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)

It is well known that oral administration of camostate induces hyperplasia and hypertrophy of the rat pancreas. It is not clear, however, whether pancreatic hormone and enzyme secretion are affected by camostate treatment. In rats, daily administration of 200 mg camostate/kg b. wt for 14 days significantly increased pancreatic weight and pancreatic content of DNA, protein, amylase, lipase, trypsin and chymotrypsin, as well as the amount of insulin, glucagon and somatostatin. In the intact animal, blood glucose levels and serum concentrations of insulin and glucagon in response to an oral glucose load were not impaired after camostate treatment. In the isolated perfused pancreas, however, insulin and glucagon secretions were reduced, whereas somatostatin release was not affected. The volume of pancreatic juice produced by the unstimulated isolated perfused organ, as well as protein and enzyme secretion, were increased after camostate treatment. Likewise, the isolated perfused pancreas from camostate-treated rats secreted a larger volume of pancreatic juice and more protein in response to cholecystokinin (CCK), while enzyme secretion was affected in a non-parallel manner: amylase release was markedly reduced, lipase release was unchanged, and release of trypsin and chymotrypsin was increased.
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PMID:Endocrine and exocrine pancreatic function after camostate-induced growth of the organ. 760 95

A periplasmic insulin-cleaving proteinase (ICP), purified to its electrophoretic homogeneity in the SDS-PAGE from the Gram-negative bacterium Acinetobacter calcoaceticus, was examined and compared in its properties with the protease III (protease Pi, pitrilysin, EC 3.4.99.44) of Escherichia coli and the insulin-destroying proteinase (IDE, insulinase, EC 3.4.99.45) from eucaryotes. The enzyme was proven to be a metalloprotease like protease III and IDE, as was shown by the inhibitory effects exerted by EDTA and o-phenanthroline. Furthermore, dialysis against EDTA and o-phenanthroline led to a complete loss of activity, which could be restored by addition of Co2+, and, to a lesser extent, but at a lower metal ion concentration by Zn2+. Similar to protease III and IDE, ICP prefers the cleavage of small polypeptides (insulin, insulin B-chain, glucagon) to the cleavage of proteins (casein, human serum albumin, globin) and was inactive against synthetic amino acid derivates (esters, p-nitranilides, and furoylacroleyl substrates) of subtilisin, thermolysin, trypsin, and chymotrypsin. The peptide-bond-specificity of the ICP in the cleavage of the oxidized insulin B-chain was investigated and the results were compared to the specificity of protease III of E. coli, IDE, protease-24,11, and thermolysin. Cleavage sites in the oxidized insulin B-chain generated by ICP are Asn3-Gln4, His10-Leu11, Ala14-Leu15, Leu17-Val18, Gly23-Phe24, Phe24-Phe25, and Phe25-Tyr26. Principally, ICP cleaves between hydrophobic amino acids and amides. The ICP shares one of the only two cleavage sites with the protease III and four sites with the IDE.
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PMID:A periplasmic insulin-cleaving proteinase (ICP) from Acinetobacter calcoaceticus sharing properties with protease III from Escherichia coli and IDE from eucaryotes. 773 84

Sixty-four kinds of cell lines were examined as to their ability to degrade glucagon using conditioned-media obtained from their protein-free cultures. Two human tumor cell lines were shown to produce this activity, and the cell line, HPC-YO, established from a human pancreatic carcinoma was shown to produce the highest level of activity. The glucagon-degrading enzyme (GDE) was purified from HPC-YO conditioned-medium by a combination of ion-exchange, gel filtration, and hydroxylapatite column chromatographies. The purified GDE also degraded vasoactive intestinal polypeptide (VIP) and secretin, however, it did not cleave EGF, gastrin, insulin, somatostatin, substance P, neurotensin, or growth hormone. The molecular weight of GDE is 83,000, as determined on SDS-polyacrylamide gel electrophoresis. The N-terminal amino acid sequence of GDE was blocked, and the five partial amino acid sequences obtained on lysyl-endopeptidase digestion were determined to be N-L-T-E-E-Y-D-V-S-D-G-E-I-E-L-L-Y-E-K, V-E-T-Y-Y-D-L-L-F-E-K, L-Y-W-F-L-D-E-A-K, S-N-S-T-S-Y-V-K, and Y-Y-A-S-T-S-Y-D-D-T-Y-K. The same or homologous amino acid sequences have not been found in known proteins, demonstrating that GDE is a novel peptidase that degrades the secretin family: glucagon, VIP, and secretin.
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PMID:A novel proteinase, glucagon-degrading enzyme, secreted by a human pancreatic cancer cell line, HPC-YO. 777 1

