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)

We generalize the principle of integral rein control to include other systems which partition in such a way that the equilibrium values of some variables are not dependent on the equations governing those variables. Instead, they are determined by the dynamics of other, "regulator" variables. We improve our earlier model for the control of glucose by insulin and glucagon by relaxing the condition necessary for it to operate. The two hormones do not have to be inhibited in the same way; they need only respond to the same combination of their concentrations. We also present a model for the control of ionized calcium by PTH and calcitonin and suggest that the role of chromogranin A may be to stabilize an otherwise unstable system.
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PMID:Integral rein control in physiology II: a general model. 1096 58

This paper discusses the use of constitutively active G-protein-coupled receptor systems for drug discovery. Specifically, the ternary complex model is used to define the two major theoretical advantages of constitutive receptor screening-namely, the ability to detect antagonists as well as agonists directly and the fact that constitutive systems are more sensitive to agonists. In experimental studies, transient transfection of Chinese hamster ovary cyclic AMP response element (CRE) luciferase reporter cells with cDNA for human parathyroid hormone receptor, glucagon receptor, and glucagon-like peptide (GLP-1) receptor showed cDNA concentration-dependent constitutive activity with parathyroid hormone (PTH-1) and glucagon. In contrast, no constitutive activity was observed for GLP-1 receptor, yet responses to GLP-1 indicated that receptor expression had taken place. In another functional system, Xenopus laevi melanophores transfected with cDNA for human calcitonin receptor showed constitutive activity. Nine ligands for the calcitonin receptor either increased or decreased constitutive activity in this assay. The sensitivity of the system to human calcitonin increased with increasing constitutive activity. These data indicate that, for those receptors which naturally produce constitutive activity, screening in this mode could be advantageous over other methods.
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PMID:Constitutive receptor systems for drug discovery. 1103 35

Glucagon binding to hepatocytes has been known for a long time to not only stimulate intracellular cAMP accumulation but also, intriguingly, induce a significant release of liver-borne cAMP in the blood. Recent experiments have shown that the well-documented but ill-understood natriuretic and phosphaturic actions of glucagon are actually mediated by this extracellular cAMP, which inhibits the reabsorption of sodium and phosphate in the renal proximal tubule. The existence of this "pancreato-hepatorenal cascade" indicates that proximal tubular reabsorption is permanently influenced by extracellular cAMP, the concentration of which is most probably largely dependent on the insulin-to-glucagon ratio. The possibility that renal cAMP receptors may be involved in this process is supported by the fact that cAMP has been shown to bind to brush-border membrane vesicles. In other cell types (i.e., adipocytes, erythrocytes, glial cells, cardiomyocytes), cAMP eggress and/or cAMP binding have also been shown to occur, suggesting additional paracrine effects of this nucleotide. Although not yet identified in mammals, cAMP receptors (cARs) are already well characterized in lower eukaryotes. The amoeba Dictyostelium discoideum expresses four different cARs during its development into a multicellular organism. cARs belong to the superfamily of seven transmembrane domain G protein-coupled receptors and exhibit a modest homology with the secretin receptor family (which includes PTH receptors). However, the existence of specific cAMP receptors in mammals remains to be demonstrated. Disturbances in the pancreato-hepatorenal cascade provide an adequate pathophysiological understanding of several unexplained observations, including the association of hyperinsulinemia and hypertension, the hepatorenal syndrome, and the hyperfiltration of diabetes mellitus. The observations reviewed in this paper show that cAMP should no longer be regarded only as an intracellular second messenger but also as a first messenger responsible for coordinated hepatorenal functions, and possibly for paracrine regulations in several other tissues.
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PMID:Extracellular cAMP inhibits proximal reabsorption: are plasma membrane cAMP receptors involved? 1183 18

Twenty-one members of the secretin family (family 2) of G-protein-coupled receptors (GPCRs) were identified via directed cloning and data-mining of the Fugu Genome Consortium database, representing the most comprehensive description of secretin GPCRs in a teleost fish to date. Duplicated genes were identified for many of the family members, namely the receptors for pituitary adenylate cyclase-activating polypeptide (PACAP)/vasoactive intestinal peptide (VIP), calcitonin, calcitonin gene-related peptide (CGRP), growth hormone releasing hormone (GHRH), glucagon receptor/glucagon-like peptide (GLP) and parathyroid hormone-related peptide (PTHrP)/PTH. Mining of other teleost genomes (zebrafish and Tetraodon) revealed that the duplicated genes identified in the Takifugu genome were also present in these fish. Additional database searching of the Escherichia coli, yeast, Drosophila, Caenorhabditis elegans and Ciona genomes revealed that the family 2 of GPCRs were only present in the multicellular organisms. Orthologues of all the human secretin receptors were identified with the exception of secretin itself. Additional database searches in the Fugu Genome Consortium database also failed to reveal a secretin ligand and so it is hypothesised that both the receptor and the ligand evolved after the divergence of teleost/tetrapod lineages. Phylogenetic analysis at both the protein and the DNA level provided strong support for each of the individual receptor family groupings, but weak support between groups, making evolutionary inferences difficult. A more critical analysis of the PACAP/VIP receptor family confirmed previous hypotheses that the vasoactive intestinal peptide receptor (VPAC(1)R) gene is the ancestral form of the receptor.
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PMID:The secretin G-protein-coupled receptor family: teleost receptors. 1595 45

