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 combined actions of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) may fully account for the incretin effect. These hormones are released from the small intestine in response to oral glucose and stimulate insulin release. Recently, evidence has been provided demonstrating the degradation of GIP-(1-42) and GLP-1-(7-36)NH2 by the serum enzyme dipeptidyl peptidase IV (DPP IV) into the biologically inactive products GIP-(3-42) and GLP-1-(9-36)NH2. The objective of the current investigation was to develop a method to monitor the degradation of these hormones in vivo. Synthetic peptides were radiolabeled and purified by HPLC. Subsequent degradation of the peptides under various conditions was then monitored by further HPLC analysis. Incubation of [125I]GIP-(1-42) or [125I]GLP-1-(7-36)NH2 with Wistar rat serum or purified DPP IV resulted in the major N-terminal-truncated products [125I]GIP-(3-42) and [125I]GLP-1-(9-36)NH2. These products were significantly reduced when the specific DPP IV inhibitor diprotin A was included in the incubation mixture and were absent when serum from DPP IV-deficient rats was used. When the labeled peptides were infused into rats at hormone levels within the physiological range, over 50% was metabolized to the truncated forms within 2 min. These products were absent when the tracers were infused into DPP IV-deficient animals. It is concluded that DPP IV may be a primary inactivating enzyme of both GIP and tGLP-1 in vivo. As the N-terminal-truncated products of the DPP IV cleavage may not be distinguished from the biologically active hormone by currently employed assays, reports of circulating hormone levels should be reconsidered. The method described in this manuscript may be useful for investigating the durations of action of GIP and tGLP-1 in normal and pathophysiological conditions.
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PMID:Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. 762 97

Dipeptidyl peptidase IV (DP IV:EC 3.4.14.5) was localized in endocrine cells of pig pancreas by immunohistochemical and enzyme histochemical methods. Immunolight microscopy with both monoclonal and polyclonal antibodies demonstrated DP IV immunoreactivity in cells located in the peripheral part of the islets of Langerhans. The antigen is enzymatically active, as shown by enzyme histochemical analysis with a synthetic DP IV substrate. By immunoelectron microscopy (immunogold labeling), the labeling of DP IV in the islets was associated with the secretory granules of the A-cells, as identified by double labeling using a monoclonal glucagon antibody as the second primary antibody. These results show that DP IV is sorted to secretory granules in the pig pancreatic islet A-cells. Furthermore, this secretory granule enzyme, as opposed to intestinal brush border DP IV, is suggested to be a soluble protein, since the gold particles appear all over the granules and are not specifically associated with the granule membrane.
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PMID:Dipeptidyl peptidase IV is sorted to the secretory granules in pancreatic islet A-cells. 809 56

Peptides of the glucagon/vasoactive-intestinal-peptide (VIP) peptide family share a considerable sequence similarity at their N-terminus. They either start with Tyr-Ala, His-Ala or His-Ser which might be in part potential targets for dipeptidyl-peptidase IV, a highly specialized aminopeptidase removing dipeptides only from peptides with N-terminal penultimate proline or alanine. Growth-hormone-releasing factor (1-29)amide and gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) with terminal Tyr-Ala as well as glucagon-like peptide-1(7-36)amide/insulinotropin [GLP-1(7-36)amide] and peptide histidine methionine (PHM) with terminal His-Ala were hydrolysed to their des-Xaa-Ala derivatives by dipeptidyl-peptidase IV purified from human placenta. VIP with terminal His-Ser was not significantly degraded by the peptidase. The kinetics of the hydrolysis of GIP, GLP-1(7-36)amide and PHM were analyzed in detail. For these peptides Km values of 4-34 microM and Vmax values of 0.6-3.8 mumol.min-1.mg protein-1 were determined for the purified peptidase which should allow their enzymic degradation also at physiological, nanomolar concentrations. When human serum was incubated with GIP or GLP-1(7-36)amide the same fragments as with the purified dipeptidyl-peptidase IV, namely the des-Xaa-Ala peptides and Tyr-Ala in the case of GIP or His-Ala in the case of GLP-1(7-36)amide, were identified as the main degradation products of these peptide hormones. Incorporation of inhibitors specific for dipeptidyl-peptidase IV, 1 mM Lys-pyrrolidide or 0.1 mM diprotin A (Ile-Pro-Ile), completely abolished the production of these fragments by serum. It is concluded that dipeptidyl-peptidase IV initiates the metabolism of GIP and GLP-1(7-36)amide in human serum. Since an intact N-terminus is obligate for the biological activity of the members of the glucagon/VIP peptide family [e. g. GIP(3-42) is known to be inactive to release insulin in the presence of glucose as does intact GIP], dipeptidyl-peptidase-IV action inactivates these peptide hormones. The relevance of this finding for their inactivation and their determination by immunoassays is discussed.
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PMID:Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. 810 May 23

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

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

Species-specific differences in the enzymatic inactivation of peptides is an important consideration in the evaluation of therapeutic efficacy. We demonstrate that glucagon-like peptide 2 (GLP-2), shown to be highly intestinotrophic in mice, promotes an increase in intestinal villus height but has no trophic effect on small bowel weight in rats. The reduced intestinotrophic activity of GLP-2 in rats is attributable to inactivation by the enzyme dipeptidyl peptidase IV (DPP-IV). GLP-2(1-33) was degraded to GLP-2(3-33) following incubation with human placental DPP-IV or rat serum but not by serum from DPP-IV-deficient rats. Administration of rat GLP-2 to DPP-IV-deficient rats was associated with markedly increased bioactivity of rat GLP-2 resulting in a significant increase in small bowel weight. A synthetic GLP-2 analog, r[Gly2]GLP-2, with an alanine to glycine substitution at position 2, was resistant to cleavage by both DPP-IV and rat serum in vitro. Treatment of wild-type rats with r[Gly2]GLP-2 produced a statistically significant increase in small bowel mass. DPP-IV-mediated inactivation of GLP-2 is a critical determinant of the growth factor-like properties of GLP-2.
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PMID:Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV. 921 72