A novel trypsin-like serine proteinase was purified to homogeneity from the bovine pancreas microsome fraction. The enzyme was solubilized with 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propanesulfonate (CHAPS), and purified by a series of column chromatographic steps on Ultrogel AcA-34, trypsin inhibitor-Sepharose 4B, and arginine-Sepharose 4B. The molecular mass of this pancreas trypsin-like proteinase (bPTLP) was estimated to be 29.5 kDa by SDS-PAGE under reducing conditions. The NH2-terminal sequence of bPTLP is very homologous, but not identical to those of other serine proteinases, especially such as elastases IV, II, and III. Substrate specificity studies involving a synthetic substrate and glucagon indicated that the enzyme hydrolyzes Arg-X, Lys-X, and Leu-X bonds. The best synthetic substrate for bPTLP was t-butyloxycarbonyl Gln-Arg-Arg-4-methylcoumaryl 7-amide. The enzyme failed to hydrolyze the substrate for chymotrypsin and elastase. The enzyme activity was inhibited by diisopropyl fluorophosphate, p-amidinophenylmethane sulfonylfluoride, and leupeptin, indicating that it is a serine-proteinase. These findings show that bPTLP is a novel serine-proteinase which differs from all known proteinases. The physiological function of the enzyme has yet to be determined.
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PMID:Purification and characterization of a novel serine proteinase from the microsomal fraction of bovine pancreas. 890 82

Somatostatin is a potent inhibitor of endocrine and exocrine pancreatic secretion. However, it is not clear whether it also inhibits pancreatic growth. Therefore we treated male Wistar rats with a somatostatin analogue, octreotide (12-192 micrograms/(kg body wt.day)), over a period of 14 days. In a dose-dependent manner, this potent and long-acting analogue caused a reduction in weight of the pancreas and a reduction in pancreatic content of protein, DNA, trypsin, chymotrypsin, amylase and lipase, as well as pancreatic content of insulin-, glucagon- and somatostatin-like immunoreactivities. When growth of rat pancreas was induced by oral administration of camostate (200 mg/(kg body wt. day) or by subcutaneous administration of cholecystokinin (2 x 10 micrograms/(kg body wt. day)) over a period of 14 days, octreotide (12-192 micrograms/(kg body wt.day)) had the same effects, but these were even more pronounced. We conclude that somatostatin is an important regulator of pancreatic growth.
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PMID:Rat pancreas after long-term treatment with the somatostatin analogue octreotide. 896 3

Although clusters of pancreatic acinar cells (CPACs) have been reported in gastric mucosa of adults, they have not been described in children. We reviewed 283 pediatric gastric (239 antral and 44 corpus) mucosal biopsies during a 2-year period and detected CPACs in 10 antral biopsy samples. These biopsy samples were stained immunohistochemically for pancreatic exocrine markers (trypsin, chymotrypsin, alpha-amylase, and lipase) and a panel of regulatory substances (insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, and serotonin). Double immunostaining for colocalization of chromogranins and trypsin as well as mucin and trypsin also were performed on all cases. CPACs were seen in antral mucosa in a background of either normal or minimally inflamed mucosa, without any atrophy or metaplasia, and were positive for all pancreatic exocrine markers. Stray chromogranin-positive cells in the CPACs were also immunopositive for somatostatin, gastrin, or serotonin. All CPACs showed a few hybrid (amphicrine) cells that coexpressed both chromogranin and trypsin. In one case, ultrastructural examination showed such cells to contain both zymogen and neurosecretory granules. Although the presence of CPACs exclusively in the antrum is most likely the result of a sampling bias, the presence of hybrid cells with an amphicrine phenotype suggests that CPACs probably result from an aberration of stem cell differentiation.
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PMID:Pancreatic acinar cell clusters in pediatric gastric mucosa. 942 22

