Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signaling systems underlying eating behavior control are complex. The current review focuses on gastrointestinal (GI) signaling systems as physiological key functions for metabolic control. Many of the peptides that are involved in the regulation of food intake in the brain are also found in the enteric nervous system and enteroendocrine cells of the mucosa of the GI tract. The only identified hunger-driving signal from the GI tract is ghrelin, which is mainly found in the mucosa of the stomach. Neuropeptides in the brain that influence food intake, of which neuropeptide Y, agouti gene-related peptide and orexins are stimulatory, while melanocortins and alpha-melanocortin stimulating hormone are inhibitory, are influenced by peptide signaling from the gut. These effects may take place directly through action of gut peptide in the brain or through nervous signaling from the periphery to the brain. The criteria for considering a gut hormone or neurotransmitter in a satiety signal seem to be fulfilled for cholecystokinin, glucagon-like peptide-1 and peptide YY(3-36). Other endogenous gut signals do not fulfill these criteria as they do not increase food intake in knock-out animals or in response to receptor antagonism, or display an inconsistent temporal profile with satiety and termination of the meal. Satiety signals from the GI tract act through the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem, where neuronal networks directly linked to hypothalamic centers for food intake and eating behavior are activated. We have primarily focused on GI effects of various gut peptides involved in the regulation of food intake, using motor activity as a biomarker for the understanding of gut peptide effects promoting satiety.
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PMID:Appetite signaling: from gut peptides and enteric nerves to brain. 1758 45

Although the orexigenic action of peptide hormones such as ghrelin and growth hormone releasing peptide is different between chickens and mammals, the anorexigenic action of peptide hormones is similar in both species. For example, central administration of peptide hormones such as leptin, cholecystokinin or glucagon has been shown to suppress food intake behavior in chickens and mammals. Central administration of insulin suppresses food intake in mammals. However, the anorexigenic action of insulin in chickens has not yet been identified. In the present study, we investigated the effects of central administration of insulin on food intake in chicks. Intracerebroventricular administration of insulin in chicks significantly suppressed food intake. Central administration of insulin significantly upregulated mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and corticotropin-releasing factor (CRF), but did not influence mRNA levels of neuropeptide Y and agouti-related protein in the hypothalamus. These results suggest that alpha-melanocyte stimulating hormone (alpha-MSH, an anorexigenic peptide from the post-translational cleavage of POMC), CART and CRF are involved in the anorexigenic action of insulin in chicks. Furthermore, central administration of alpha-MSH or CART significantly suppressed food intake. In addition, alpha-MSH significantly upregulated CRF mRNA expression, suggesting that the anorexigenic action of alpha-MSH is mediated by CRF. Our findings demonstrate that insulin functions in chicks as an appetite-suppressive peptide in the central nervous system and suggest that this anorexigenic action is mediated by CART, alpha-MSH and CRF.
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PMID:Central administration of insulin suppresses food intake in chicks. 1769 22

