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

The GLP-1 receptor (GLP-1R) mediates the insulinotropic effects of the incretion hormone glucagon-like peptide 1 (7-36) amide (GLP-1). Recently, we cloned the 5'-flanking region of the human GLP-1R gene. To characterize tissue- and cell-specific cis-regulatory elements, we constructed a series of 5'-deletions of the promoter. The activity of these constructs was tested in different cell lines. An element with high homology to PS1 was found to repress GLP-1R promoter activity in fibroblasts and pancreatic D-cells, but was not active in pancreatic A- and B-cells. PS1 was described to inhibit activation of a D-cell-specific enhancer. Cloning the PS1-like element upstream a heterologous promoter (SV40) revealed that it is functionally active independently from this enhancer. Our data suggest that basal activity of the GLP-1R promoter is silenced in a tissue- and cell-specific manner by negatively acting cis-regulatory elements, including a PS1-like element.
 ...
PMID:Contribution of a PS1-like element to the tissue- and cell-specific expression of the human GLP-1 receptor gene. 978 71

The genomic organization of the human gene encoding the receptor for glucagon-like peptide-1 (GLP-1 (7-37)/(7-36) amide) was analyzed to reveal the relationship to other G-protein-coupled receptors. The coding sequence of the GLP-1 receptor is interrupted by 12 introns. These introns are uniformly distributed within the open reading frame. The length of the introns varies between 6.6 kb and 100 bp, in contrast to the relative constant length of 100 bp of the exons. All of the exon/intron splice junctions characterized followed the consensus GT-AG rule. A comparison of the genomic structure with other related receptor genes indicates that the exon/intron organization is well-conserved among the VIP/ glucagon/secretin receptor family.
 ...
PMID:The genomic organization of the human GLP-1 receptor gene. 979 62

The insulinotropic hormone, glucagon-like peptide 1 (GLP-1), which has been proposed as a new treatment for type 2 diabetes, is metabolized extremely rapidly by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP-IV), resulting in the formation of a metabolite, which may act as an antagonist at the GLP-1 receptor. Because of this, the effects of single injections of GLP-1 are short-lasting, and for full demonstration of its antidiabetogenic effects, continuous intravenous infusion is required. To exploit the therapeutic potential of GLP-1 clinically, we here propose the use of specific inhibitors of DPP-IV. We have demonstrated that the administration of such inhibitors may completely protect exogenous GLP-1 from DPP-IV-mediated degradation, thereby greatly enhancing its insulinotropic effect, and provided evidence that endogenous GLP-1 may be equally protected. Preliminary studies by others in glucose-intolerant experimental animals have shown that DPP-IV inhibition greatly ameliorates the condition. GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on the beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and slowing of gastric emptying, all of which contribute to normalizing elevated glucose levels. Because of this, we predict that inhibition of DPP-IV, which will elevate the levels of active GLP-1 and reduce the levels of the antagonistic metabolite, may be useful to treat impaired glucose tolerance and perhaps prevent transition to type 2 diabetes. The actions of DPP-IV, other than degradation of GLP-1, particularly in the immune system are discussed, but it is concluded that side effects of inhibition therapy are likely to be mild. Thus, DPP-IV inhibition may be an effective supplement to diet and exercise treatment in attempts to prevent the deterioration of glucose metabolism associated with the Western lifestyle.
 ...
PMID:Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. 979 33

