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PubMed1981

The amino acid sequence of porcine glicentin.

Glicentin or gut GLI-1 has previously been isolated from porcine small intestine. On the basis of the available chemical data, the molecule was thought to contain 100 amino acid residues. A redetermination of the amino acid composition of the molecule has shown it to contain 69 amino acid residues, and the full sequence has been established. The sequence of glicentin can be outlined as: GRPP1--30-Lys-Arg-Glucagon33--61-Lys-Arg-Hexapeptide64--69 where GRPP1--30 probably corresponds to the glicentin related pancreatic peptide previously isolated from porcine pancreas. In the pancreas, the two dibasic sequences (Lys31-Arg32 and Lys62-Arg63) probably represent sites of post-synthetic enzymatic cleavages by analogy with the two dibasic sequences of proinsulin. Glicentin thus fulfills the structural requirements for being all or a part of porcine proglucagon. In the intestine, glicentin could be the precursor of oxyntomodulin, a small molecular weight gut GLI presumably identical to glicentin 33--69, i.e., glucagon extended at the C-terminal end by an octapeptide.

Amino Acid Sequence↗
PubMed1980

Glicentin and gastric inhibitory polypeptide immunoreactivity in endocrine cells of the gut and pancreas.

The distribution of the postulated glucagon precursor, glicentin, as well as of the gastrointestinal hormone GIP (gastric inhibitory polypeptide), has been studied by immunocytochemistry and radioimmunoassay. Our results show that GIP antisera may contain a population of antibodies recognizing an immunoreactant common to glicentin and GIP. The occurrence of such common immunoreactants makes immunological distinction between the two hormones difficult and may explain previous results indicating that GIP is stored by glucagon cells. The present results indicate that GIP is produced by endocrine cells of the duodenum and jejunem and is absent from the pancreas, stomach, and large intestine. Glicentin-like immunoreactivity is displayed by A cells of the pancreas and by oxyntic A cells of the stomach, as well as by numerous glucagon-like immunoreactant (GLI) cells of the ileum and colon. Use of glucagon ad glicentin antisera of differing specificities indicates that the processing of this putative prohormone differs between A cells and GLI cells. Studies on the ontogeny of pancreatic A cells also reveal differences in the reactivity pattern of glicentin-like immunoreactivity between fetal and adult rats. Ultraimmunocytochemical studies show that glicentin-like immunoreactivity is mainly, stored in the cytoplasmic granules of pancreatic A cells.

Aging↗
PubMed1988

Oxyntomodulin and glicentin: brain-gut peptides in the rat.

Glucagon-like materials and glucagon have been identified by immunoassay and immunocytochemistry in the mammalian central nervous system. However, the molecular forms relevant to brain glucagon-like immunoreactivity (GLI) have not been precisely defined. In the rat small intestine, more than 90% of GLI is constituted by two peptides: oxyntomodulin (OXM) and glicentin. This work was initiated to characterize and determine the concentrations of these two peptides and glucagon in the rat central nervous system and to compare their relative proportions with those found in the gut. Different regions from the adult rat brain were analyzed by HPLC in association with RIA, using a central glucagon antiserum and an antibody directed toward the C-terminal end of OXM and glicentin. The elution profiles of hypothalamus extracts were constituted by two main peaks, both detected by the two antibodies used and displaying the same retention times as glicentin and OXM, respectively. A third small peak, which coeluted with glucagon, was constantly recorded with the central glucagon antiserum. The percentages of glicentin, OXM, and glucagon in 10 hypothalami were 37 +/- 1%, 55 +/- 1%, and 8 +/- 2%, respectively (n = 8). This distribution was quite similar to that in small intestinal extracts (38 +/- 1%, 59 +/- 1%, and 1.3 +/- 0.1%, respectively; n = 7); however, the peptide concentrations were almost 50-fold greater in intestine than in hypothalamus. In the medulla oblongata, the same peptide ratio was observed, with 10-fold lower concentrations compared to those in hypothalamus. In olfactory bulb, cerebellum, and cortex the concentrations were close the the detection limit, whereas they could be not detected in the pituitary. The combination of HPLC and specific RIAs allowed us to unambiguously characterize OXM and glicentin as the major components of GLI in the rat hypothalamus and medulla oblongata. The same proportion of these two peptides in the central nervous system and the gut indicates that a similar posttranslational processing exists in these rat tissues, another example of the brain-gut axis.