Albright hereditary osteodystrophy is caused by heterozygous inactivating mutations in GNAS, a gene that encodes not only the alpha-chain of Gs (Galphas), but also NESP55 and XLalphas through use of alternative first exons. Patients with GNAS mutations on maternally inherited alleles are resistant to multiple hormones such as PTH, TSH, LH/FSH, GHRH, and glucagon, whose receptors are coupled to Gs. This variant of Albright hereditary osteodystrophy is termed pseudohypoparathyroidism type 1a and is due to presumed tissue-specific paternal imprinting of Galphas. Previous studies have shown that mice heterozygous for a targeted disruption of exon 2 of Gnas, the murine homolog of GNAS, showed unique phenotypes dependent on the parent of origin of the mutated allele. However, hormone resistance occurred only when the disrupted gene was maternally inherited. Because disruption of exon 2 is predicted to inactivate Galphas as well as NESP55 and XLalphas, we created transgenic mice with disruption of exon 1 to investigate the effects of isolated loss of Galphas. Heterozygous mice that inherited the disruption maternally (-m/+) exhibited PTH and TSH resistance, whereas those with paternal inheritance (+/-p) had normal hormone responsiveness. Heterozygous mice were shorter and, when the disrupted allele was inherited maternally, weighed more than wild-type littermates. Galphas protein and mRNA expression was consistent with paternal imprinting in the renal cortex and thyroid, but there was no imprinting in renal medulla, heart, or adipose. These findings confirm the tissue-specific paternal imprinting of GNAS and demonstrate that Galphas deficiency alone is sufficient to account for the hormone resistance of pseudohypoparathyroidism type 1a.
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PMID:A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. 1609 56

Ghrelin is produced by A-like cells (ghrelin cells) in the mucosa of the acid-producing part of the stomach. The mobilization of ghrelin is stimulated by nutritional deficiency and suppressed by nutritional abundance. In an attempt to identify neurotransmitters and regulatory peptides that may contribute to the physiological, nutrient-related regulation of ghrelin secretion, we challenged the ghrelin cells in situ with a wide variety of candidate messengers, including known neurotransmitters (e.g. acetylcholine, catecholamines), candidate neurotransmitters (e.g. neuropeptides), local tissue hormones (e.g. serotonin, histamine, bradykinin, endothelin), circulating gut hormones (e.g. gastrin, CCK, GIP, neurotensin, PYY, secretin) and other circulating hormones/regulatory peptides (e.g. calcitonin, glucagon, insulin, PTH). Microdialysis probes were placed in the submucosa of the acid-producing part of the rat stomach. Three days later, the putative messenger compounds were administered via the microdialysis probe (reverse microdialysis) at a screening dose of 0.1 mmol l(-1) for regulatory peptides and 0.1 and 1 mmol l(-1) for amines and amino acids. The rats were awake during the experiments. The resulting microdialysate ghrelin concentration was monitored continuously for 3 h (radioimmunoassay), thereby revealing stimulators or inhibitors of ghrelin secretion. Dose-response curves were constructed for each candidate messenger that significantly (p<0.05) affected ghrelin mobilization at the screening dose. Peptides that showed a (non-significant) tendency to affect ghrelin release at the screening dose were also given at a dose of 0.3 or 1 mmol l(-1). Adrenaline, noradrenaline, endothelin and secretin stimulated ghrelin release, while somatostatin and GRP inhibited. Whether these agents act directly or indirectly on the ghrelin cells remains to be investigated. All other candidate messengers were without measurable effects, including acetylcholine, serotonin, histamine, GABA, aspartic acid, glutamic acid, glycine, VIP, PACAP, CGRP, substance P, NPY, PYY, PP, gastrin, CCK, GIP, insulin, glucagon, GLP and glucose.
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PMID:Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: a microdialysis study. 1757 35

Gastrointestinal hormones including gastric inhibitory polypeptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2 are secreted immediately after meal ingestion, and GIP and GLP-2 have been shown to regulate bone turnover. We hypothesize that endogenous GLP-1 may also be important for control of skeletal homeostasis. We investigated the role of GLP-1 in the regulation of bone metabolism using GLP-1 receptor knockout (Glp-1r(-/-)) mice. A combination of bone density and histomorphometry, osteoclast activation studies, biochemical analysis of calcium and PTH, and RNA analysis was used to characterize bone and mineral homeostasis in Glp-1r(-/-) and Glp-1r(+/+) littermate controls. Glp-1r(-/-) mice have cortical osteopenia and bone fragility by bone densitometry as well as increased osteoclastic numbers and bone resorption activity by bone histomorphometry. Although GLP-1 had no direct effect on osteoclasts and osteoblasts, Glp-1r(-/-) mice exhibited higher levels of urinary deoxypyridinoline, a marker of bone resorption, and reduced levels of calcitonin mRNA transcripts in the thyroid. Moreover, calcitonin treatment effectively suppressed urinary levels of deoxypyridinoline in Glp-1r(-/-), mice and the GLP-1 receptor agonist exendin-4 increased calcitonin gene expression in the thyroid of wild-type mice. These findings establish an essential role for endogenous GLP-1 receptor signaling in the control of bone resorption, likely through a calcitonin-dependent pathway.
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PMID:The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. 1803 76

