neuropeptide-y and Diabetes-Mellitus--Type-2

Patients with Type 2 diabetes have an excess risk for cardiovascular disease. One of the several approaches, included in the guidelines for the management of Type 2 diabetes, is based on dipeptidyl peptidase 4 (DPP-4; also termed CD26) inhibitors, also called gliptins. Gliptins inhibit the degradation of glucagon-like peptide-1 (GLP-1): this effect is associated with increased circulating insulin-to-glucagon ratio, and a consequent reduction of HbA1c. In addition to incretin hormones, there are several proteins that may be affected by DPP-4 and its inhibition: among these some are relevant for the cardiovascular system homeostasis such as SDF-1α and its receptor CXCR4, brain natriuretic peptides, neuropeptide Y and peptide YY. In this review, we will discuss the pathophysiological relevance of gliptin pleiotropism and its translational potential.

Topics: Cardiovascular Diseases; Cardiovascular System; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Natriuretic Peptide, Brain; Neuropeptide Y; Practice Guidelines as Topic; Proteolysis; Receptors, CXCR4

Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.

Topics: Animals; Appetite Depressants; Appetite Regulation; Bone and Bones; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Insulin Secretion; Lipocalin-2; Models, Biological; Neuropeptide Y; Osteoblasts; Osteocalcin; Osteoclasts; Prediabetic State; RANK Ligand; Recombinant Proteins; Secretagogues

Impaired insulin secretion from pancreatic β-cells is a major factor in the pathogenesis of type 2 diabetes. The main regulator of insulin secretion is the plasma glucose concentration. Insulin secretion is modified by other nutrients, circulating hormones and the autonomic nervous system, as well as local paracrine and autocrine signals. Autocrine signalling involves diffusible molecules that bind to receptors on the same cell from which they have been released. The first transmitter to be implicated in the autocrine regulation of β-cell function was insulin itself. The importance of autocrine insulin signalling is underscored by the finding that mice lacking insulin receptors in β-cells are glucose intolerant. In addition to insulin, β-cells secrete a variety of additional substances, including peptides (e.g. amylin, chromogranin A and B and their cleavage products), neurotransmitters (ATP and γ-aminobutyric acid) and ions (e.g. zinc). Here we review the autocrine effects of substances secreted from β-cells, with a focus on acute effects in stimulus-secretion coupling, present some novel data and discuss the general significance of autocrine signals for the regulation of insulin secretion.

Topics: Adenosine Triphosphate; Animals; Autocrine Communication; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; gamma-Aminobutyric Acid; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Knockout; Neuropeptide Y; Rats; Receptor, Insulin; Signal Transduction; Zinc

Several peptides are involved in the regulation of food intake and energy expenditure, among which are leptin, adiponectin, ghrelin and neuropeptide Y (NPY). These peptides may be implicated in the obesity seen in the majority of patients with type 2 diabetes mellitus (T2DM).. The present review considers: i) the role of leptin, adiponectin, ghrelin and NPY in patients with T2DM, and, ii) the effect of insulin as well as oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet agents on these peptides in patients with T2DM.. Patients with T2DM have either lower or similar leptin levels, decreased adiponectin and ghrelin levels, and increased NPY circulating levels compared with nondiabetic controls. Treatment with insulin, oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet drugs may influence the levels of these peptides. It is not widely appreciated that several drugs commonly administered to patients with T2DM can influence adipokine levels. The clinical relevance of these effects needs to be evaluated.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Hypoglycemic Agents; Leptin; Male; Neuropeptide Y

The clinical outcomes achieved by bariatric surgery have been impressive. However, the physiologic mechanisms and complex metabolic effects of bariatric surgery are only now beginning to be understood. Ongoing research has contributed a large amount of data and shed new light on the science behind obesity and its treatment, and this article reviews the current understanding of metabolic and bariatric surgery physiology.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Neuropeptide Y; Obesity, Morbid; Peptide YY; Weight Loss

Neuropeptide Y (NPY) is an abundant and widespread peptide in mammalian nervous system, both in the central and peripheral nervous systems. NPY is a multifunctional neurotransmitter with multiple modulator effects in the regulation of physiological functions and responses in the body. NPY is a potent orexigenic peptide, which has effects on energy balance at the level of energy intake, expenditure, and partition. There are many association studies between the NPY gene variants and cardiovascular and metabolic disease. Most of them are done by using p.L7P substitution as a marker. At the moment it seems that the p.L7P substitution of preproNPY protein causes altered NPY secretion, which leads to haemodynamic disturbances caused by sympathetic hyperactivity and to various effects caused by altered local signalling by NPY. SNP association studies using p.L7P polymorphism suggest that this functional substitution may be a strong independent risk factor for various metabolic and cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Metabolic Diseases; Neuropeptide Y; Obesity; Polymorphism, Genetic

Early onset obesity and type II diabetes is rapidly becoming an epidemic, especially within the United States. This dramatic increase is likely due to many factors including both prenatal and postnatal environmental cues. The purpose of this review is to highlight some of the recent advances in our knowledge of the development of the hypothalamic circuits involved in the regulation of energy balance, with a focus on the neuropeptide Y (NPY) system. Unlike the adult rat, during the postnatal period NPY is transiently expressed in several hypothalamic regions, along with the expected expression within the arcuate nucleus (ARH). These transient populations of NPY neurons during the postnatal period may provide local NPY production to sustain the necessary energy intake during this critical growth phase. This may be physiologically important since ARH-NPY projections do not fully develop until the 3rd postnatal week. The significance of this ontogeny is that many peripheral metabolic signals have little effect of feeding prior to the development of the ARH projections. The essential questions now are whether prenatal and/or postnatal exposure to high levels of insulin or leptin during development can cause permanent changes in the function of hypothalamic circuits. It is vital to understand not only the natural development of the hypothalamic circuits that regulate energy homeostasis, but also their abnormal development caused by maternal and postnatal environmental cues. This will be pivotal for designing intervention and therapeutics to treat early onset obesity/type II diabetes, which may very well need to be different from those designed to prevent/treat adult onset obesity/type II diabetes.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Humans; Hypothalamus; Insulin; Leptin; Male; Nerve Net; Neuropeptide Y; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains

Leptin is a hormone produced primarily by the adipocytes. It works through different receptors and seems to provide information to the hypothalamus about the energy status of the body. Although leptin appears to exert its anti-obesity effect through its central action, the full spectrum of its action is yet to be determined. Most obese subjects in studies have high serum levels of leptin, suggesting that the major problem is leptin resistance rather than leptin deficiency. Consequently, these patients may not respond to exogenous leptin. Recent trials have indicated, however, that leptin may have therapeutic potential in leptin-deficient as well as leptin-resistant states.

