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 incretins glucose-dependent insulinotropic polypeptide (GIP1-42) and glucagon-like peptide-1-(7-36)-amide (GLP-17-36), hormones that potentiate glucose-induced insulin secretion from the endocrine pancreas, are substrates of the circulating exopeptidase dipeptidyl peptidase IV and are rendered biologically inactive upon cleavage of their N-terminal dipeptides. This study was designed to determine if matrix-assisted laser desorption/ionization-time of flight mass spectrometry is a useful analytical tool to study the hydrolysis of these hormones by dipeptidyl peptidase IV, including kinetic analysis. Spectra indicated that serum-incubated peptides were cleaved by this enzyme with only minor secondary degradation due to other serum protease activity. Quantification of the mass spectrometric signals allowed kinetic constants for both porcine kidney- and human serum dipeptidyl peptidase IV-catalyzed incretin hydrolysis to be calculated. The binding constants (Km) of these incretins to purified porcine kidney-derived enzyme were 1.8 +/- 0.3 and 3.8 +/- 0.3 microM, whereas the binding constants observed in human serum were 39 +/- 29 and 13 +/- 9 microM for glucose-dependent-insulinotropic polypeptide and glucagon-like peptide-1-(7-36)-amide respectively. The large range of Km values found in human serum suggests a heterogeneous pool of enzyme. The close correlation between the reported kinetic constants and those previously described validates this novel approach to kinetic analysis.
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PMID:Investigation of glucose-dependent insulinotropic polypeptide-(1-42) and glucagon-like peptide-1-(7-36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A novel kinetic approach. 879 18

The effect of gastric inhibitory polypeptide (GIP) and the related glucagon-like peptides-1 and -2 (GLP-1 and GLP-2) on jejunal basolateral membrane glucose transport was investigated to determine if the upregulation produced by luminal hexoses could be explained by the release of one or more of these peptides. Luminal perfusion of the rat jejunum for 4 h, under pentobarbital sodium anesthesia, with 100 mM D-glucose produced a significant increase in plasma GIP levels. Vascular infusion of saline containing 100-800 pM GIP also increased the maximal transport rate for carrier-mediated glucose uptake in jejunal basolateral membrane vesicles. The effect of vascular 400 pM GIP was maximal after 1 h and maintained out to 4 h. The effect of luminal glucose could be blocked by preinjection with anti-GIP antibodies, whereas an antineurotensin antibody had no effect. Vascular infusion with 800 pM GLP-1-(7-36) amide had no effect, but GLP-2 (400 and 800 pM) increased the D-glucose maximal transport rate. An anti-GLP antibody was able to block the response to luminal glucose.
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PMID:The effect of GIP and glucagon-like peptides on intestinal basolateral membrane hexose transport. 884 73

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and mediates its actions via the cyclic AMP (cAMP) pathway. The GLP-I receptor belongs to the family of seven-transmembrane domain receptors coupled to G proteins. We have analyzed the regulation of GLP-I receptor function and expression by its own ligand and the cAMP-dependent pathway in rat insulinoma-derived beta cells (RINm5F). The GLP-I receptor underwent rapid homologous desensitization, which occurred at the receptor level. This was characterized by a reduced binding capacity not mediated by protein kinase A (PKA). GLP-I receptor mRNA levels were down-regulated during incubation of cells by agents increasing cAMP levels including GLP-I itself. This effect was dependent upon time and concentration. Forskolin, the PKA activator 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3, 5-monophosphorothiotate, and GLP-I stabilized the GLP-I receptor mRNA. All induced down-regulation of the GLP-I receptor number within 3 h, a time point at which GLP-I receptor mRNA levels were not decreased. This effect was not influenced by cycloheximide. Therefore, in addition to transcriptional effects, posttranslational mechanisms exist to regulate GLP-I receptor numbers in insulin-secreting cells.
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PMID:Ligand-induced regulation of glucagon-like peptide-I receptor function and expression in insulin-secreting beta cells. 888 49

Glucagon-like peptide-I (GLP-I) is an important insulinotropic incretin hormone. The GLP-I receptor belongs to the family of seven transmembrane domain receptors. We studied the regulation of its expression by the protein kinase C (PKC)-dependent pathway in rat insulinoma RINm5F cells. Cells were incubated for 3, 6 and 24 h with an optimal concentration of tissue plasminogen activator (TPA), an activator of PKC. TPA induced significantly lower GLP-I receptor mRNA levels under steady-state conditions after 6 and 24 h. The stability of the GLP-I receptor mRNA was unchanged. The number of GLP-I receptors present on RINm5F cells was reduced after 6 and 24 h. TPA did not influence the affinity of remaining receptors to its specific ligand. These data indicate that PKC activation downregulates the expression of the GLP-I receptor gene, mainly at the transcriptional level.
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PMID:Regulation of glucagon-like peptide-I receptor expression and transcription by the protein kinase C pathway. 890 97

