the diabetic group compared with those in the normal group (p < 0.05). The NPY concentrations were higher in the normal subjects (p < 0.05) but no change in the mean level occurred in either group during hypoglycaemia. No group differences or changes in mean plasma concentrations were found for galanin, DSIP and CRH. These observations support the view that regulatory peptides, if involved in glucose homeostasis, may rather have a modulatory effect than a direct action in restoring normoglycaemia.

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; Arginine Vasopressin; Blood Glucose; Diabetes Mellitus, Type 1; Epinephrine; Galanin; Gastrin-Releasing Peptide; Hormones; Humans; Hydrocortisone; Hypoglycemia; Neuropeptide Y; Norepinephrine; Pancreatic Polypeptide; Peptides; Reference Values; Time Factors

The BB rat is among the best models of insulin-dependent diabetes mellitus--with onset and pathogenesis closely resembling the human disease. One unusual feature is a severe T-cell lymphopenia, which appears to be inherited as a recessive trait controlled by a single gene, Lyp. Based on genetic analysis of several crosses, we show that development of diabetes involves at least three genes: Lyp, which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, a gene linked to the major histocompatibility complex (MHC) on chromosome 20, and a third unmapped gene for which the Fischer rat strain carries an allele conferring resistance.

Topics: Animals; Base Sequence; Chromosome Mapping; Crosses, Genetic; Diabetes Mellitus, Type 1; DNA; Female; Genes, Recessive; Genetic Linkage; Genetic Markers; Lymphopenia; Major Histocompatibility Complex; Male; Molecular Sequence Data; Neuropeptide Y; Rats; Rats, Inbred BB; Rats, Inbred F344; Rats, Inbred Lew; T-Lymphocytes

Plasma neuropeptide Y (NPY), plasma galanin and plasma catecholamines were determined before and during an ergometer exercise test in 11 type 1 diabetic patients (age 19-36 years, mean 30; duration of diabetes 2-18 years, mean 9) with autonomic dysfunction and in 13 age-matched healthy controls (age 24-36 years, mean 29). Before exercise, plasma NPY (100 +/- 6 pmol/l vs 144 +/- 7 pmol/l; P less than 0.001) and plasma galanin (54 +/- 3 pmol/l vs 77 +/- 5 pmol/l; P less than 0.005) were significantly lower in patients than in controls. During exercise, plasma NPY, plasma adrenaline, and plasma noradrenaline increased in patients and controls while galanin only increased in patients. Since there was a direct correlation between plasma NPY before exercise and the increment (delta 80%) in noradrenaline during exercise (r = 0.54; P less than 0.01), it is suggested that plasma NPY determined in the basal situation may be a useful marker of sympathetic nerve failure in diabetic patients.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Epinephrine; Female; Galanin; Humans; Male; Neuropeptide Y; Norepinephrine; Peptides; Physical Exertion; Reference Values

To compare the neuropeptide specificity of dystrophic axon formation in aging versus diabetic human sympathetic ganglia we have immunohistochemically characterized neuropeptide Y (NPY) and substance P containing intraganglionic nerve terminals. Prevertebral superior mesenteric but not paravertebral superior cervical ganglia developed markedly swollen NPY containing axonal termini with both aging and diabetes. Substance P containing nerve terminals failed to develop dystrophic changes. Selective loss of classes of nerve terminals may result in discrete functional sequellae.

Topics: Aged; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Ganglia, Sympathetic; Humans; Immunohistochemistry; Nerve Endings; Neurons; Neuropeptide Y; Substance P