Animals↗
PubMed1997

Helicobacter pylori infection accelerates gene expression of glicentin in the gastric mucosa. Its association with intestinal metaplasia of the stomach.

BACKGROUND: Glicentin is an intestinal polypeptide hormone which seems to promote intestinal metaplasia (IM) in the gastric mucosa. The aim of this study was to clarify whether Helicobacter pylori infection accelerates glicentin gene expression. METHOD: Glicentin mRNA was investigated by reverse-transcription polymerase chain reaction using gastric biopsies from 47 patients examined endoscopically and denying IM. RESULTS: IM was observed in 18 (38.3%) cases histologically, but not in the other 29 (62.7%). Glicentin mRNA was significantly correlated with histological IM (P < 0.01) and was positively correlated with H. pylori infection (P < 0.05). CONCLUSION: Our results indicate that H. pylori infection is associated with the induction of glicentin in the gastric mucosa, thus supporting the hypothesis that H. pylori infection accelerates IM of the stomach.

Adult↗
PubMed1988

Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study.

Although glucagonlike immunoreactants (GLIs) are present in the central nervous system of several mammalian species, their structural relationship with pancreatic proglucagon is not defined, and their precise anatomical distribution has not been studied extensively. To obtain further information about the structure and biological significance of brain GLIs, the anatomical distribution of three different antigenic determinants of pancreatic proglucagon--glucagonlike peptide I (GLP-I), glucagon, and glicentin--was mapped in the brain of colchicine-treated rats by immunocytochemistry using the avidin-biotin-peroxidase method. Neuronal cell bodies immunoreactive with antisera specific for GLP-I, glucagon, and glicentin were found only in the caudal medulla oblongata. Within the caudal medulla immunostained cell bodies were found at levels from approximately 0.55 mm rostral to the obex to 0.45 mm caudal to the obex, and were located within the nucleus of the solitary tract (NTS) and the dorsal (MdD) and ventral (MdV) parts of the medullary reticular nucleus. The NTS contained three times more immunoreactive cell bodies than the MdD and MdV, and these cell bodies were located in the midline, medial, and lateral subnuclei of the caudal third of the NTS. Immunostaining of the same cell bodies in paired adjacent sections incubated with GLP-I and glucagon antisera or glucagon and glicentin antisera provided evidence for coexistence of the three antigens within the same neurons of the NTS. Nerve fibers and terminals immunoreactive with GLP-I, glucagon, and glicentin antisera were widely distributed throughout the rat brain and there was no discernible difference in the distribution of fibers and terminals immunoreactive with each of the three antisera. The highest densities of immunostained fibers and terminals were observed in the hypothalamus, thalamus, and septal regions, and the lowest in the cortex and hindbrain. The localization of neuronal cell bodies containing GLP-I, glucagon, and glicentin within the NTS and the MdD and MdV, and the extensive distribution of immunoreactive fibers and terminals throughout the rat brain suggest a role for these peptides in the integration of autonomic as well as central nervous system functions.

Animals↗
PubMed1986

Glicentin 1-61 probably represents a major fraction of glucagon-related peptides in plasma of anaesthetized uraemic pigs.

Uraemia was induced in pigs by ligation of the renal vascular pedicle, and uraemic plasma was analysed for glucagon and glucagon-related peptides. A preponderance of large molecular weight (Mr) components comprising glicentin and moieties of slightly lower Mr was found, accounting for 73 +/- 3% (mean +/- SEM, n = 12) of the total plasma glucagon-like immunoreactivity. Comparisons with glicentin 1-61, produced by controlled, stepwise, consecutive digestion of purified natural glicentin with carboxypeptidases (carboxypeptidase A followed by carboxypeptidase B, and again by carboxypeptidase A and B), gel filtration, ion exchange chromatography, reverse phase HPLC and radioimmunoassays for the glucagon sequences 6-15 and 19-29 and for the glicentin sequence 12-30 all indicate that glicentin 1-61 constitutes approximately 57% of the large Mr glucagon-related peptides found in uraemia in pigs.