Evidence has accumulated that the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1(7-36) amide) are degraded and rendered biologically inactive in plasma by the enzyme dipeptidyl peptidase IV (DPIV). A strain of Fischer rats lacking the DPIV enzyme were used in the current investigation as a model for examining the enteroinsular axis under conditions in which normal inactivation of GIP and GLP-1(7-36) does not occur. This was assessed by comparing GIP and GLP-1(7-36) responses following oral glucose in normal versus DPIV-deficient Fischer rats, and by comparing the insulinotropic potency of both peptides in the perfused pancreas of both groups. The insulin response to an oral glucose challenge was decreased slightly in DPIV-negative rats compared with control animals. Of the two incretins, the GIP response to oral glucose was reduced by 50% compared with controls, whereas GLP-1(7-36) release in response to glucose was unchanged. A decrease of 30% in the sensitivity of the perfused pancreas of DPIV-negative rats to GIP was observed, whereas the insulin response to GLP(7-36) was identical in both groups. Incubation of both peptides in plasma from DPIV-positive and -negative rats was performed to determine the effect of the presence or absence of DPIV on the insulinotropic activity of GLP-1(7-36) and GIP in the isolated perfused rat pancreas. Incubation in plasma from DPIV-positive rats resulted in a 65% decrease in insulinotropic activity of both incretins compared with incubation in plasma from DPIV-deficient rats. It was hypothesized that the reduced GIP response and decreased sensitivity of the pancreas to GIP are compensatory mechanisms that maintain insulin and glucose levels within a normal range despite abnormal degradation of GIP. An explanation of the lack of effect of the absence of DPIV on the GLP-1(7-36) response to oral glucose and insulinotropic action of this peptide must await further study.
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PMID:The enteroinsular axis in dipeptidyl peptidase IV-negative rats. 893 36

The mechanisms by which glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion were investigated by measurements of whole-cell Ca2+ currents, the cytoplasmic Ca2+ concentration, and cell capacitance as an indicator of exocytosis in individual mouse pancreatic beta-cells maintained in short-term culture. GIP produced a 4.2-fold potentiation of depolarization-induced exocytosis. This stimulation of exocytosis was not associated with a change in the whole-cell Ca2+-current, and there was only a small increase (30%) in the cytoplasmic Ca2+ concentration [intercellular free Ca2+([Ca2+]i)]. The stimulatory effect of GIP on exocytosis was blocked by pretreatment with the specific protein kinase A (PKA) inhibitor Rp-8-Br-cAMPS. Glucagon-like peptide-I(7-36) amide (GLP-I) stimulated exocytosis (90%) in the presence of a maximal GIP concentration (100 nmol/l). Replacement of GLP-I with forskolin produced a similar stimulatory action on exocytosis. These effects of GLP-I and forskolin in the presence of GIP did not involve a change in the whole-cell Ca2+-current or [Ca2+]i. GIP was ineffective in the presence of both forskolin and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Under the same experimental conditions, the protein kinase C (PKC)-activating phorbol ester 4-phorbol 12-myristate 13-acetate (PMA) stimulated exocytosis (60%). Collectively, our data indicate that the insulinotropic hormone GIP stimulates insulin secretion from pancreatic beta-cells, through the cAMP/PKA signaling pathway, by interacting with the secretory machinery at a level distal to an elevation in [Ca2+]i.
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PMID:Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. 907 1

The distribution and identity of the various endocrine cell types were examined in the pancreas, stomach, and anterior intestine of the phylogenetically ancient actinopterygian, the gar (Lepisosteus osseus L.), using immunohistochemistry. Antisera used were directed against several insulins (INSs) and somatostatins (SSTs), and members of the pancreatic polypeptide (PP, aPY, NPY) and glucagon (GLUC, GLP) families. In the gar pancreas the most pronounced aggregation of islet tissue is among the exocrine acini near the union of extrahepatic common bile duct with the gastrointestinal junction. Four immunoreactive cell types were identified within well-defined islets (A, B, D, and F cells) but immunoreactive cell types were also seen isolated among the exocrine acini. Centrally located B cells were immunoreactive with mammalian and lamprey INS antisera whereas the widely dispersed D cells immunostained with anti-SST-14, -25, and -34. SST was also localized in the epithelium of the pancreatic ducts. There was a colocalization of immunoreactivity for each member of the PP and GLU families at the periphery of each islet to identify F and A cells, respectively. However, colocalization of peptides from both families is suspected for at least some cells. Although the gastric and intestinal mucosae showed a similar pattern of immunoreactivity to GLP and not GLU, they had contrasting immunoreactivity with the two INS antisera. SST immunoreactivity was restricted to the stomach, whereas three of the four PP-family peptides were only immunoreactive in the intestine. Immunoreactivity to the various antisera used in the study imply that there may be an organ-specific processing of preproinsulin, that the gar SST profile may be more similar to agnathan and bowfin rather than either elasmobranch or teleost SSTs, and that only the GLP portion of the preproglucagon gene is expressed in the gastrointestinal mucosa. Our results are consistent with other recent endocrine studies showing that the gar is a widely distinct actinopterygian.
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PMID:An immunohistochemical study of the endocrine cells within the pancreas, intestine, and stomach of the gar (Lepisosteus osseus L.) 912 60

