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)

Cortistatin (CST), a 17-amino acid peptide partially homologous to somatostatin (SRIF), has been originally isolated from the cerebral cortex and recently found in monocytes and macrophages of the immune system. CST binds all 5 SRIF receptors, as well the GH secretagogue (GHS)/ghrelin receptors. CST exerts sleep promoting activities, acts on animal motility and behavior and inhibits GH and insulin secretion. To investigate the possible occurrence and activities in peripheral tissues, expression of CST at the mRNA and peptide level was analyzed in the human pancreas by means of RT-PCR, in situ hybridization and immunohistochemistry. The specific CST mRNA was found in 3 of 4 pancreatic RNA extracts and in the control cerebral cortex. By in situ hybridization, CST mRNA was localized in the pancreatic islets, but not in the exocrine pancreas. This finding was confirmed by immunostaining with a specific antibody to CST-17 which detected CST in single islet cells. These cells also expressed SRIF receptors types 2, 3 and 5, ghrelin and GHS receptors. Thus, our findings show the presence of CST in the human endocrine pancreas. Local autocrine or paracrine circuits, only in part overlapped with those of SRIF, may be active to modulate insulin and/or glucagon levels.
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PMID:Presence of cortistatin in the human pancreas. 1466 20

Ghrelin is produced mainly by endocrine cells in the stomach and is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). It also influences feeding behavior, metabolic regulation, and energy balance. It affects islet hormone secretion, and expression of ghrelin and GHS-R in the pancreas has been reported. In human islets, ghrelin expression is highest pre- and neonatally. We examined ghrelin and GHS-R in rat islets during development with immunocytochemistry and in situ hybridization. We also studied the effect of ghrelin on insulin secretion from INS-1 (832/13) cells and the expression of GHS-R in these cells. We found ghrelin expression in rat islet endocrine cells from mid-gestation to 1 month postnatally. Islet expression of GHS-R mRNA was detected from late fetal stages to adult. The onset of islet ghrelin expression preceded that of gastric ghrelin. Islet ghrelin cells constitute a separate and novel islet cell population throughout development. However, during a short perinatal period a minor subpopulation of the ghrelin cells co-expressed glucagon or pancreatic polypeptide. Markers for cell lineage, proliferation, and duct cells revealed that the ghrelin cells proliferate, originate from duct cells, and share lineage with glucagon cells. Ghrelin dose-dependently inhibited glucose-stimulated insulin secretion from INS-1 (832/13) cells, and GHS-R was detected in the cells. We conclude that ghrelin is expressed in a novel developmentally regulated endocrine islet cell type in the rat pancreas and that ghrelin inhibits glucose-stimulated insulin secretion via a direct effect on the beta-cell.
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PMID:Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells. 1496 97

The pancreatic islet is necessary for maintaining glucose homeostasis. Within the pancreatic islet, the homeodomain protein Nkx2.2 is essential for the differentiation of all insulin-producing beta cells and a subset of glucagon-producing alpha cells (1). Mice lacking Nkx2.2 have relatively normal sized islets, but a large number of cells within the mutant islet fail to produce any of the four major islet hormones. In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach. Intriguingly, normal mouse pancreas also contains a small population of ghrelin-producing cells, defining a new islet "epsilon" cell population. The expansion of ghrelin-producing cells at the expense of beta cells may be a general phenomenon, because we demonstrate that Pax4 mutant mice display a similar phenotype. We propose that insulin and ghrelin cells share a common progenitor and that Nkx2.2 and Pax4 are required to specify or maintain differentiation of the beta cell fate. This finding also suggests that there is a genetic component underlying the balance between insulin and ghrelin in regulating glucose metabolism.
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PMID:Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. 1497 Mar 13

Oxyntomodulin (OXM) is a circulating gut hormone released post prandially from cells of the gastrointestinal mucosa. Given intracerebroventricularly to rats, it inhibits food intake and promotes weight loss. Here we report that peripheral (ip) administration of OXM dose-dependently inhibited both fast-induced and dark-phase food intake without delaying gastric emptying. Peripheral OXM administration also inhibited fasting plasma ghrelin. In addition, there was a significant increase in c-fos immunoreactivity, a marker of neuronal activation, in the arcuate nucleus (ARC). OXM injected directly into the ARC caused a potent and sustained reduction in refeeding after a fast. The anorectic actions of ip OXM were blocked by prior intra-ARC administration of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin(9-39), suggesting that the ARC, lacking a complete blood-brain barrier, could be a potential site of action for circulating OXM. The actions of ip GLP-1, however, were not blocked by prior intra-ARC administration of exendin(9-39), indicating the potential existence of different OXM and GLP-1 pathways. Seven-day ip administration of OXM caused a reduction in the rate of body weight gain and adiposity. Circulating OXM may have a role in the regulation of food intake and body weight.
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PMID:Peripheral oxyntomodulin reduces food intake and body weight gain in rats. 1500 46