Topics: Animals; Diabetes Mellitus, Type 2; Gene Expression; Humans; Leptin; Neuropeptide Y; Obesity, Morbid; Receptors, Cell Surface; Receptors, Leptin

Topics: Animals; Brain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Energy Metabolism; Homeostasis; Hormones; Humans; Hypothalamus; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Rats

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

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Appetite; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Mice; Mice, Obese; Neuropeptide Y; Obesity; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Tumor Necrosis Factor-alpha

To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the "insulinized" than in the control groups. Conversely muscles from "insulinized" rats became insulin resistant. Such divergent consequences of prior "insulinization" on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally.

Topics: Animals; Awards and Prizes; Brain; Central Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Europe; Glucose; Glucose Transporter Type 4; History, 20th Century; Humans; Hyperinsulinism; Hypothalamus; Monosaccharide Transport Proteins; Muscle Proteins; Neuropeptide Y; Obesity; Peripheral Nervous System Diseases; Rats; Rats, Mutant Strains; Societies, Medical; Switzerland

DPP (dipeptidyl peptidase)-4 inhibitors are antidiabetic drugs that may increase heart failure in high-risk patients. NPY (neuropeptide Y) is coreleased with norepinephrine, causes vasoconstriction via the Y1 receptor, and is degraded by DPP4 to NPY (3-36) in vitro. NPY (3-36) decreases release of norepinephrine via the Y2 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the vasoconstrictor effect of NPY. Eighteen nonsmokers (12 healthy controls and 6 with type 2 diabetes mellitus) participated in 1 of 2 randomized, double-blind, placebo-controlled crossover studies. First, subjects were randomized to order of treatment with sitagliptin 100 mg/d versus placebo for 7 days separated by 4-week washout. On the last day of treatment, NPY was infused by brachial artery and forearm blood flow was measured using plethysmography. Blood samples were collected after each dose. NPY infusions were repeated after 90-minute washout and intra-arterial enalaprilat. Second, 5 healthy subjects were randomized to crossover treatment with sitagliptin 100 mg/d plus valsartan 160 mg/d versus placebo plus valsartan. NPY infusions were performed on the seventh day of treatment. NPY caused dose-dependent vasoconstriction. During enalaprilat, sitagliptin significantly potentiated NPY-induced vasoconstriction in controls and diabetics ( P≤0.02 for forearm blood flow in either group). Baseline norepinephrine release was increased during sitagliptin and enalaprilat, but not further by NPY. Sitagliptin increased the ratio of NPY to NPY (3-36). During valsartan, sitagliptin also significantly potentiated NPY-induced vasoconstriction ( P=0.009 for forearm blood flow). Potentiation of endogenous NPY could contribute to cardiovascular effects of DPP4 inhibitors in patients taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Synergism; Female; Humans; Male; Middle Aged; Neuropeptide Y; Renin-Angiotensin System; Sitagliptin Phosphate; Valsartan; Vasoconstriction; Young Adult

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of enteroendocrine cells located in the proximal small intestine. Many effects of Xen are mediated by neurotensin receptor-1 on neurons. In healthy humans with normal glucose tolerance (NGT), Xen administration causes diarrhea and inhibits postprandial glucagon-like peptide-1 (GLP-1) release but not insulin secretion. This study determines (i) if Xen has similar effects in humans with Roux-en-Y gastric bypass (RYGB) and (ii) whether neural pathways potentially mediate effects of Xen on glucose homeostasis. Eight females with RYGB and no history of type 2 diabetes received infusions with 0, 4 or 12pmol Xen/kg/min with liquid meals on separate occasions. Plasma glucose and gastrointestinal hormone levels were measured and insulin secretion rates calculated. Pancreatic polypeptide and neuropeptide Y levels were surrogate markers for parasympathetic input to islets and sympathetic tone, respectively. Responses were compared to those in well-matched non-surgical participants with NGT from our earlier study. Xen similarly increased pancreatic polypeptide and neuropeptide Y responses in patients with and without RYGB. In contrast, the ability of Xen to inhibit GLP-1 release and cause diarrhea was severely blunted in patients with RYGB. With RYGB, Xen had no statistically significant effect on glucose, insulin secretory, GLP-1, glucose-dependent insulinotropic peptide, and glucagon responses. However, insulin and glucose-dependent insulinotropic peptide secretion preceded GLP-1 release suggesting circulating GLP-1 does not mediate exaggerated insulin release after RYGB. Thus, Xen has unmasked neural circuits to the distal gut that inhibit GLP-1 secretion, cause diarrhea, and are altered by RYGB.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diarrhea; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Neuropeptide Y; Neurotensin; Pancreatic Polypeptide

Alterations in entero-endocrine signaling may play a role in improvements in satiety and glucose tolerance after Roux-en-Y gastric bypass (RYGB). We report our findings of gut hormone secretion in a cohort of diabetic and nondiabetic morbidly obese patients.. Ten morbidly obese subjects who underwent uncomplicated RYGB were studied: 5 were diabetic and 9 were female. Nonfasting plasma levels of glucagon-like peptide-1 (GLP-1), insulin, desacyl ghrelin, active ghrelin, neuropeptide Y (NPY), and gastric inhibitory polypeptide (GIP) were determined preoperatively and 6 months postoperatively.. Mean patient age was 42 +/- 11 years, and the mean preoperative body mass index was 50 +/- 6 kg/m(2). At 6 months mean BMI fell to 33 +/- 5 kg/m(2) (P < 0.0001), and there were no differences between diabetics and nondiabetics with respect to amount of weight loss. In non-diabetics, compared to preoperative levels, there were significant increases in GLP-1 and desacyl-ghrelin in the nondiabetic patients (P = 0.046 and P = 0.016, respectively); no change in plasma insulin, active ghrelin, NPY, or GIP was demonstrated. In contrast, when compared to preoperative levels, there were no significant changes in entero-endocrine hormone levels in the diabetic cohort postoperatively.. At 6 months postoperation, RYGB significantly alters the hormone levels for GLP-1 and desacyl-ghrelin in morbidly obese nondiabetic patients. No significant change was noted in a matched cohort of diabetic patients. Weight loss was similar in diabetics and nondiabetics, suggesting that GLP-1 and ghrelin are not the only mechanisms producing weight loss after RYGB.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Neuropeptide Y; Obesity, Morbid; Peptide Hormones; Weight Loss