Isolated postchallenge hyperglycemia (IPH) with normal fasting plasma glucose <100 mg/dL and plasma glucose with diabetic 2-hour plasma glucose >or=200 mg/dL after an oral glucose tolerance test (OGTT) is a common occurrence in the elderly. We sought to understand what unique characteristics this population might have that puts it at risk for this particular metabolic finding. We therefore conducted a longitudinal study of volunteers in the Baltimore Longitudinal Study of Aging (BLSA). All volunteers had an OGTT performed (75 g) on 2 or more occasions. We measured plasma levels of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, leptin, adiponectin, resistin, C-reactive protein, cytokines, and their soluble receptors, as well as nonesterified free fatty acids (NEFAs). We determined that 22 subjects in BLSA had IPH, accounting for 2.1% of the BLSA population. All 22 were older than 65 years. They were then matched by age, sex, and body mass index to 12 subjects who had isolated impaired glucose tolerance (IGT) and 15 subjects with normal glucose tolerance (NGT). All subjects had normal fasting glucose levels <100 mg/dL in accordance with the American Diabetes Association Expert Committee on the Classification and Diagnosis of Diabetes Mellitus criteria (2003). We found that subjects with IPH had similar plasma insulin levels to the other 2 groups, except at the 2-hour time when their insulin levels were higher than NGT (P < .05). Although there was a clear trend for differences in the insulinogenic index, the areas under the curves for insulin, systolic blood pressure, adiponectin, and C-reactive protein across the glucose tolerance categories revealed no statistical significance. Cytokines and their soluble receptors, gut hormones, and adipokines were similar in all 3 groups. The NEFA levels were significantly elevated in the fasting state (P < .05) in the IPH compared with NGT, with IGT intermediate between the other 2 groups. The rate of clearance of NEFAs after the OGTT decreased progressively from the NGT to the IPH group (in micromoles per liter per minute: NGT, 11.9 vs IGT, 7.6 vs IPH, 3.0). We conclude that the rate of suppression of lipolysis in the elderly determines the sensitivity of glucose uptake to insulin after OGTT.
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PMID:Contribution of nonesterified fatty acids to insulin resistance in the elderly with normal fasting but diabetic 2-hour postchallenge plasma glucose levels: the Baltimore Longitudinal Study of Aging. 1788 59

Body mass--strictly speaking: the adipose tissue mass--is regulated in a feed-back system by the hypothalamus and brainstem, where adiposity signals (leptin, insulin, amylin) and intestinal peptides (ghrelin, PYY, PP, GLP-1, OXM, CCK) and the vagal nerve provide afferent information to the central controller on the size of white adipose tissue and the actual nutritional state, respectively. Two distinct groups of neurons in the arcuate nucleus accept and process the afferent information provided by leptin produced by white adipocytes in proportion to their mass. Leptin binding to the leptin-receptors on the surface of these neurons initiates intracellular signal transduction and activation of target genes, resulting in the synthesis and release of neuropeptides (POMC, CART) with anorectic effects. Secondary centers in the brain are also activated, and finally integrated effector mechanisms are generated in order to regulate the balance between energy intake and expenditure. The regulation of body weight is carried out by the central nervous system in a complex and redundant way, characterized by interconnections and overlaps with other neuroendocrine functions, such as growth, thyroid and adrenal function, memory, addictive and reward mechanisms. Targeting one or another component of this complicated system with drugs might result in interference with other systems and functions, so the occurrence of adverse events is probable. The worldwide epidemic of obesity--resulting mostly from the abundance of energy-dense foods and sedentary lifestyle coupled with a regulatory system unable to cope with this environment--has resulted in a continuous increase of research activities in both academic and industrial centers to develop new drugs and treatment strategies beyond lifestyle changes (diet, physical activity and behavioral therapy) to fight obesity more effectively.
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PMID:[The regulation of body mass and its relation to the development of obesity]. 1789 Jan 70