Heterotopic pancreas transplantation in type I diabetic patients does not correct hyperglucagonemia, which is thought to be due to insufficiently suppressed glucagon release by the host pancreas. The diabetogenic effects of glucagon then have to be corrected by higher than normal insulin secretion from the transplant, with the attendant risk of earlier loss of islet cell function, and development of atherosclerosis. To establish whether this situation can be prevented, we investigated glucose homeostasis and blood lipids, as well as fecal fat and chymotrypsin as indicators for pancreatic exocrine function 14 weeks after orthotopic pancreas transplantation in inbred rats. The pancreas was resected before orthotopic transplantation of the donor pancreas with portal venous drainage (n=8). Laparotomized animals served as controls (n=8). Basal plasma glucagon, basal plasma insulin to glucagon molar ratio, and basal and integrated incremental responses of plasma glucose, insulin, and C-peptide after an oral glucose load (2 g/kg body weight) were similar in both groups. However, hepatic insulin clearance was slightly but significantly lower in the transplanted group (1.1+/- 0.1 vs 1.6+/-0.2; P<0.05). Basal plasma levels of free fatty acids, phospholipids, triglycerides, cholesterol, low-density lipoproteins, and high-density lipoproteins were unchanged after transplantation. Also unchanged were fecal fat and chymotrypsin levels, thus indicating preserved pancreatic exocrine function. We concluded that orthotopic pancreas transplantation with portal venous drainage achieves almost optimal metabolic control with respect to endocrine and exocrine pancreatic function as well as blood lipids. This technique could therefore be used to treat combined endocrine and exocrine insufficiency in chronic pancreatitis and thus enlarges the spectrum of indications for pancreas transplantation.
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PMID:Orthotopic pancreas transplantation with portal venous drainage in rats. Surgical technique and metabolic effects(*). 1055 Jun 40

Eight Angus steers (290 +/- 8 kg), surgically prepared with pancreatic pouch-duodenal reentrant cannulas and abomasal infusion catheters were used in a replicated 4 x 4 Latin square experiment to investigate the effects of abomasal infusion of starch hydrolyzate (SH) and/or casein on pancreatic exocrine secretion and plasma concentration of hormones. Steers were fed a basal diet of alfalfa (1.2 x NEm) in 12 equal portions daily. Abomasal infusion treatments (6-L total volume infused per day) were water (control), SH [2.7 g/(kg BW x d)], casein [0.6 g/(kg BW x d)], and SH + casein. Periods were 3 d for adaptation and 8 d of full infusion. Pancreatic juice and jugular blood samples were collected over 30-min intervals for 6 h on d 11. Weight and pH of pancreatic samples were measured, and a 10% subsample was composited and frozen until analysis of total protein and pancreatic enzyme activities. The remaining sample was returned to the duodenum. Plasma was harvested and frozen until analyzed. Pancreatic juice (67 mL/h) and protein (1.8 g/h) secretion rates were not affected by nutrient infusion. There were SH x casein interactions for all pancreatic enzyme secretions (U/h; alpha-amylase, P < 0.03; trypsin, P < 0.08; and chymotrypsin, P < 0.03) and plasma insulin concentration (P < 0.10). Secretion of pancreatic enzymes was increased by SH (trypsin) and casein (alpha-amylase, trypsin, and chymotrypsin) but not when SH + casein were infused together. Glucose (P < 0.10) and cholecystokinin octapeptide concentrations (CCK-8; P < 0.05) were increased by SH, but glucagon was decreased (P < 0.10). Casein decreased (P < 0.10) plasma CCK-8 concentrations. These data indicate that positive effects of postruminal casein on enzyme secretion were inhibited by SH, emphasizing the complexity of the regulatory mechanisms involved in dietary adaptation of pancreatic exocrine secretion. Changes in hormone concentration may not relate directly to changes in enzyme secretion.
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PMID:Pancreatic exocrine secretion and plasma concentration of some gastrointestinal hormones in response to abomasal infusion of starch hydrolyzate and/or casein. 1521 6