Exosomes (sEVs) are extracellular vesicles involved in the pathogenesis of obesity. Notably, exosomal microRNAs (miRNAs) have emerged as crucial mediators of communication between cells and are involved in the development of obesity. One region of the brain known to be dysregulated in obesity is the hypothalamus. It coordinates whole-body energy homeostasis through stimulation and inhibition of the orexigenic neuropeptide (NPY)/agouti-related peptide (AgRP) neurons and anorexigenic proopiomelanocortin (POMC) neurons. A role for hypothalamic astrocytic exosomes in communication with POMC neurons was previously elucidated. Yet, it was unknown whether NPY/AgRP neurons secreted exosomes. We previously established that the saturated fat palmitate alters the intracellular levels of miRNAs and we now questioned whether palmitate would also alter the miRNA content of exosomal miRNAs. We found that the mHypoE-46 cell line secreted particles consistent with the size of exosomes and that palmitate altered levels of a spectrum of miRNAs associated with exosomes. The predicted KEGG pathways of the collective miRNA predicted targets included fatty acid metabolism and type II diabetes mellitus. Of note, one of these altered secreted miRNAs was miR-2137, which was also altered within the cells. We also found that while sEVs collected from the mHypoE-46 neurons increased Pomc mRNA in the mHypoA-POMC/GFP-2 cells after 48 h, the effect was absent with sEVs isolated following palmitate treatment, indicating another potential route by which palmitate promotes obesity. Hypothalamic neuronal exosomes may therefore play a role in the control of energy homeostasis that may be disrupted in obese conditions.

Topics: Agouti-Related Protein; Diabetes Mellitus, Type 2; Extracellular Vesicles; Humans; Hypothalamus; Neurons; Neuropeptide Y; Obesity; Palmitates; Pro-Opiomelanocortin

Type 2 diabetes (T2D) is a common metabolic disorder. Due to insufficient insulin secretion or insulin resistance, increased blood glucose often leads to impaired wound healing in T2D patients. Our previous research showed that adipose-derived stem cells (ASCs) from normal mice and T2D mice improved the cutaneous wound healing of diabetic mice. We also found that the expression of neuropeptide Y (NPY) in T2D ASCs was significantly decreased.. In order to explore the effects of NPY on ASCs and diabetic wound healing, we investigated the effects of NPY on ASCs proliferation and growth factors expression and secretion, the effects of NPY on skin fibroblasts, and the effects of NPY combined with ASCs on T2D wound healing.. The results showed that a certain concentration of NPY could promote the proliferation and the growth factors expression and secretion of ASCs, and promote the proliferation and migration of fibroblasts. At the same time, NPY and ASCs have a synergistic effect, which can promote wound healing and decrease inflammation in T2D wounds. NPY may regulate ASCs through the ERK pathway. These results are conducive to promoting ASCs and NPY in the treatment of diabetic wounds.. NPY can promote the effect of ASCs in the treatment of diabetic wounds.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Mice; Neuropeptide Y; Stem Cells

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behaviour. Ghrelin, a major orexigenic hormone, activates AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signalling mechanisms in AgRP/NPY neurons remain poorly defined. Here we show that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated upon ghrelin stimulation and acts in AgRP/NPY neurons to mediate ghrelin-dependent food intake. Global Camk1d-knockout male mice are resistant to ghrelin, gain less body weight and are protected against high-fat-diet-induced obesity. Deletion of Camk1d in AgRP/NPY, but not in POMC, neurons is sufficient to recapitulate above phenotypes. In response to ghrelin, lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY in fibre projections to the paraventricular nucleus (PVN). Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons.

Topics: Agouti-Related Protein; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 1; Diabetes Mellitus, Type 2; Eating; Ghrelin; Male; Mice; Mice, Knockout; Neurons; Neuropeptide Y; Obesity

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).

Topics: Agouti-Related Protein; Amphetamines; Animals; Appetite Regulation; Cocaine; Cytokines; Diabetes Mellitus, Type 2; Forkhead Box Protein O1; High-Intensity Interval Training; Hypothalamus; Insulin; Janus Kinase 2; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Wistar; STAT3 Transcription Factor

Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D.. The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese (db/db) T2D mouse models were assessed.. In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice.. Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.

Topics: Animals; Arginine; Diabetes Mellitus, Type 2; Glucose; Glycemic Control; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y

To investigate the features of neuropeptide Y (NPY), α-melanocyte stimulating hormone (α-MSH), and agouti-related protein (AgRP) in type 2 diabetes mellitus (T2DM) patients with hypertension.. Patients with T2DM (n = 384) and healthy volunteers (n = 80) were enrolled into this study. Serum NPY, α-MSH, and AgRP levels were detected using ELISA.. Significantly higher NPY and lower α-MSH and AgRP levels were observed in patients with diabetes compared with those without diabetes, and the mean NPY levels increased, while α-MSH and AgRP levels decreased, with the development of hypertension compared with diabetic patients without hypertension. α-MSH and AgRP levels decreased with an increase in blood pressure in hypertension compared with the non-hypertension patients. Multiple stepwise linear regression analysis showed that NPY, α-MSH, and AgRP levels were closely associated with blood pressure and glucose control. Receiver operating characteristic (ROC) curve analyses indicated that α-MSH may be a better marker compared with NPY and AgRP for regulating glucose and blood pressure and to distinguish between T2DM patients with and without hypertension.. NPY, α-MSH, and AgRP might play different roles and be closely related to the occurrence and development of diabetes and hypertension.

Topics: Aged; Agouti-Related Protein; alpha-MSH; Animals; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Healthy Volunteers; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; ROC Curve

Animal studies indicate that hypothalamic dysfunction plays a major role in type 2 diabetes mellitus (T2DM) development, and that insulin resistance and inflammation are important mechanisms involved in this disorder. However, it remains unclear how T2DM and antidiabetic treatments affect the human hypothalamus. Here, we characterized the proopiomelanocortin (POMC) immunoreactive (-ir) neurons, the neuropeptide-Y-ir (NPY-ir) neurons, the ionized calcium-binding adapter molecule 1-ir (iba1-ir) microglia, and the transmembrane protein 119-ir (TMEM119-ir) microglia in the infundibular nucleus (IFN) of human postmortem hypothalamus of 32 T2DM subjects with different antidiabetic treatments and 17 matched nondiabetic control subjects. Compared with matched control subjects, T2DM subjects showed a decrease in the number of POMC-ir neurons, but no changes in NPY-ir neurons or microglia. Interestingly, T2DM subjects treated with the antidiabetic drug metformin had fewer NPY-ir neurons and microglia than T2DM subjects not treated with metformin. We found that the number of microglia correlated with the number of NPY-ir neurons, but only in T2DM subjects. These results indicate that different changes in POMC and NPY neurons and microglial cells in the IFN accompany T2DM. In addition, T2DM treatment modality is associated with highly selective changes in hypothalamic neurons and microglial cells.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Male; Membrane Proteins; Metformin; Microglia; Neurons; Neuropeptide Y; Pituitary Gland; Pro-Opiomelanocortin

Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to β-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from β-cell loss in these models. We have developed transgenic mice that overexpress [

Topics: Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Phenotype; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