The effect of exendin-(9-39), a described antagonist of the glucagon-like peptide-1 (GLP-1) receptor, was evaluated on the formation of cAMP- and glucose-stimulated insulin secretion (GSIS) by the conditionally immortalized murine betaTC-Tet cells. These cells have a basal intracellular cAMP level that can be increased by GLP-1 with an EC50 of approximately 1 nM and can be decreased dose dependently by exendin-(9-39). This latter effect was receptor dependent, as a beta-cell line not expressing the GLP-1 receptor was not affected by exendin-(9-39). It was also not due to the endogenous production of GLP-1, because this effect was observed in the absence of detectable preproglucagon messenger RNA levels and radioimmunoassayable GLP-1. Importantly, GSIS was shown to be sensitive to this basal level of cAMP, as perifusion of betaTC-Tet cells in the presence of exendin-(9-39) strongly reduced insulin secretion. This reduction of GSIS, however, was observed only with growth-arrested, not proliferating, betaTC-Tet cells; it was also seen with nontransformed mouse beta-cells perifused in similar conditions. These data therefore demonstrated that 1) exendin-(9-39) is an inverse agonist of the murine GLP-1 receptor; 2) the decreased basal cAMP levels induced by this peptide inhibit the secretory response of betaTC-Tet cells and mouse pancreatic islets to glucose; 3) as this effect was observed only with growth-arrested cells, this indicates that the mechanism by which cAMP leads to potentiation of insulin secretion is different in proliferating and growth-arrested cells; and 4) the presence of the GLP-1 receptor, even in the absence of bound peptide, is important for maintaining elevated intracellular cAMP levels and, therefore, the glucose competence of the beta-cells.
 ...
PMID:Exendin-(9-39) is an inverse agonist of the murine glucagon-like peptide-1 receptor: implications for basal intracellular cyclic adenosine 3',5'-monophosphate levels and beta-cell glucose competence. 979 51

Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.
 ...
PMID:A synthetic glucagon-like peptide-1 analog with improved plasma stability. 979 46

Glucagon-like peptide-1 (GLP-1) is derived from the peptide precursor pre-pro-glucagon (PPG) by enzymatic cleavage and acts via its receptor, glucagon-like peptide-1 receptor (GLP-1R). By using riboprobes complementary to PPG and GLP-1R, we described the distribution of PPG and GLP-1R messenger RNAs (mRNAs) in the central nervous system of the rat. PPG mRNA-expressing perikarya were restricted to the nucleus of the solitary tact or to the dorsal and ventral medulla and olfactory bulb. GLP-1R mRNA was detected in numerous brain regions, including the mitral cell layer of the olfactory bulb; temporal cortex; caudal hippocampus; lateral septum; amygdala; nucleus accumbens; ventral pallium; nucleus basalis Meynert; bed nucleus of the stria terminalis; preoptic area; paraventricular, supraoptic, arcuate, and dorsomedial nuclei of the hypothalamus; lateral habenula; zona incerta; substantia innominata; posterior thalamic nuclei; ventral tegmental area; dorsal tegmental, posterodorsal tegmental, and interpeduncular nuclei; substantia nigra, central gray; raphe nuclei; parabrachial nuclei; locus ceruleus, nucleus of the solitary tract; area postrema; dorsal nucleus of the vagus; lateral reticular nucleus; and spinal cord. These studies, in addition to describing the sites of GLP-1 and GLP-1R synthesis, suggest that the efferent connections from the nucleus of the solitary tract are more widespread than previously reported. Although the current role of GLP-1 in regulating neuronal physiology is not known, these studies provide detailed information about the sites of GLP-1 synthesis and potential sites of action, an important first step in evaluating the function of GLP-1 in the brain. The widespread distribution of GLP-1R mRNA-containing cells strongly suggests that GLP-1 not only functions as a satiety factor but also acts as a neurotransmitter or neuromodulator in anatomically and functionally distinct areas of the central nervous system.
 ...
PMID:Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. 988 47

This study was designed to gain better insight into the relationship between glucagon-like peptide-1 (GLP-1) (7-36) amide and vasopressin (AVP) and oxytocin (OX). In situ hybridization histochemistry revealed colocalization of the mRNAs for GLP-1 receptor, AVP, and OX in neurons of the hypothalamic supraoptic and paraventricular nuclei. To determine whether GLP-1(7-36)amide alters AVP and/or OX release, both in vivo and in vitro experimental study designs were used. In vivo, intravenous administration of 1 microg of GLP-1(7-36)amide into the jugular vein significantly decreased plasma AVP and OX concentrations. In vitro incubation of the neurohypophysis with either 0.1 or 1 microg of GLP-1(7-36)amide did not modify the release of AVP. However, addition of 1 microg of GLP-1(7-36)amide to the incubation medium increased slightly the secretion of OX. The coexpression of GLP-1 receptor and AVP mRNAs in hypothalamic supraoptic and paraventricular nuclei gives further support to the already reported central effects of GLP-1 (7-36)amide on AVP. Our findings also suggest a dual secretory response of AVP and OX to the effect of GLP-1 (7-36)amide, which most likely is related to the amount and/or the route of peptide administration.
 ...
PMID:Coexpression of glucagon-like peptide-1 (GLP-1) receptor, vasopressin, and oxytocin mRNAs in neurons of the rat hypothalamic supraoptic and paraventricular nuclei: effect of GLP-1(7-36)amide on vasopressin and oxytocin release. 988 49