Glucagon-like peptide-2 (GLP-2) stimulates small intestinal growth through induction of intestinal epithelial proliferation. To examine the physiology of GLP-2-induced bowel, mice were treated with GLP-2 (2.5 micrograms) or vehicle for 10 days. Small intestinal weight increased to 136 +/- 2% of controls in GLP-2-treated mice, in parallel with 1.4 +/- 0.1- and 1.9 +/- 0.5-fold increments in duodenal RNA and protein content, respectively (P < 0.05-0.001). Similarly, the activities of duodenal maltase, sucrase, lactase, glutamyl transpeptidase, and dipeptidyl-peptidase IV (215 +/- 28% of controls; P < 0.001) were increased by GLP-2. Oral or duodenal administration of glucose or maltose did not reveal any differences in the ability of GLP-2-treated mice to absorb these nutrients, possibly because of decreases in expression of the glucose transporters sodium-dependent glucose transporter-1 (SGLT-1) and GLUT-2. In contrast, absorption of leucine plus triolein was increased after duodenal administration in GLP-2-treated mice (P < 0.01-0.001). Finally, GLP-2 did not alter other markers of intestinal or pancreatic gene expression, including levels of mRNA transcripts for ornithine decarboxylase, multidrug resistance gene, amylase, proglucagon, proinsulin, and prosomatostatin. Thus induction of intestinal growth by GLP-2 in wild-type mice results in a normal-to-increased capacity for nutrient digestion and absorption in vivo.
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PMID:Intestinal function in mice with small bowel growth induced by glucagon-like peptide-2. 922 51

A dipeptidyl-peptidase IV was purified from the culture medium of the human-pathogenic fungus Aspergillus fumigatus. The enzyme has an apparent molecular mass of 95 kDa and contained approximately 10 kDa of N-linked carbohydrate. This glycoprotein is antigenic and has all characteristics of the class IV dipeptidyl-peptidases: removal of Xaa-Pro and to a lesser extent Xaa-Ala dipeptides from the N termini of peptides, including bioactive peptides such as neuropeptide Y, [des-Arg1] bradykinin, and glucagon-like peptide 1, activity at neutral pH, and presence in the amino acid sequence of the Gly-X-Ser-X-Gly consensus motif of the serine-hydrolases and the putative catalytic triad (Ser613, Asp690, His725) of the dipeptidyl-peptidases. Moreover, the last 200 amino acids displayed 60 to 65% similarity with the other dipeptidyl-peptidases IV from rat, mouse, human, and yeast. However, unlike the other dipeptidyl-peptidases, the dipeptidyl-peptidase IV of A. fumigatus is a secreted enzyme with a cleavable signal peptide. Expression of a recombinant dipeptidyl-peptidase IV of A. fumigatus has been attained in the yeast Pichia pastoris.
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PMID:Dipeptidyl-peptidase IV secreted by Aspergillus fumigatus, a fungus pathogenic to humans. 923 52

The control of intestinal epithelial growth is regulated by interactions of growth factors in various cellular compartments of the small and large bowel. Little information is available on the intestinal growth response to combinations of growth factors. We studied the intestinotrophic properties of a dipeptidyl peptidase IV resistant glucagon-like peptide 2 (GLP-2) analog, human [Gly2]GLP-2 (h[Gly2]GLP-2), as well as of epidermal growth factor (EGF), long [Arg3]insulin-like growth factor I (LR3IGF-I), [Gly1]IGF-II, and human growth hormone (hGH), administered by subcutaneous injection alone or in combination in mice. At the doses tested, h[Gly2]GLP-2 was the most potent agent for increasing small and large bowel mass. Mice treated with h[Gly2]GLP-2 and either GH or IGF-I exhibited greater increases in histological parameters of small intestinal growth than did mice treated with h[Gly2]GLP-2 alone. Administration of all five growth factors together induced significant increases in crypt plus villus height and in small and large bowel length and weight. The results of these experiments define regional differences in both the cellular targets and relative activities of intestinotrophic molecules and raise the possibility that selective growth factor combinations may be useful for enhancement of intestinal adaptation in vivo.
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PMID:Intestinal response to growth factors administered alone or in combination with human [Gly2]glucagon-like peptide 2. 943 50

Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vivo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p < 0.01), but these did not exceed the C-terminal t1/2 (intact plus metabolite: analogues, 3.5-4.4 min; GLP-1 (7-36) amide, 4.1 min). Analogues were assessed for receptor binding using a cell line expressing the cloned receptor, and for ability to stimulate insulin or inhibit glucagon secretion from the isolated perfused porcine pancreas. All bound to the receptor, but only the Aib8 and Gly8 analogues had similar affinities to GLP-1 (7-36) amide (IC50; Aib8=0.45 nmol/l; Gly8=2.8 nmol/l; GLP-1 (7-36) amide=0.78 nmol/l). All analogues were active in the isolated pancreas, with the potency order reflecting receptor affinities (Aib8 > Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically active and have prolonged metabolic stability in vivo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy.
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PMID:Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. 954 Nov 66


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