It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear. Since GLP-1 is decreased in the latter condition, we evaluated some bone characteristics in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rat models compared to normal (N) and the effect of GLP-1 or saline (control) treatment (3 days by osmotic pump). Blood was taken before and after treatment for plasma measurements; tibiae and femora were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis. Compared to N, plasma glucose and insulin were, respectively, higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b were lower; phosphate in IR showed a tendency to be higher; PTH was not different in T2D and IR; all parameters were unchanged after GLP-1 infusion. Bone OC, osteoprotegerin (OPG) and RANKL mRNA were lower in T2D and IR; GLP-1 increased OC and OPG in all groups and RANKL in T2D. Compared to N, trabecular bone parameters showed an increased degree of anisotropy in T2D and IR, which was reduced after GLP-1. These findings show an insulin-independent anabolic effect of GLP-1 and suggest that GLP-1 could be a useful therapeutic agent for improving the deficient bone formation and bone structure associated with glucose intolerance.
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PMID:Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. 1921 81

The "J shape" curve linking the risk of poor bone health to alcohol intake is now well recognized from epidemiological studies. Ethanol and nonethanol components of alcoholic beverages could influence bone remodeling. However, in the absence of a solid underlying mechanism, the positive association between moderate alcoholic intake and BMD remains questionable because of confounding associated social factors. The objective of this work was to characterize the short-term effects of moderate alcohol consumption on circulating bone markers, especially those involved in bone resorption. Two sequential blood-sampling studies were undertaken in fasted healthy volunteers (age, 20-47 yr) over a 6-h period using beer of different alcohol levels (<0.05-4.6%), solutions of ethanol or orthosilicic acid (two major components of beer), and water +/- calcium chloride (positive and negative controls, respectively). Study 1 (24 subjects) assessed the effects of the different solutions, whereas study 2 (26 subjects) focused on ethanol/beer dose. Using all data in a "mixed effect model," we identified the contributions of the individual components of beer, namely ethanol, energy, low-dose calcium, and high-dose orthosilicic acid, on acute bone resorption. Markers of bone formation were unchanged throughout the study for all solutions investigated. In contrast, the bone resorption marker, serum carboxy terminal telopeptide of type I collagen (CTX), was significantly reduced after ingestion of a 0.6 liters of ethanol solution (>2% ethanol; p <or= 0.01, RM-ANOVA), 0.6 liters of beer (<0.05-4.6% ethanol; p < 0.02), or a solution of calcium (180 mg calcium; p < 0.001), but only after calcium ingestion was the reduction in CTX preceded by a significant fall in serum PTH (p < 0.001). Orthosilicic acid had no acute effect. Similar reductions in CTX, from baseline, were measured in urine after ingestion of the test solutions; however, the biological variability in urine CTX was greater compared with serum CTX. Modeling indicated that the major, acute suppressive effects of moderate beer ingestion (0.6 liters) on CTX were caused by energy intake in the early phase (approximately 0-3 h) and a "nonenergy" ethanol component in the later phase (approximately 3 to >6 h). The early effect on bone resorption is well described after the intake of energy, mediated by glucagon-like peptide-2, but the late effect of moderate alcohol ingestion is novel, seems to be ethanol specific, and is mediated in a non-calcitonin- and a non-PTH-dependent fashion, thus providing a mechanism for the positive association between moderate alcohol ingestion and BMD.
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PMID:Moderate ingestion of alcohol is associated with acute ethanol-induced suppression of circulating CTX in a PTH-independent fashion. 1925 29

Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [(125)I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25 degrees C; in these conditions, [(125)I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10(-6) M GLP-1. GLP-1, Ex-9, insulin or glucagon failed to modify cellular cAMP content, while GLP-2 and Ex-4 increased it. However, GLP-1 induced an immediate hydrolysis of glycosylphosphatidylinositols (GPIs) generating short-lived inositolphosphoglycans (IPGs), and an increase in phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) activities; Ex-4 also affected GPIs, but its action was delayed with respect to that of GLP-1. This incretin was found to decrease Runx2 but increased osteocalcin gene expression, without affecting that of osteoprotegerin or the canonical Wnt pathway activity in MC3T3-E1 cells which do not express the pancreatic GLP-1 receptor. Our data demonstrate for the first time that GLP-1 can directly and functionally interact with osteoblastic cells, possibly through a GPI/IPG-coupled receptor.
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PMID:Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. 2050 94


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