Amino Acid Sequence↗
PubMed1984

Glicentin-containing cells in intestinal metaplasia, adenoma and carcinoma of the stomach.

Glicentin-containing cells (Glic. cells) in intestinal metaplasia, adenoma and carcinoma of the stomach were examined using immuno-histochemical techniques. Glic. cells first occurred in the gastric mucosa of the transitional area between metaplastic and intact gastric glands. They frequently showed hyperplasia or micronoduli in the budding area of the deeper metaplastic glands, but in completely intestinalized mucosa these endocrine cells decreased remarkably. Gastric adenomas with mild dysplasia had a good number of glicentin-immunoreactive cells which were located in the deeper adenoma glands. Gastrin- and somatostatin-positive cells were also detected in the adenomas. The incidence of glicentin-positive tumor cells was significantly higher in well differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. Among the seven cases of scirrhous argyrophil cell carcinoma, three showed glicentin- and glucagon-immunoreactivity in the same area of the tumor. These findings suggest that the selective increase of Glic. cells in intestinal metaplasia may be closely related to the development of gastric adenoma. Glicentin positive tumor cells in gastric carcinomas can be regarded to be an expression of intestinal or fetal markers.

Adenoma↗
PubMed1981

Effect of highly purified porcine gut glucagon-like immunoreactivity (glicentin) on glucose release from isolated rat hepatocytes.

We studied the effect of the highly purified gut peptide glicentin on the glucose production and cyclic AMP accumulation of isolated rat hepatocytes. Glicentin at 2.10(-7) mol/l had the same effect on glucose production as maximally effective concentrations of glucagon, but did not stimulate cyclic AMP to the same extent; furthermore, glicentin apparently had only 1/100 of the potency of glucagon on glucose production. During incubation with hepatocytes glicentin was degraded to low molecular weight fragments one of which were chromatographically very similar to fragments of glucagon. It is suggested that glicentin exerts its glucagon-like effects on hepatocytes only after degradation to glucagon-like fragments. The results also demonstrate that the coupling between cyclic AMP accumulation and glucose production depends on the nature of the stimulatory peptide.

Animals↗
PubMed1980

Glucagon-, glicentin-, and pancreatic polypeptide-like immunoreativities in rectal carcinoids and related colorectal cells.

Three nonargentaffin rectal carcinoids have been investigated immunohistochemically. In one case most tumor cells reacted with antiglucagon sera as well as with antiglicentin, antibovine pancreatic polypeptide (BPP), and antihuman pancreatic polypeptide (HPP) sera; they were identified ultrastructurally as L cells. Another case showed glucagon-, glicentin-, and BPP-immunoreactive cells but lacked HPP immunoreactivity. In the third case glucagon- and glicentin-immunoreactive cells were well represented, while PP immunoreactivities were scarce. Parallel investigations of human rectal and sigmoid mucosa showed numerous cells reacting with glucagon, glicentin, and BPP antisera, most of which lacked HPP immunoreactivity. Cells reacting with glucagon and glicentin antisera, while lacking PP immunoreactivities, were also found. Thus, both tumor and nontumor cells produce glucagonlike immunoreactive (GLI) peptides--one of which may be glicentin or a related molecule--as well as PP-related sequences, although differing histochemically and ultrastructurally from glucagon or PP cells of the human pancreas. It is concluded that nonargentaffin rectal carcinoids are histogenetically linked to nonargentaffin endocrine cells of the human rectum.

Adult↗
PubMed1981

The primary structure of porcine glicentin (proglucagon).

The primary structure of porcine glicentin has been established. The molecule consists of 69 amino acid residues and has a molecular weight of 8128. The sequence of glicentin 1-30 represents the glicentin-related pancreatic peptide (GRPP) previously isolated from porcine pancreas. The sequence 33-61 represents the full sequence of glucagon and the sequence 64-69 is a C-terminal hexapeptide. These three sequences, GRPP, glucagon and the hexapeptide are linked by two Lys-Arg pairs which probably represent the sites for post-synthetic enzymatic cleavages. Glicentin thus fulfils the structural requirements for being proglucagon.