Proghrelin, the precursor of the orexigenic and adipogenic peptide hormone ghrelin, is synthetized in endocrine (A-like) cells in the gastric mucosa. During its cellular processing, proghrelin gives rise to the 28-amino acid peptide desacyl ghrelin, which after octanoylation becomes active acyl ghrelin, and to the 23-amino acid peptide obestatin, claimed to be a physiological opponent of acyl ghrelin. This study examines the effects of the proghrelin products, alone and in combinations, on the secretion of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin from isolated islets of mice and rats. Surprisingly, acyl ghrelin and obestatin had almost identical effects in that they stimulated the secretion of glucagon and inhibited that of PP and somatostatin from both mouse and rat islets. Obestatin inhibited insulin secretion more effectively than acyl ghrelin. In mouse islets, acyl ghrelin inhibited insulin secretion at low doses and stimulated at high. In rat islets, acyl ghrelin inhibited insulin secretion in a dose-dependent manner but the IC(50) for the acyl ghrelin-induced inhibition of insulin release was 7.5 x 10(-8) M, while the EC(50) and IC(50) values, with respect to stimulation of glucagon release and to inhibition of PP and somatostatin release, were in the 3 x 10(-12)-15 x 10(-12) M range. The corresponding EC(50) and IC(50) values for obestatin ranged from 5 x 10(-12) to 20 x 10(-12) M. Desacyl ghrelin per se did not affect islet hormone secretion. However, at a ten times higher concentration than acyl ghrelin (corresponding to the ratio of the two peptides in circulation), desacyl ghrelin abolished the effects of acyl ghrelin but not those of obestatin. Acyl ghrelin and obestatin affected the secretion of glucagon, PP and somatostatin at physiologically relevant concentrations; with obestatin this was the case also for insulin secretion. The combination of obestatin, acyl ghrelin and desacyl ghrelin in concentrations and proportions similar to those found in plasma resulted in effects that were indistinguishable from those induced by obestatin alone. From the data it seems that the effects of endogenous, circulating acyl ghrelin may be overshadowed by obestatin or blunted by desacyl ghrelin.
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PMID:Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. 1794 70

Inulin-type fructans have been tested for their capacity to modulate lipid and glucose metabolism in several animal models. Oligofructose (OFS) decreases food intake, fat mass development, and hepatic steatosis in normal and in obese rats; moreover, it exerts an antidiabetic effect in streptozotocin-treated rats and high-fat-fed mice. In most cases, the beneficial effects of OFS are linked to an increase of glucagon-like peptide-1 (GLP-1) level in the portal vein and of GLP-1 and proglucagon mRNA, its precursor, in the proximal colon. In this organ, OFS increases the number of GLP-1-positive L cells by promoting factors (Neurogenin 3 and NeuroD) involved in the differentiation of stem cells into L cells. The chronic administration of GLP-1 receptor antagonist exendin 9-39 totally prevents the beneficial effects of OFS (improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, insulin-sensitive hepatic glucose production, and reduced body weight gain). Furthermore GLP-1 receptor knockout mice are completely insensitive to the antidiabetic actions of OFS. These findings highlight the potential interest of enhancing endogenous GLP-1 secretion by inulin-type fructans for the prevention/treatment of obesity and type 2 diabetes. Moreover, OFS is also able to modulate other gastrointestinal peptides (such as PYY and ghrelin) that could be involved in the control of food intake. Several studies in humans already support interest in OFS in the control of satiety, triglyceridemia, or steatohepatitis. The link with gut peptides production in humans remains to be proven.
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PMID:Modulation of glucagon-like peptide 1 and energy metabolism by inulin and oligofructose: experimental data. 1795

Diets that are high in dietary fiber are reported to have substantial health benefits. We sought to compare the metabolic effects of 3 types of dietary fibers -- sugarcane fiber (SCF), psyllium (PSY), and cellulose (CEL) -- on body weight, carbohydrate metabolism, and stomach ghrelin gene expression in a high-fat diet-fed mouse model. Thirty-six male mice (C57BL/6) were randomly divided into 4 groups that consumed high-fat diet alone (HFD) or high-fat diet containing 10% SCF, PSY, and CEL, respectively. After baseline measurements were assessed for body weight, plasma insulin, glucose, leptin, and glucagon-like peptide 1 (GLP-1), animals were treated for 12 weeks. Parameters were reevaluated at the end of study. Whereas there was no difference at the baseline, body weight gains in the PSY and SCF groups were significantly lower than in the CEL group at the end of study. No difference in body weight was observed between the PSY and SCF animals. Body composition analysis demonstrated that fat mass in the SCF group was considerably lower than in the CEL and HFD groups. In addition, fasting plasma glucose and insulin and areas under the curve of intraperitoneal glucose tolerance test were also significantly lower in the SCF and PSY groups than in the CEL and HFD groups. Moreover, fasting plasma concentrations of leptin were significantly lower and GLP-1 level was 2-fold higher in the SCF and PSY mice than in the HFD and CEL mice. Ghrelin messenger RNA levels of stomach in the SCF group were significantly lower than in the CEL and HFD groups as well. These results suggest differences in response to dietary fiber intake in this animal model because high-fat diets incorporating dietary fibers such as SCF and PSY appeared to attenuate weight gain, enhance insulin sensitivity, and modulate leptin and GLP-1 secretion and gastric ghrelin gene expression.
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PMID:Effects of dietary fibers on weight gain, carbohydrate metabolism, and gastric ghrelin gene expression in mice fed a high-fat diet. 1799 14