We combined in vitro and in vivo methods to investigate the effects of ghrelin, a novel gastric hormone, on insulin and glucagon release. Studies of isolated mouse islets showed that ghrelin concentrations in the physiological range (0.5-3 nmol l(-1)) had no effect on glucose-stimulated insulin release, while low ghrelin concentrations (1-100 pmol l(-1)) inhibited and high (0.1 and 1 micromol l(-1)) stimulated. The insulin response to glucose was enhanced in the presence of a high ghrelin concentration (100 nmol l(-1)). Glucagon release was stimulated by ghrelin (0.1 pmol l(-1) to 1 micromol l(-1)); this effect was maintained in the presence of glucose (0-20 mmol l(-1)). In intact mice, basal plasma insulin was suppressed by 1 and 10 nmol kg(-1) of ghrelin, 2 and 6 min after i.v. injection. Ghrelin (0.2-10 nmol kg(-1) i.v.) suppressed also the glucose-stimulated insulin response and impaired the glucose tolerance (at a ghrelin dose of 3.3 nmol kg(-1)). Ghrelin (1 or 10 nmol kg(-1) i.v.) inhibited the insulin response to the phospholipase C stimulating agent carbachol and enhanced the insulin response to the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX) but did not affect the response to the membrane-depolarizing amino acid l-arginine. These observations suggest that the inhibitory effect of ghrelin on glucose-induced insulin release is in part exerted on phospholipase C pathways (and not on Ca(2+)entry), while the stimulatory effect of high doses of ghrelin depends on cyclic AMP. In contrast to the spectacular glucagon-releasing effect of ghrelin in vitro, ghrelin did not raise plasma glucagon. Carbachol, IBMX and l-arginine stimulated glucagon release. These responses were impaired by ghrelin, suggesting that it suppresses the various intracellular pathways (phospholipase C, cyclic AMP and Ca(2+)), that are activated by the glucagon secretagogues. Together these observations highlight (but do not explain) the different effects of ghrelin on glucagon release in vitro and in vivo. The results show that ghrelin has powerful effects on islet cells, suggesting that endogenous ghrelin may contribute to the physiological control of insulin and glucagon release. However, the narrow "window" of circulating ghrelin concentrations makes this doubtful.
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PMID:Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. 1500 30

Plasma ghrelin is elevated in Prader-Willi syndrome (PWS). This might contribute to obesity or GH deficiency in such patients. Visceral adiposity and insulin resistance are reduced in PWS, which might lead to hyperghrelinemia. We measured fasting plasma ghrelin in control female (n = 39), PWS female (n = 12), and PWS male (n = 6) adults. In controls and PWS, ghrelin was negatively correlated with visceral adiposity, fasting insulin, and homeostasis model insulin resistance index. There was no significant correlation with serum IGF-I in PWS. In stepwise linear regression, visceral adiposity (P < 0.02) had a stronger inverse correlation with ghrelin than sc fat depots in controls and PWS, possibly through hyperinsulinemia, as the correlations with insulin resistance were even stronger (P < 0.01). PWS females had significantly (P < 0.001) elevated ghrelin (mean +/- SD, 661 +/- 360 pg/ml), compared with both nonobese (363 +/- 163) and obese (191 +/- 66) controls. Ghrelin was increased 3.4- to 3.6-fold in PWS females adjusting for total adiposity, 3.2- to 3.4-fold adjusting for visceral adiposity, and 3.0-fold adjusting for insulin resistance. Fasting plasma glucagon-like peptide-1 was normal in PWS females. The hyperghrelinemia in PWS adults is therefore not solely explained by their reduced visceral adiposity and relative hypoinsulinemia. Its cause and consequences await further elucidation.
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PMID:Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance. 1507 Sep 36

Gastrointestinal tract (GIT) and nervous system, both central (CNS) and enteric (ENS), are involved in two-way extrinsic communication by parasympathetic and sympathetic nerves, each comprising efferents fibers such as cholinergic and noradrenergic, respectively, and afferent sensory fibers required for gut-brain signaling. Afferent nerves are equipped with numerous sensors at their terminals in the gut related to visceral mechano- chemo- and noci-receptors, whose excitations may trigger a variety of visceral reflexes regulating GIT functions, including the appetitive behaviour. Food intake depends upon various influences from the CNS as well as from the body energy stores (adipocytes) that express and release the product of Ob gene, leptin, in proportion to fat stored and acting in long-term regulation of food intake. Leptin acts through receptors (Ob-R) present in afferent visceral nerves and hypothalamic arcuate nucleus (ARC), whose neurons are capable of expressing and releasing neuropeptide Y (NPY) and agouti related protein (AgRP) that activate the ingestive behaviour through paraventricular nucleus (PVN) (iVfeeding centerli). In addition, to this long-term regulation, a short-term regulation, on meal-to-meal basis, is secured by several gut hormones, such as cholecystokinin (CCK), peptides YY (PYY) and oxyntomodulin (OXM), released from the endocrine intestinal cells and acting via G-protein coupled receptors (GPCR) either on afferent nerves or directly on ARC neurons, which in turn inhibit expression and release of food-intake stimulating NPY and AgRP, thereby inducing satiety through inhibition of PVN. In contrast, during fasting, the GIT, especially oxyntic mucosa, expresses and releases appetite stimulating (orexigenic) factors such as ghrelin and orexins (OX) -A and OX-B, and cannabinoid CB1 agonist. Ghrelin activates growth-hormone secretagogue receptor (GHS-R) in hypothalamic ARC and stimulates growth hormone (GH) release and in vagal afferents to promote the expression and release of hypothalamic NPY and AgRP stimulating PVN and driving ingestive behaviour. The balance and interaction between anorexigenic (CCK, PYY, OXM) and orexigenic (ghrelin and OX) factors originating from GIT appears to play an important role in short-term regulation of food intake and growth hormone (GH) release. An impairment of this balance may result in disorders of feeding behaviour and weight gain (obesity) or weight loss (cachexia).
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PMID:Brain-gut axis and its role in the control of food intake. 1508 74