A gain-of-function polymorphism in human neuropeptide Y (

Topics: Adrenergic Neurons; Animals; Cholesterol; Diabetes Mellitus, Type 2; Energy Intake; Energy Metabolism; Fatty Acids; Fatty Liver; Gene Expression; Glucose; Hypercholesterolemia; Liver; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Sympathetic Nervous System

Diabetes mellitus (DM) influences the trigeminal nerve function by changing the pain response and transduction of the orofacial sensory pathways. It affects the inflammatory response via neuropeptide Y (NPY) and vascular endothelial growth factor (VEGF), which could potentially have a relevant role in the pathophysiology of diabetic neuropathy. The aim was to investigate expression of VEGF and NPY in subpopulations of trigeminal ganglion (TG) neurons in rat models of early DM1 and DM2.. DM1 model was induced by an intraperitoneal (i.p.) injection of streptozotocin (STZ) (55mg/kg). DM2 rats were fed with a high fat diet (HFD) for two weeks and then received 35mg/kg of STZ i.p. Two weeks and 2months after the STZ-diabetes induction, rats were sacrificed and TG was immunohistochemically analyzed for detection of VEGF and NPY expression, and also double immunofluorescence labeling with isolectin (IB4) was completed.. An increased percentage of NPY+ neurons was observed 2weeks after DM1 and 2months post DM2 induction. NPY immunoreactivity was restricted to IB4-negative small-diameter and IB4+ neurons. Two weeks post induction, DM1 rats showed an increased percentage of VEGF/IB4- large neurons and DM2 rats showed an increased percentage of VEGF/IB4+ neurons. Two months after DM induction, the DM1 group showed a reduced percentage of VEGF/IB4- small neurons.. The observed changes may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. The results contribute to the understanding of the basic pathophysiology of trigeminal diabetic neuropathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Male; Neurons; Neuropeptide Y; Rats, Sprague-Dawley; Trigeminal Ganglion; Vascular Endothelial Growth Factor A

Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1 receptors (GLP-1Rs). The rodent and nonhuman primate hypothalamus show clear GLP-1R expression. However, a detailed description of GLP-1R expression in the human hypothalamus is lacking, and it is unknown whether this expression is altered in T2DM patients.. The objective of the study was to investigate the GLP-1R distribution in the human postmortem hypothalamus and to determine whether hypothalamic GLP-1R expression is altered in T2DM patients.. We investigated the distribution of GLP-1R expression throughout the human hypothalamus by means of in situ hybridization. We also performed quantifications of GLP-1R mRNA expression in two hypothalamic nuclei (ie, the paraventricular nucleus [PVN] and infundibular nucleus [IFN]), comparing patients with T2DM and control subjects.. We found that GLP-1R mRNA was expressed in a number of hypothalamic nuclei including the PVN and the IFN, both involved in the regulation of energy metabolism. We observed sporadic colocalization of the GLP-1R in the IFN with the orgexigenic neuropeptide Y, agouti-related peptide, or proopiomelanocortin transcripts. Comparison of GLP-1R mRNA in the PVN and IFN between T2DM patients and control subjects revealed a decreased expression in T2DM patients.. Our studies show that GLP-1R is widely expressed throughout the human hypothalamus. The decreased expression of GLP-1R in the PVN and IFN of T2DM patients may be related to the dysregulation of feeding behavior and glucose homeostasis in T2DM.

Topics: Aged; Aged, 80 and over; Agouti-Related Protein; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypothalamus; Male; Middle Aged; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin

Depression is a major comorbidity factor of diabetes and the outcome of one disorder influences the other. Our aim is to scrutinize the link between the two, if any. Since neuropeptide Y (NPY) system plays an important role in regulating central glucose sensing mechanisms, and also depression-related behavior, we test the involvement of NPY in the modulation of depression in type 2 diabetic mice. The mice were fed on high-fat diet and administered with low dose of streptozotocin to induce type 2 diabetes. These animals showed augmented plasma glucose and increased immobility time in tail suspension test (TST) suggesting induction of diabetes and depression. Intracerebroventricular (icv) treatment with NPY or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY and intraperitoneal treatment with imipramine decreased immobility time. However, opposite effect was produced by NPY Y1 receptor antagonist BIBP3226 (icv). Moreover, reduced immobility time by imipramine was potentiated by NPY and [Leu(31), Pro(34)]-NPY, but attenuated by BIBP3226. Immunohistochemical analysis of the different nuclei of the extended amygdala, the region primarily involved in affective disorders, was undertaken. A significant reduction in NPY immunoreactivity in the central nucleus of amygdala, nucleus accumbens shell and lateral division of bed nucleus of stria terminalis of the diabetic mice was noticed; the response was ameliorated in imipramine treated animals. The results suggest that decreased NPY expression in the extended amygdala might be causally linked with the depression induced following type 2 diabetes and that the antidepressant action of imipramine in diabetic mice might be mediated by NPY-NPY Y1 receptor system.

Topics: Animals; Antidepressive Agents, Tricyclic; Arginine; Blood Glucose; Central Amygdaloid Nucleus; Depression; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Imipramine; Male; Mice; Motor Activity; Neuropeptide Y; Nucleus Accumbens; Receptors, Neuropeptide Y; Septal Nuclei; Streptozocin

Neuropeptide Y (NPY) is known to play a role in the regulation of satiety, energy balance, body weight, and insulin release. Interleukin-1beta (IL1B) has been associated with loss of beta-cell mass in type-II diabetes (TIID).. The present study attempts to investigate the association of NPY exon2 +1128 T/C (Leu7Pro; rs16139), NPY promoter -399 T/C (rs16147) and IL1B -511 C/T (rs16944) polymorphisms with TIID and their correlation with plasma lipid levels, BMI, and IL1B transcript levels.. PCR-RFLP was used for genotyping these polymorphisms in a case-control study involving 558 TIID patients and 1085 healthy age-matched controls from Gujarat. Linkage disequilibrium and haplotype analysis of the NPY polymorphic sites were performed to assess their association with TIID. IL1B transcript levels in PBMCs were also assessed in 108 controls and 101 patients using real-time PCR.. Our results show significant association of both structural and promoter polymorphisms of NPY (p<0.0001 and p<0.0001 respectively) in patients with TIID. However, the IL1B C/T polymorphism did not show any association (p = 0.3797) with TIID patients. Haplotype analysis revealed more frequent association of CC and CT haplotypes (p = 3.34 x 10-5, p = 6.04 x 10-9) in diabetics compared to controls and increased the risk of diabetes by 3.02 and 2.088 respectively. Transcript levels of IL1B were significantly higher (p<0.0001) in patients as compared to controls. Genotype-phenotype correlation of IL1B polymorphism did not show any association with its higher transcript levels. In addition, NPY +1128 T/C polymorphism was found to be associated with increased plasma LDL levels (p = 0.01).. The present study provides an evidence for a strong correlation between structural and promoter polymorphisms of NPY gene and upregulation of IL1B transcript levels with susceptibility to TIID and altering the lipid metabolism in Gujarat population.