An unresolved issue in the field of diet and health is if and how changes in meal frequency affect energy metabolism in humans. We therefore evaluated the influence of reduced meal frequency without a reduction in energy intake on glucose metabolism in normal-weight, healthy male and female subjects. The study was a randomized crossover design, with two 8-week treatment periods (with an intervening 11-week off-diet period) in which subjects consumed all of their calories for weight maintenance distributed in either 3 meals or 1 meal per day (consumed between 4:00 pm and 8:00 pm). Energy metabolism was evaluated at designated time points throughout the study by performing morning oral glucose tolerance tests and measuring levels of glucose, insulin, glucagon, leptin, ghrelin, adiponectin, resistin, and brain-derived neurotrophic factor (BDNF). Subjects consuming 1 meal per day exhibited higher morning fasting plasma glucose levels, greater and more sustained elevations of plasma glucose concentrations, and a delayed insulin response in the oral glucose tolerance test compared with subjects consuming 3 meals per day. Levels of ghrelin were elevated in response to the 1-meal-per-day regimen. Fasting levels of insulin, leptin, ghrelin, adiponectin, resistin, and BDNF were not significantly affected by meal frequency. Subjects consuming a single large daily meal exhibit elevated fasting glucose levels and impaired morning glucose tolerance associated with a delayed insulin response during a 2-month diet period compared with those consuming 3 meals per day. The impaired glucose tolerance was reversible and was not associated with alterations in the levels of adipokines or BDNF.
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PMID:Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normal-weight middle-aged men and women. 1799 28

Since adipose tissue was shown to be more than a storage organ, the many cytokines it produces have been identified, along with their roles in energy homeostasis, appetite, and insulin resistance. Concurrently, numerous gut hormones with a diversity of effects have been discovered. They include, amongst many others, peptide YY, ghrelin and oxyntomodulin. As these peptides have been investigated, the potential for their use as novel anti-obesity and antidiabetic therapies has been realized. In this chapter we describe the actions of four of the peptides that have been proposed as the basis for promising new therapies for diabetes: leptin, adiponectin, obestatin and peptide YY. They each have an effect on appetite and, directly or indirectly, on glucose metabolism. We synthesize available data for these peptides and consider the therapeutic potential of each.
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PMID:Potential therapies based on antidiabetic peptides. 1805 40

Pax4-deficient mice have a severe gastrointestinal endocrine deficiency: they lack most pancreatic cells that produce insulin or somatostatin and various duodenal endocrine cell types. Remarkably, Pax4-deficient mice also have an overabundance of ghrelin-expressing cells in the pancreas and duodenum. Detailed analysis of the Pax4 nullizygous pancreas determined that the mutant islets are largely composed of a distinctive endocrine cell type that expresses ghrelin, glucagon, islet amyloid polypeptide (IAPP), and low levels of Pdx1. Lineage-tracing analysis revealed that most of these unique endocrine cells directly arose from Pax4-deficient progenitors. Previous in vitro work reported that Pax4 is a transcriptional repressor of islet amyloid polypeptide (IAPP) and glucagon. In this study, we expanded those results by showing that Pax4 is also a repressor of gherlin. Together, our data further support the notion that Pax4 activity is necessary to establish appropriate patterns of gene expression in endocrine progenitors of the digestive tract.
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PMID:Ghrelin is a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum. 1805 10


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