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, was originally purified from the rat stomach. Although ghrelin has been recognized as an important regulator of energy metabolism, the regulation of the ghrelin secretion is largely unknown. Here, we examined the direct effects of insulin, leptin, and glucagon on the release of ghrelin from the isolated rat stomach. The isolated pancreas-spleen-duodenum deprived preparation of rat stomach was used. After a baseline control infusion into the left gastric artery, insulin, leptin, or glucagon were infused for 15 min at concentrations of 0.1, 1, and 10 nM. The levels of immunoreactive ghrelin in the venous effluents were measured with a radioimmunoassay. Insulin and leptin inhibited ghrelin secretion dose-dependently (total amount of ghrelin release: insulin at 1 nM, 73.5+/-7.3% of the control infusion; leptin at 1 nM, 81.8+/-2.5% of the control infusion; n=5, P<0.05), while glucagon increased it dose-dependently (total amount of ghrelin released at 10 nM was 143.9+/-19.3% of the control infusion; n=5, P<0.01). These results indicate that the ghrelin responses observed in vivo could be due to direct effects of multiple hormonal signals on the stomach.
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PMID:Effects of insulin, leptin, and glucagon on ghrelin secretion from isolated perfused rat stomach. 1509

Ghrelin release in man depends on the macronutrient composition of the test meal. The mechanisms contributing to the differential regulation are largely unknown. To elucidate their potential role, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), insulin, gastrin and somatostatin were examined on isolated rat stomach ghrelin secretion, which offers the advantage of avoiding systemic interactions. Basal ghrelin secretion was in a range that did not permit to consistently evaluate inhibiting effects. Therefore, the effect of gastrointestinal hormones and insulin was analyzed during vagal prestimulation. GLP-1(7-36)amide 10(-8) and 10(-7) M decreased ghrelin secretion significantly. In contrast, GIP 10(-8) and 10(-7) M augmented not only prestimulated, but also basal ghrelin secretion (p<0.05). Insulin reduced ghrelin at 10(-10), 10(-8) and 10(-6) M (p<0.05). Both gastrin 10(-8) M and somatostatin 10(-6) M also significantly inhibited ghrelin secretion. These data demonstrate that GLP-1(7-36)amide, insulin, gastrin and somatostatin are potential candidates to contribute to the postprandially observed inhibition of ghrelin secretion with insulin being the most effective inhibitor in this isolated stomach model. GIP, on the other hand, could attenuate the postprandial decrease. Because protein-rich meals do not effectively stimulate GIP release, other as yet unknown intestinal factors must be responsible for protein-induced stimulation of ghrelin release.
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PMID:Effect of GIP, GLP-1, insulin and gastrin on ghrelin release in the isolated rat stomach. 1509 2

This review's objective is to give a critical summary of studies that focused on physiologic measures relating to subjectively rated appetite, actual food intake, or both. Biomarkers of satiation and satiety may be used as a tool for assessing the satiating efficiency of foods and for understanding the regulation of food intake and energy balance. We made a distinction between biomarkers of satiation or meal termination and those of meal initiation related to satiety and between markers in the brain [central nervous system (CNS)] and those related to signals from the periphery to the CNS. Various studies showed that physicochemical measures related to stomach distension and blood concentrations of cholecystokinin and glucagon-like peptide 1 are peripheral biomarkers associated with meal termination. CNS biomarkers related to meal termination identified by functional magnetic resonance imaging and positron emission tomography are indicators of neural activity related to sensory-specific satiety. These measures cannot yet serve as a tool for assessing the satiating effect of foods, because they are not yet feasible. CNS biomarkers related to satiety are not yet specific enough to serve as biomarkers, although they can distinguish between extreme hunger and fullness. Three currently available biomarkers for satiety are decreases in blood glucose in the short term (<5 min), which have been shown to be involved in meal initiation; leptin changes during longer-term (>2-4 d) negative energy balance; and ghrelin concentrations, which have been implicated in both short-term and long-term energy balance. The next challenge in this research area is to identify food ingredients that have an effect on biomarkers of satiation, satiety, or both. These ingredients may help consumers to maintain their energy intake at a level consistent with a healthy body weight.
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PMID:Biomarkers of satiation and satiety. 1515 23


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