Dipeptidyl peptidase-IV is a cell surface protease which plays an important role in glucose homeostasis through proteolytic inactivation of incretin hormones, primarily glucagon like peptide-1 (GLP-1). Substrate N-terminal amino acid (S2-S1) specificity is rather clearly defined, while no substantial information is available on the significance of amino acid interactions towards the C-terminus after the scissile bond (so called prime S1'-S4' or distant S5'-S28' sites). In the present study the increasing length of the peptide towards prime sites (S1'-S4') resulted in approximately 7-fold decrease in Km. Moreover, the Km for GLP-1 cleavage was comparable to that of an S2-S4' peptide, suggesting that few, if any, important enzyme-substrate interactions occur beyond the active site. Effect of substrate length on kcat was less obvious, but kcat/Km showed an increasing trend when His-Ala-pNA (representing the natural two N-terminal residues) was compared to GLP-1. To probe the impact of increasing substrate length on the free energy of activation (as has been suggested for elastase and chymotrypsin) we performed temperature studies. To adequately interpret thermodynamic data we sought to understand what steps limit the kcat expression. Steady-state parameters of the reactions catalyzed by serine proteases are composed of microscopic constants describing binding, acylation, and deacylation steps. Viscosity and pre-steady-state studies suggested that His-Ala-pNA cleavage is limited in the deacylation half-reaction, most likely the product release step. Thus, the free energy of activation, as calculated from the Eyring equation, is underestimated (at least for His-Ala-pNA) and the effect of substrate length on the acylation step (and transition-state stabilization) could not be unambiguously assessed.
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PMID:Probing prime substrate binding sites of human dipeptidyl peptidase-IV using competitive substrate approach. 1579 49

Cultivation of functional pancreatic cells isolated from adult mammalian pancreas remains difficult. We developed a differentiation protocol that gradually induced the formation of mouse pancreatic exocrine cells from embryonic stem cells (ESCs). This process mimicked in vivo pancreatic development by directing cells through definitive endoderm (DE), gut tube endoderm, and pancreatic progenitor cells to differentiated cells that expressed pancreatic exocrine enzymes. Mouse ESCs were cultured in hanging drops to form embryoid bodies. Treatment of embryoid bodies with activin A induced the formation of DE cells that expressed marker mRNAs Goosecoid and Mixl1 and that were double-positive with Foxa2 and Sox17 proteins. Subsequent treatment of the DE cells by retinoic acid induced the formation of gut tube endoderm cells that expressed the specific marker Hnf1b. Expression of Goosecoid and Mixl1 was downregulated during this period. Fibroblast growth factor 7 (FGF7) promoted differentiation of PDX1-expressing pancreatic progenitor cells that also expressed Foxa2 mRNA, an endodermal marker, suggesting derivation from the DE cells. Exocrine cell differentiation was induced with FGF7, glucagon-like peptide-1, and nicotinamide. The differentiated cells expressed mature pancreatic exocrine cell mRNAs, such as Amylase, Elastase, and Carboxypeptidase A. Additionally, they produced pancreatic elastase, amylase, carboxypeptidase A, and chymotrypsin proteins that were identified in cytoplasmic granules by immunocytochemistry. Active amylase was released into the medium. Moreover, FGF7 was associated with differentiation of pancreatic exocrine cells. The findings reported here offer a novel and effective process to develop pancreatic exocrine cells from ESCs.
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PMID:A novel stepwise differentiation of functional pancreatic exocrine cells from embryonic stem cells. 2088 97


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