Glucagon-like peptide I (GLP-I), an intestine-derived incretin hormone, is a potent stimulator of insulin and somatostatin secretion. In some studies, GLP-I is an inhibitor of glucagon secretion. It remains uncertain, however, whether the effect of GLP-I on the inhibition of glucagon secretion is direct, owing to interactions with GLP-I receptors on alpha-cells, or indirect, via paracrine suppression by insulin or somatostatin. The localization of the GLP-I receptor on insulin and somatostatin-producing cells in the islets is well established. Whether the GLP-I receptor also resides on the glucagon-producing alpha-cells remains controversial and is reported to be absent on rat alpha-cells. To investigate the distribution of the GLP-I receptor on islet cells, we examined the expression of GLP-I receptor mRNA in phenotypically distinct islet cell lines and islets, and the presence of immunoreactive GLP-I receptor in dispersed rat islet cells using a specific antiserum. GLP-I receptor mRNA was readily detected by reverse transcription-polymerase chain reaction (RT-PCR) in both rat islets and in established islet cell lines representing distinct alpha-, beta-, and delta-cell phenotypes. In addition, GLP-I receptor expression was detected in single rat alpha-cells by single-cell RT-PCR. In dispersed rat islet cells analyzed by double immunofluorescent staining, 90% of the insulin, 76% of the somatostatin, and 20% of the glucagon positive cells colocalized with the GLP-I receptor immunoreactivity. Thus, a substantial population of glucagon immunoreactive a-cells express the GLP-I receptor. These findings imply that GLP-I may have a direct receptor-mediated action in the regulation of the physiological functions on a substantial subpopulation of alpha-cells. We suggest that a possible role for GLP-I receptors on alpha-cells may be to provide positive autocrine feedback control on glucagon secretion during fasting and/or to dampen the potent paracrine suppression of glucagon secretion by insulin during feeding.
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PMID:Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. 913 45

High-resolution capacitance measurements were used to explore the effects of the gut hormones GLP-I(7-36) amide [glucagon-like peptide I(7-36) amide] and GIP (glucose-dependent insulinotropic polypeptide) on Ca2+-dependent exocytosis in glucagon-secreting rat pancreatic alpha-cells. Both peptides produced a greater than threefold potentiation of secretion evoked by voltage-clamp depolarizations, an effect that was associated with an approximately 35% increase of the Ca2+ current. The stimulatory actions of GLP-I(7-36) amide and GIP were mimicked by forskolin and antagonized by the protein kinase A (PKA)-inhibitor Rp-8-Br-cAMPS. The islet hormone somatostatin inhibited the stimulatory action of GLP-I(7-36) amide and GIP via a cyclic AMP-independent mechanism, whereas insulin had no effect on exocytosis. These data suggest that the alpha-cells are equipped with receptors for GLP-I and GIP and that these peptides, in addition to their well-established insulinotropic capacity, also stimulate glucagon secretion. We propose that the reported inhibitory action of GLP-I on glucagon secretion is accounted for by a paracrine mechanism (e.g., mediated by stimulated release of somatostatin that in turn suppresses exocytosis in the alpha-cell).
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PMID:Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. 913 46

To establish potential effects of glucagon-like peptide I (GLP-I) on blood glucose control in insulin-deficient states, GLP-I [GLP-I(7-36) amide; 10 pmol x kg(-1) x min(-1)] was infused intravenously in six fasting, canine C-peptide-negative, chronically diabetic dogs for 8 h. Blood samples were saved for the analysis of hormones, metabolites, and turnover rates of glucose (6-(3)H-glucose), alanine (U-(14)C-alanine), and urea ((15)N(2)-urea) starting 22 h after the last subcutaneous dose of exogenous insulin. Circulating plasma GLP-I levels rose under infusion from 2.9 +/- 0.8 to 41.4 +/- 10.1 pmol/l. This was efficient to significantly reduce the preexisting diabetic hyperglucagonemia. Since in the utilized model functioning pancreatic beta-cells are lacking, GLP-I had no insulinogenic effect. Compared with control experiments in the same animals receiving saline infusion, glycemia dropped from 20.8 +/- 1.9 to 16.2 +/- 1.0 mmol/l (P < 0.05). This was in parallel to the infusion of GLP-I and was most likely caused by a decrease of elevated glucose production since overall glucose turnover decreased with no alteration in glucose metabolic clearance. Alanine turnover was significantly reduced, obviously reflecting a decline in alanine production in relation to changed muscle glucose uptake under conditions of lower glycemia and overall glucose turnover. There was, however, neither an effect of GLP-I on alanine conversion into circulating glucose nor an effect on urea production rate, indicating unchanged gluconeogenesis from amino acid precursors. We conclude that the blood glucose-lowering effect of GLP-I in an animal model of insulinopenia was shown to be due to a reduction in hepatic glucose output, possibly secondary to reduction in glucagon concentrations leading to decreased glycogenolysis. Whether GLP-I might be therapeutically useful in clinical insulin-deficient diabetes needs to be verified.
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PMID:Blood glucose lowering and glucagonostatic effects of glucagon-like peptide I in insulin-deprived diabetic dogs. 913 50


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