Topics: Adult; Alleles; Blood Glucose; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Exons; Female; Gene Frequency; Genetic Association Studies; Genotype; Haplotypes; Humans; Interleukin-1beta; Linkage Disequilibrium; Lipids; Lipoproteins, LDL; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; Risk; RNA, Messenger; Triglycerides

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

Compared with other insulin analogues, insulin detemir induces less weight gain. This study investigated whether this effect was achieved by influencing the hypothalamic appetite regulators neuropeptide Y (NPY) and galanin (GAL).. Type  2 diabetic rat models were established with a high-fat diet and intraperitoneal injection of STZ. All rats were divided into NC, DM, DM+DE and DM+GLA groups. Glycemic levels of all study groups were checked at study onset and after 4 weeks of insulin treatment. Food intake and body weight were monitored during treatment. After 4 weeks, the hypothalamus of rats was examined for NPY and GAL mRNA and protein expression.. After 4 weeks of treatment, compared with the DM+GLA group, the DM+DE group exhibited less food intake (P < 0.05) and less weight gain (P < 0.05), but showed similar glycemic control. The expression of hypothalamic NPY and GAL at both mRNA and protein level were significantly lower (P < 0.05) in the DM+DE group.. Insulin detemir decreased food intake in type 2 diabetic rats, which led to reduced weight gain when compared to insulin glargine treatment. This effect is likely due to downregulation of hypothalamic NPY and GAL.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Feeding Behavior; Galanin; Hypoglycemic Agents; Hypothalamus; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Neuropeptide Y; Protein Precursors; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin; Weight Gain

It has been reported that plasma NPY levels were increased in obesity, type 2 diabetes mellitus and hypertension. The symptoms of metabolic syndrome frequently appear in patients with acute ischemic stroke. The association between plasma NPY levels and metabolic markers in women with acute ischemic stroke was investigated in the current study.. Plasma NPY concentrations were determined using radioimmunoassay in 58 women aged 60-85 (mean age: 76.5±0.8) with acute ischemic stroke and in 24 women aged 63-67 (mean age: 65.6±0.6) of the control group. Stroke was defined according to the NIHSS (National Institute of Health Stroke Scale) and was confirmed using CT or MR scan.. The prevalence of type 2 diabetes, hypertension and insulin resistance was higher in the group of patients with stroke. Plasma NPY levels measured during the 1st day and 10 days after the acute phase of stroke were significantly lower (p<0.001) compared to the control group.. In women with acute ischemic stroke plasma NPY concentrations were decreased in spite of higher frequency of the occurrence of the symptoms of metabolic syndrome.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Middle Aged; Neuropeptide Y; Obesity; Radioimmunoassay; Stroke

Rodent data show that altered hypothalamic signaling contributes to the development of obesity and insulin resistance.. To determine differences in hypothalamic expression levels of neuropeptide Y (NPY), agouti-related peptide (AgRP), and αMSH in the infundibular nucleus, the human equivalent of the arcuate nucleus, in relation to body mass index (BMI). In addition, the expression in the infundibular nucleus of eight subjects diagnosed with type 2 diabetes was measured to determine possible interference of type 2 diabetes with the association observed between neuropeptides and BMI.. We studied AgRP, NPY, and αMSH expression by means of quantitative immunocytochemistry in postmortem hypothalami of 30 subjects with known BMI. In separate experiments, we compared neuropeptide expression in eight subjects with type 2 diabetes with eight matched controls.. We found that AgRP immunoreactivity showed a U-shaped correlation with BMI. No evidence was found for possible influences of corticosteroid treatment. NPY immunoreactivity was significantly lower in overweight and obese subjects. αMSH did not correlate with BMI but was significantly lower in subjects with type 2 diabetes compared with controls. By contrast, NPY and AgRP expression was not affected in type 2 diabetes.. Our results indicate that the expression of AgRP and NPY are correlated with body weight changes, rather than the presence of type 2 diabetes, whereas changes in αMSH immunoreactivity are related to the presence of type 2 diabetes, indicating separate hypothalamic mechanisms.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Agouti-Related Protein; alpha-MSH; Body Mass Index; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Immunohistochemistry; Male; Middle Aged; Neuropeptide Y; Pituitary Gland, Posterior; Signal Transduction

Ample animal studies demonstrate that neuropeptides NPY and α-MSH expressed in Arcuate Nucleus and Nucleus of the Tractus Solitarius, modulate glucose homeostasis and food intake. In contrast is the absence of data validating these observations for human disease. Here we compare the post mortem immunoreactivity of the metabolic neuropeptides NPY, αMSH and VGF in the infundibular nucleus, and brainstem of 11 type-2 diabetic and 11 non-diabetic individuals. α-MSH, NPY and tyrosine hydroxylase in human brain are localized in the same areas as in rodent brain. The similar distribution of NPY, α-MSH and VGF indicated that these neurons in the human brain may share similar functionality as in the rodent brain. The number of NPY and VGF immuno positive cells was increased in the infundibular nucleus of diabetic subjects in comparison to non-diabetic controls. In contrast, NPY and VGF were down regulated in the Nucleus of the Tractus Solitarius of diabetic patients. These results suggest an activation of NPY producing neurons in the arcuate nucleus, which, according to animal experimental studies, is related to a catabolic state and might be the basis for increased hepatic glucose production in type-2 diabetes.

Topics: Adult; Aged; alpha-MSH; Arcuate Nucleus of Hypothalamus; Autopsy; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Growth Factors; Neurons; Neuropeptide Y; Solitary Nucleus

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

Neuropeptide Y (NPY) is an important hormone in appetite regulation. Although the contribution of NPY to metabolic disease has been previously demonstrated, there are only a few reports addressing NPY plasma levels under distinct diabetic conditions. In this study we evaluated NPY plasma levels in diabetes mellitus type 2 (DM2) patients with (n=34) and without (n=34) diabetic polyneuropathy (PNP) and compared these with age and gender matched healthy controls (n=34). We also analyzed NPY plasma levels in gestational diabetes mellitus (GDM) patients with age and pregnancy-week matched controls with normal glucose tolerance (NGT). NPY concentration was determined using a commercially available radioimmunoassay kit. In addition, metabolic parameters of DM2 and GDM patients were recorded. One-way ANOVA tests with appropriate post hoc corrections showed elevated levels of NPY in DM2 patients with and without PNP when compared with those of healthy controls (122.32±40.86 and 117.33±29.92 vs. 84.65±52.17 pmol/L; p<0.001, p<0.005, respectively). No significant difference was observed between diabetic patients with and without PNP. The NPY levels were similar in the GDM group and in pregnant women with NGT (74.87±14.36 vs. 84.82±51.13 pmol/L, respectively). Notably, the NPY concentration correlated positively with insulin levels in DM2 patients (R=0.35, p<0.01). Our data suggest a potential involvement of circulating NPY in DM2 pathology.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diabetic Neuropathies; Female; Humans; Male; Middle Aged; Neuropeptide Y; Pregnancy; Radioimmunoassay