Central nervous system glucagon-like peptide-1-(7-36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (i.c.v.) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9-39), affects food intake and body weight. Daily i.c.v. injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 +/- 5 g (P < 0.02 compared with saline-injected controls). Daily i.c.v. administration of 30 nmol exendin-(9-39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 +/- 2 g (P < 0.02 compared with saline-injected controls). Twice daily i.c.v. injections of 30 nmol exendin-(9-39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 +/- 4 g compared with 14 +/- 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to i.c.v. GLP-1 or exendin-(9-39). GLP-1 may thus be involved in the regulation of body weight in the rat.
 ...
PMID:Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. 988 31

The human glucagon-like peptide-1 (GLP-1) receptor mediates the insulinotropic effects of the incretin hormone GLP-1. It is expressed in a cell- and tissue-specific manner. Recently, we cloned the 5'-region of the GLP-1 receptor gene and found that tissue and cell specificity is lost by 5'-deletion to -574. In this region proximal to the main transcription start point three putative binding sites for Sp1 were localized. Now, in vitro binding of Sp1 was shown by deoxyribonuclease footprint analysis with DNA fragments using either recombinant Sp1 or nuclear extracts from HIT cells. To elucidate the roles of the three Sp1-binding sites, we mutated each of the sites individually as well as in different combinations. The activity of each construct was analyzed in comparison to the wild-type promoter. Mutation of two adjacent Sp1-binding sites showed a clear reduction of activity. Contrasting results were obtained after mutation of the third, more distal Sp1-binding site. Here, a clear increase (approximately 150%) revealed a silencing effect of this cis-regulatory element, possibly resembling a Sp3-binding site. Electrophoretic mobility shift analysis revealed binding of Sp1 and Sp3, which was demonstrated by supershifts using specific antibodies. Cotransfection with Sp1 and Sp3 expression vectors in insect cells lacking endogenous Sp factors clearly demonstrated the involvement of Sp1 and Sp3. Therefore, the basal activity of the GLP-1 receptor gene is mediated by two proximal Sp1-binding sites, whereas a more distal site acts as a repressor.
 ...
PMID:Gene expression of the human glucagon-like peptide-1 receptor is regulated by Sp1 and Sp3. 992 86

Glucagon-like peptide-1 is the main hormonal mediator of the enteroinsular axis. Recently, it has additionally received considerable attention as a possible new treatment for Type II (non-insulin-dependent) diabetes mellitus. Its major disadvantage is that its duration of action is too short to achieve good 24-h metabolic control. Exendin-4, which is produced in the salivary glands of Gila monster lizards, is structurally similar to glucagon-like peptide-1 and shares several useful biological properties with glucagon-like peptide-1. It binds the glucagon-like peptide-1 receptor, stimulates insulin release and increases the cAMP production in beta cells. We report that exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagon-like peptide-1 (ED50 0.19 nmol/kg for glucagon-like peptide-1 vs 0.0143 nmol/kg for exendin-4) and causes a greater elevation in cAMP concentrations in isolated islets. Of even greater interest we found that when given intraperitoneally only once daily to diabetic mice it had a prolonged effect of lowering blood glucose. After 1 week of treatment blood glucoses were 5.0+/-2.6 mmol/l compared to diabetic concentrations of 13.2+/-2.8 mmol/l. After 13 weeks of daily treatment HbA1c was 8.8+/-0.4% in non-treated diabetic animals compared with 4.7+/-0.25% in treated diabetic animals. Blood glucoses also were lower (p < 0.005) and insulin concentrations higher (p < 0.02) in the treated animals. Exendin-4 could therefore be preferable to glucagon-like peptide-1 as a long-term treatment of Type II diabetes.
 ...
PMID:Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. 1002 77


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>