Amino Acid Sequence↗
PubMed1988

Effect of intraluminal administration of amino acids upon plasma glicentin.

To see what effect intraluminal amino acids would have on glicentin secretion, we put a mixture of 10 amino acids (1 g/kg) into the duodenum of five normal, conscious piglets. Their plasma nitrogen rose, as did insulin and glucagon measured with C-terminal-specific antiserum. Plasma total immunoreactive glucagon, determined with non-specific antiserum, rose from 2753 +/- 460 pg/ml to a peak of 4434 +/- 1352 pg/ml at 30 min. Plasma glicentin, determined with R 64 antiserum, rose from a fasting level of 297 +/- 70 pmol/l to a peak of 702 +/- 167 pmol/l at 45 min. We also gave oral arginine to 6 pancreatectomized dogs to investigate why the plasma glicentin rises after amino acid ingestion. Arginine raised the plasma total immunoreactive glucagon from 1120 +/- 214 pg/ml to a peak of 2266 +/- 512 pg/ml at 45 min. We conclude that intraluminally administered amino acids enhance glicentin secretion from the gut.

Amino Acids↗
PubMed1984

Cyclic-AMP-dependent phosphorylation of glicentin.

Highly purified glicentin, a 69-amino-acid-residue peptide isolated from porcine intestine that contains the full sequence of glucagon and is probably biosynthetically related to glucagon, is a substrate for cyclic-AMP-dependent protein kinase in a cell-free system. Glicentin-related pancreatic peptide (residues 1-30 of glicentin) and glucagon were not phosphorylated under the same reaction conditions. It is postulated that the serine residue at position 34 of glicentin (position 2 of glucagon), that is part of the sequence Lys.Arg. His.Ser., is the probable site of phosphorylation.

Animals↗
PubMed1982

Ontogeny of immunoreactive glicentin in the human gastrointestinal tract and endocrine pancreas.

The gestational time of appearance and distribution of immunoreactive glicentin was compared to that of immunoreactive glucagon in the gastrointestinal tract and endocrine pancreas of human fetuses, aged between 5 and 24 weeks, by an indirect immunoperoxidase method. With the glicentin antiserum No. R 64, the first immunoreactive cells were detected at the 10th week of gestation in the oxyntic mucosa and proximal small intestine, at the 8th week in the ileum and at the 12th week in the colon. In the endocrine pancreas, the first immunoreactive cells were observed as early as 8 weeks within the walls of the primitive pancreatic ductules. At a more advanced stage of development (12 weeks), they were found interspersed among the islet cell clusters and still later (16 weeks) inside the recognizable islets of Langerhans. With the glucagon antiserum No. GB 5667, no immunoreactive cells were demonstrated in the gastrointestinal tract whatever the age of the fetuses. In the endocrine pancreas, the first immunoreactive cells were observed at the 8th week of gestation in the pancreatic parenchyma. The distribution of glucagon-containing cells in the pancreas was similar to that of glicentin immunoreactivity throughout ontogenesis. In the pancreatic islets of one 18-week-old human fetus, the study of consecutive semithin sections treated by both antisera showed that the same cells were labelled. The significance of these findings concerning the role of glicentin as a glucagon precursor is discussed.

Colon↗
PubMed1980

Evidence that glicentin contains the entire sequence of glucagon.

Glicentin (a highly purified 100-amino acid peptide with glucagon-like immunoreactivity from porcine gut) was subjected to limited digestion with trypsin and carboxypeptidase B, and the resulting peptides were studied by gel filtration and region-specific glucagon radioimmunoassays. Similar digests of glucagon and purified fragments of glucagon were studied in parallel. Glicentin gave rise to peptides that corresponded closely to the 1-17 and 19-29 fragments of glucagon. Also, 125I-labelled glicentin and 125I-labelled glucagon gave rise to identical fragments after trypsin treatment. On the basis of this and other evidence [Jacobsen, Demandt, Moody & Sundby (1977) Biochim. Biophys. Acta 493, 452-459] it is concluded that glicentin contains the entire glucagon sequence at residues number 64-92 and thus fulfills one of the requirements for being a 'proglucagon'.