This investigation was made in regard to the changes of plasma Leptin, Tumor Necrosis Factor-alpha (TNF-alpha) and Neuropeptide Y (NPY) levels and their association with insulin resistance and beta-cell secretion function in normal glucose tolerant first-degree relatives of familial type 2 diabetic pedigrees in Chengdu area. Levels of Leptin, TNF-alpha, NPY and lipids (TG, TC, HDL-C) were determined in 86 type 2 diabetic mellitus (DM) patients, 73 normal glucose tolerant (NGT) first-degree relatives in familial type 2 diabetic pedigrees and 65 normal controls (NC) from non-diabetic families. All of the subjects underwent 75 g oral glucose tolerance test (OGTT). Plasma glucose, immunoreactive insulin (IRI) and true insulin (TI) levels were also determined. Fasting glucose and TI levels were used to calculate homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA-beta cell indexes. After being adjusted for age and body mass index (BMI), the levels of Leptin in DM and NGT first-degree relatives were all significantly higher than that in normal controls (P < 0.05). Type 2 diabetic patients showed significantly elevated TNF-alpha levels than did the normal controls (P < 0.05). Furthermore, diabetic subjects showed significantly higher HOMA-IR and lower HOMA-B levels, compared with those in NGT and NC groups (P < 0.05). No statistically significant difference was found in regard to NPY among three groups. NGT first-degree relatives showed significantly higher levels of TG, fasting IRI, OGTT-2h IRI and HOMA-IR than did the normal controls (P < 0.05). Leptin was positively correlated with age, BMI, waist, A1c, fasting and OGTT-2h glucose, OGTT-2h TI and TNF-alpha in all subjects, and was negatively correlated with HOMA-B in females. Leptin levels were significantly elevated in NGT first-degree relatives, which implied that genetic defects of Leptin may play a role in the development of familial type 2 diabetic pedigrees.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Middle Aged; Neuropeptide Y; Pedigree; Tumor Necrosis Factor-alpha

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

Adipose tissue has been the object of intense research in the field of obesity and diabetes diseases in the last decade. Examination of adipocyte-secreted peptides led to the identification of a unique polypeptide, resistin (RSTN), which has been suggested as a link between obesity and diabetes. RSTN plays a clearly documented role in blocking insulin (INS)-induced hypoglycaemia. As brain injection of INS affects feeding behaviour, we studied the possible interaction between INS and RSTN in food-deprived rats, measuring effects on food intake. In addition, we examined how RSTN might affect neuropeptide Y (NPY)-induced feeding, as studies have shown that rat RSTN can interfere with the NPY system.. Overnight food-deprived rats were injected into the third brain ventricle (3V) with either INS (10 or 20 mUI), RSTN (0.1-0.4 nmol/rat), or saline before access to food. Another group of rats was injected into the 3V with RSTN alone, NPY alone or RSTN plus NPY. Their food intake and body weight were measured.. Our results confirm the hypophagic effect of RSTN on food deprivation-induced food intake, and more importantly, show that RSTN neither potentiates nor blocks the effects of INS on food intake, but does reduce the hyperphagic effect of NPY.. The observation that RSTN does not modify feeding INS-induced hypophagia, but does influence NPY-induced feeding, points to the possibility that RSTN may be involved in control of food intake through an NPY-ergic mechanism as INS.

Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Brain; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hyperphagia; Injections, Intraventricular; Insulin; Male; Metabolic Networks and Pathways; Neuropeptide Y; Obesity; Rats; Rats, Wistar; Resistin

Topics: Adamantane; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glycoproteins; Humans; Neuropeptide Y; Nitriles; Pyrrolidines; Vildagliptin

Neuropeptide Y (NPY) plays a central in energy homeostasis and potentially in the development of obesity-related comorbidities, like type II diabetes. As the PreproNPY Leu7Pro polymorphism probably changes the intracellular processing of the synthesized preproNPY peptide, we assessed the hypothesis that PreproNPY Leu7Pro polymorphism is a risk factor for type II diabetes, impaired glucose tolerance and hypertension.. Blood pressure recordings and oral glucose tolerance test were performed in the hypertensive (n=515) and control cohorts (n=525) of our well-defined Oulu Project Elucidating Risk of Atherosclerosis (OPERA) study. The prevalence of type II diabetes was 9% (n=93). The genotypes, insulin and glucose metabolism indexes and plasma ghrelin of the subjects were determined.. Pro7 allele frequencies were 5.9, 5.3 and 11.3% in the total cohort, in subjects without and with type II diabetes, respectively. The PreproNPY Pro7 carrier status was a significant risk factor for type II diabetes, and the effect remained significant after adjustment for age, sex, waist circumference and study group (odds ratio=3.02, confidence interval: 1.67-5.44 and P<0.001). Pro7 carriers were more insulin resistant and showed lower ghrelin levels compared to non-carriers.. The PreproNPY Pro7 allele is associated with an increased risk for type II diabetes. The risk seems to be associated with a higher insulin resistance among Pro7 carriers whereas low ghrelin concentrations in Pro7 carriers are possibly a consequence of high insulin levels.

Topics: Adult; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Ghrelin; Humans; Hypertension; Insulin; Insulin Secretion; Leucine; Male; Middle Aged; Neuropeptide Y; Peptide Hormones; Polymorphism, Genetic; Proline; Protein Precursors; Risk Factors

The neuropeptide Y (NPY) family of peptides and receptors regulate food intake. Inherited variation in this pathway could influence susceptibility to obesity and its complications, including type 2 diabetes. We genotyped a set of 71 single nucleotide polymorphisms (SNPs) that capture the most common variation in NPY, PPY, PYY, NPY1R, NPY2R, and NPY5R in 2,800 individuals of recent European ancestry drawn from the near extremes of BMI distribution. Five SNPs located upstream of NPY2R were nominally associated with BMI in men (P values = 0.001-0.009, odds ratios [ORs] 1.27-1.34). No association with BMI was observed in women, and no consistent associations were observed for other genes in this pathway. We attempted to replicate the association with BMI in 2,500 men and tested these SNPs for association with type 2 diabetes in 8,000 samples. We observed association with BMI in men in only one replication sample and saw no association in the combined replication samples (P = 0.154, OR = 1.09). Finally, a 9% haplotype was associated with type 2 diabetes in men (P = 1.73 x 10(-4), OR = 1.36) and not in women. Variation in this pathway likely does not have a major influence on BMI, although small effects cannot be ruled out; NPY2R should be considered a candidate gene for type 2 diabetes in men.

Topics: Aged; Body Mass Index; Diabetes Mellitus, Type 2; Ethnicity; Female; Humans; Linkage Disequilibrium; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Receptors, Neuropeptide Y; Reference Values; Sex Characteristics

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that plays a role in e.g. circulation, hormone release and angiogenesis. Earlier studies have shown that the Leucine 7 to Proline 7 (Leu7Pro) polymorphism of preproNPY is associated with increased risk for vascular complications in type 2 diabetes. The mechanism for this maybe altered transmitter and hormone levels or altered cardiovascular functions, which have been observed in healthy subjects having the Leu7Pro polymorphism. The current study was undertaken to explore if the Leu7Pro polymorphism has an impact on these functions in subjects with type 2 diabetes. Diurnal measurements were performed for Finnish Caucasian type 2 diabetes patients of two preproNPY genotypes (matched by sex, age, BMI, duration of diabetes and HbA1c) in resting position to prevent sympathetic stimulation. Standard meals were offered during the 24-hour study period. Nine subjects with the Leu7Pro polymorphism and ten subjects without this polymorphism were studied. Plasma concentrations of NPY, glucose, insulin, cortisol, prolactin and leptin were measured by taking blood samples at 20 time points (from 8 a.m. to 8 a.m.). Heart rate and blood pressure were measured at the same time points. The results show that NPY concentrations were similar in both preproNPY genotypes. Glucose, insulin, cortisol and leptin concentrations as well as heart rate and blood pressure were also similar. However, a significant difference between genotypes was found in the association of NPY concentrations with cortisol concentrations (p for difference=0.002). Also a statistically significant negative association of plasma NPY levels with plasma glucose levels was found in both genotypes. Since no impact of preproNPY genotype on mean NPY or hormone levels were detected in subjects with type 2 diabetes, the mechanisms for the increased risk for diabetic complications in the subjects with the Leu7Pro polymorphism need to be further explored.

Topics: Aged; Amino Acid Substitution; Blood Glucose; Blood Pressure; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; Humans; Hydrocortisone; Leptin; Leucine; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Proline; Protein Precursors

Several studies have shown genetic predisposition for diabetic complications. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY has been shown to be a risk factor for diabetic retinopathy in type 1 diabetes. In the current study we examined the contribution of this polymorphism on the progression of retinopathy in Caucasian type 1 and type 2 diabetes patients. Patients with type 2 diabetes and the Leu7Pro polymorphism developed retinopathy at younger age because of markedly earlier disease onset of diabetes (RC- 6.8, 95% CI-12.2 - [- 1.5]), but no association of the Leu7Pro polymorphism with the current severity of retinopathy was detected. A strong association of the polymorphism with proteinuria in type 2 diabetes patients with retinopathy could be detected (OR 3.1, 95% CI 1.1-8.8); 31% of subjects having both retinopathy and proteinuria had the polymorphism compared to only 13% of retinopathy patents without concomitant proteinuria (p = 0.032). Plasma concentrations of NPY were increased in subjects with proteinuria (79.2+/-28.4 and 64.7+/-26.2 pmol/l, p = 0.001). These results suggest that the Leu7Pro polymorphism could be used to predict earlier onset of type 2 diabetes and retinopathy, and increased risk for diabetic nephropathy.

Topics: Adult; Age Factors; Aged; Amino Acid Substitution; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Predictive Value of Tests; Protein Precursors; Proteinuria; Retrospective Studies; Risk Factors; White People

The neuropeptide Y (NPY) is a neuropeptide with a role in the regulation of satiety and energy balance of body weight, insulin release, cardiovascular and central endocrine systems. In order to evaluate whether the NPY gene variations contribute to development of type 2 diabetes (T2DM), we have performed a genetic association study for Leu7Pro (T1128 C) polymorphism of the NPY gene in impaired glucose tolerance (IGT) and T2DM. Genotyping experiments for this non-synonymous single nucleotide polymorphism (SNP) in 263 patients with T2DM, 309 subjects with IGT and 469 non-diabetic healthy individuals in Swedish Caucasians were performed by using Dynamic Allele Specific Hybridisation (DASH). We found that the frequencies of the "risk" allele C in the subjects with IGT and the patients with T2DM in Swedish men were 13 % (p = 0.002, OR = 3.70, 1.65 - 8.29 95 % CI) and 10 % (p = 0.007, OR = 4.80, 1.47 - 11.33 95 % CI) respectively, which were significantly higher than the C allele frequency in non-diabetic controls (6 %). Furthermore, we found that the carriers with TC and CC genotypes in the subjects with IGT in Swedish men had significantly higher fasting plasma glucose in comparison with the TT carriers (5.6 +/- 0.7 mmol/l vs. 5.2 +/- 0.7 mmol/l, p = 0.021). The present study thus provides the evidence that Leu7Pro polymorphism in the NPY gene is associated with IGT and T2DM in Swedish men, and indicates that the NPY gene variations contribute to development of T2DM. Questions of gender specificity may be explained by genetic backgrounds, sense of coherence for stress and other factors in environment.

Topics: Adult; Alleles; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Fasting; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Glucose Intolerance; Heterozygote; Humans; Insulin; Leucine; Male; Middle Aged; Neuropeptide Y; Odds Ratio; Polymerase Chain Reaction; Polymorphism, Genetic; Proline; Sex Characteristics; Sweden

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

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

In this study we tested the hypothesis that the Leu7Pro7 polymorphism in prepro neuropeptide Y (NPY) gene could be a risk marker for the development of diabetic retinopathy and analyzed a well characterized cohort of patients with Type 2 diabetes followed-up for 10 years from the time of diagnosis. The frequency of Leu7/Pro7-polymorphism was 9.3% (8 out of 86). At baseline, the frequency of retinopathy in patients with the Leu7/Pro7-polymorphism was 25% (2 out of 8) and in those without it 6.4% (5 out of 78) (p=0.126). At 10-year the respective figures were 88% and 50% (p=-0.040). The odds ratio for Leu7/Pro7-polymorphism in logistic regression analysis adjusted for age, gender and HbA1c was 8.97 (95% confidence intervals 1.09-98.0; p=0.049). Our finding based on elderly Finnish Type 2 diabetic subjects suggests that the Leu7Pro7-genotype in preproNPY gene is associated with the development of diabetic retinopathy.

Topics: Aged; Amino Acid Substitution; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Finland; Follow-Up Studies; Glycated Hemoglobin; Humans; Leucine; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Proline; Time Factors

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.