Amino Acid Sequence↗
PubMed1982

Glicentin precedes glucagon in the developing human pancreas.

A quantitative evaluation of immunofluorescence elicited by anti-insulin, anti-glucagon, anti-glicentin, anti-somatostatin and anti-pancreatic polypeptide antisera has been carried out in the pancreas of 5 human fetuses from 3.0 to 9.6 cm C.R. The data obtained indicate that while insulin and somatostatin-containing cells are approximately in similar proportions with respect to the other endocrine cell types in the five fetuses studied, the glucagon and glicentin immunoreactive cells and the pancreatic polypeptide cells are not : a) pancreatic polypeptide-containing cells increase in proportion as fetuses grow older; b) the youngest fetuses (3.0 to 4.3 cm C.R.) contain a high proportion of cells reacting to anti-glicentin antiserum only (GLI-cells) and a small proportion of cells stained both with the anti-glicentin and anti-glucagon antisera (GLI/GLU-cells). However, the latter cell type which stains similarly as the postnatal and adult pancreatic A-cell (GLI-cells are not detectable in the postnatal and adult pancreas) increases iin proportion in older fetuses, while the proportion of GLI-cells decrease. The data suggest that the definitive adult-type A-cell matures from a GLI-cell type which is not able to convert glucagon precursors GLI(s) into glucagon.

Female↗
PubMed2003

Expression, purification, and PC1-mediated processing of human proglucagon, glicentin, and major proglucagon fragment.

To examine the cleavage specificity of different members of the furin/propeptide convertase (PC) family of enzymes, we have selected proglucagon (PG) as a model substrate. PG was selected because it is subject to differential processing in vivo. PG is thought to be cleaved initially at an interdomain site to produce glicentin and the major proglucagon fragment (MPGF). These intermediates are subsequently cleaved, most likely by the convertases PC2 and PC1, respectively. To determine the exact sites within PG that are cleaved by PC1 and PC2, we attempted to produce milligram quantities of human PG, glicentin, and MPGF for use in an in vitro conversion assay. A methionine residue was added to the N-terminus of each protein to initiate translation. Purification was achieved using cation exchange and reversed-phase chromatography, and the integrity of the methionylated proteins was confirmed by both electrospray ionization-mass spectrometry and amino acid analysis. The combined expression and purification scheme is fast, efficient, and results in milligram quantities of > or =95% pure proglucagon, > or =95% pure MPGF, and > or =93% pure glicentin. These prohormones are cleaved by PC1 to produce product peptides consistent with the processing of PG observed in vivo, and should therefore be suitable for further analysis of the post-translational processing of PG.

Electrophoresis, Polyacrylamide Gel↗
PubMed1982

Glucagon and glicentin immunoreactive cells in human colon.

An immunohistochemical study of glucagon and glicentin immunoreactive endocrine cells in the human colon epithelium was performed. Serial sections and qualitative analysis show a cell population containing both immunoreactivities. However, there is another cell population exhibiting only an immunoreactivity with glicentin. The exact distribution of these immunoreactive endocrine cells within the colon crypt segments is also analysed. The significance of these findings concerning the synthesis of glucagon and glicentin and their function is discussed.

Adult↗
PubMed1985

Isolation and chemical characterization of glicentin C-terminal hexapeptide in porcine pancreas.

Using a radioimmunoassay specific for porcine glicentin C-terminal hexapeptide, we isolated a peptide from porcine pancreas and characterized it as the C-terminal 64-69 sequence of glicentin: H-Asn-Lys-Asn-Asn-Ile-Ala-OH. The purification steps included gel filtration, ion-exchange chromatography and HPLC. In each step, the recovery of the desired peptide, radioimmunologically estimated from the respective elution profile, was 71.4-91.7%. The final yield of the hexapeptide was 22 micrograms (4.3%) from 800 g pancreas. The pancreatic content of this peptide was estimated to be approximately equimolar to that of pancreatic glucagon. No hexapeptide-like component was detected in porcine intestinal extracts. The data confirmed that the processing of pancreatic proglucagon liberates the C-terminal hexapeptide of the intramolecular glicentin sequence in a tissue-specific manner during the production of glucagon.

Amino Acid Sequence↗