Topics: Body Constitution; Body Mass Index; Cholecystokinin; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Insulin; Leptin; Middle Aged; Neuropeptide Y; Neuropeptides; Obesity

Neuropeptide Y (NPY) is a potent vasoconstrictor peptide that is abundant in the brain and the peripheral sympathetic nervous system. In the present study we investigated possible changes in plasma immunoreactive (IR)-NPY concentrations and urinary IR-NPY excretion in patients with non-insulin dependent diabetes mellitus (NIDDM) and the relationship to diabetic complications, such as nephropathy and neuropathy. IR-NPY in plasma and urine was measured by radioimmunoassay in 69 patients with NIDDM. Plasma IR-NPY concentrations in patients with advanced nephropathy (creatinine clearance <30 ml/min) (100.5 +/- 10.3 pmol/l, n=9, mean +/- SEM) were higher than in the control subjects (55.0 +/- 6.8 pmol/l, n=15) (P<0.02). Urinary excretion of IR-NPY and fractional excretion of NPY were also increased in the patients with advanced nephropathy. Sephadex G-50 column chromatography of the urine extracts obtained from healthy subjects, diabetic patients with renal failure and non-diabetic patients with renal failure showed an immunoreactive peak eluting in the NPY position. On the other hand, neither plasma nor urinary IR-NPY was high in patients with retinopathy, or in patients with peripheral neuropathy. The present study has, for the first time, shown high plasma IR-NPY concentrations and urinary IR-NPY excretion in NIDDM patients with advanced nephropathy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Neuropeptide Y; Reference Values

Topics: Adipose Tissue; Animals; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin

The study objective was to determine circulating levels of the appetite-controlling neuropeptides, neuropeptide Y (NPY), galanin, and leptin, in subjects with eating disorders. The study group consisted of 48 obese women aged 19 to 45 years, 15 women with anorexia nervosa aged 18 to 23 years, and 19 lean healthy women aged 18 to 42 years (control group). The obese women were divided into four groups: (A) body mass index (BMI) = 25 to 30 kg/m2, n = 9 (overweight); (B) BMI = 31 to 40 kg/m2, n = 23 (moderate obesity); (C) BMI greater than 40 kg/m2, n = 9 (severe obesity); and (D) BMI = 31 to 40 kg/m2, n = 7 (moderate obesity + non-insulin-dependent diabetes mellitus [NIDDM]). Plasma NPY, galanin, and leptin concentrations were measured in peripheral blood samples with radioimmunoassay methods. Plasma NPY levels in obese women (groups A, B, C, and D) were significantly higher as compared with the control group (P < .01, P < .001, P < .001, and P < .001, respectively). The highest plasma NPY concentrations were observed in obese women with NIDDM. Plasma galanin levels were significantly higher in groups B, C, and D (P < .001, P < .001, and P < .001, respectively). Plasma leptin concentrations were significantly higher in groups C and D as compared with the control group (P < .001 and P < .001, respectively). Plasma NPY and galanin concentrations in women with anorexia nervosa did not differ from the levels in the control group. However, plasma leptin concentrations were significantly lower in anorectic women than in the control group (P < .01). Our results indicate that inappropriate plasma concentrations of NPY, galanin, and leptin in obese women may be a consequence of their weight status, or could be one of many factors involved in the pathogenesis of obesity.

Topics: Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Leptin; Neuropeptide Y; Obesity; Proteins; Radioimmunoassay

Glutamic acid decarboxylase (GAD), among other potential autoantigens, is thought to play a crucial role in type I diabetes, particularly in a spontaneous model of the disease, the nonobese diabetic (NOD) mouse. In the pancreas, the presence of GAD and gamma-aminobutyric acid (GABA), the decarboxylation product of GAD and a putative neurotransmitter in the islets of Langerhans, is well documented in the beta-cells. This is particularly true in rats, in which another GABAergic structure exists near the islets, the neuronal bodies. In this study, first the GABA content was measured in isolated islets from NOD and C57BL/6 mice (controls), and a decrease was found in NOD females as their insulitis progressed. Second, for the first time in mice, confocal analysis of immunofluorescent-labeled pancreatic sections revealed near the islets neuronal structures in which GAD and neuropeptide Y were colocalized, as they are in the brain. These structures were always observed in the pancreata of both sexes of C57BL/6 mice at the various ages investigated. In NOD mice, however, these neuronal structures were only detected in young females ( < 10 weeks old) and in males until an intermediate age. Moreover, patches of T cells surrounding GAD-containing fibers were seen in the vicinity of the islets with incipient periinsulitis.

Topics: Animals; Antibodies, Monoclonal; Diabetes Mellitus, Type 2; Female; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Immunohistochemistry; Islets of Langerhans; Isoantibodies; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Neuropeptide Y; Pancreas; Reference Values; T-Lymphocytes; Tissue Distribution

Topics: Amyloid; Colipases; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Enzyme Precursors; Humans; Islet Amyloid Polypeptide; Leptin; Neuropeptide Y; Neurotransmitter Agents; Obesity; Protein Precursors; Proteins; Serotonin; Tryptophan

The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Height; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Female; Fertility; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Proteins; RNA, Messenger

Vascular smooth muscle contractile responses to neuropeptide Y, alpha,beta-methyleneATP and noradrenaline were studied in circular segments of isolated vessels with intact endothelium in vitro from 12 patients with diabetes mellitus type 2 (NIDDM) and 12 control subjects. The dilatory effect of acetylcholine was used to test the function of the endothelium. Subcutaneous arteries and veins (diameter 0.1-1.1 mm) were obtained during surgery. There was no difference in contractile responses to noradrenaline or alpha,beta-methyleneATP between diabetic and control vessels. The contractile response to neuropeptide Y, however, was markedly reduced in the diabetic group. The maximal contractile effect (46.0 +/- 14.0%, p < 0.05) but not the sensitivity to neuropeptide Y was significantly less in diabetic veins compared to control (107.5 +/- 19.6%). Thus, the attenuation of neuropeptide Y responses was present in humans as previously observed in alloxan-induced diabetes mellitus in rabbits. There was no difference in the dilator effect of acetylcholine between the diabetic and the control group in any of the vessel types, indicating that the difference in vascular reactivity to neuropeptide Y was not endothelium-dependent. In conclusion, the present study has shown that the postjunctional effects of neuropeptide Y, a co-transmitter of the peripheral sympathetic nervous system, is selectively attenuated in diabetes mellitus.

Topics: Acetylcholine; Adenosine Triphosphate; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; GTP-Binding Proteins; Humans; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular; Neuropeptide Y; Norepinephrine; Potassium; Vasoconstriction; Vasoconstrictor Agents

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

Topics: Adipose Tissue; Animals; Autonomic Nervous System; Brain; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucocorticoids; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipids; Liver; Muscles; Neuropeptide Y; Obesity; Rats; Weight Gain

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