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PubMed1988

Oxyntomodulin (glicentin-(33-69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs.

The pharmacokinetics of purified synthetic oxyntomodulin were studied after infusing it into euglycaemic pigs at two rates. The elimination of the peptide from plasma was characterized by two components, a fast one (t1/2 7.2 +/- 0.6 min) and a slow one (t1/2 20.4 +/- 3.8 min) (mean +/- S.E.M., n = 7). The metabolic clearance rate was independent of infusion rate (6.96 +/- 0.99 vs 7.44 +/- 0.98 ml/kg . min (mean +/- S.E.M., n = 7). The synthetic peptide bound to pig hepatic glucagon receptors, but with approximately 2% of the affinity of glucagon, and showed insulinotropic and somatostatinotropic effects when infused into isolated perfused pig pancreases at concentrations higher than 10(-10) M. A dose-dependent increase was also shown for pancreatic glucagon output. A naturally occurring peptide, identified as oxyntomodulin by gel filtration and HPLC, was released into the circulation from the pig lower small intestinal mucosa upon intraluminal administration of glucose, and represented 25 +/- 3.8% of the secreted glucagon-like immunoreactivity. 11 +/- 2.3% of the secreted glucagon-like immunoreactivity was indistinguishable from glucagon itself upon gel filtration; thus at least 36% of the glucagon-like immunoreactivity secreted from the intestinal mucosa is already in an active form.

Animals↗
PubMed1983

Gut glucagon, enteroglucagon, gut glucagonlike immunoreactivity, glicentin--current status.

Glucagonlike substances in extracts of intestinal mucosa were already described in 1948 by Sutherland and deDuve (1), who used a bioassay technique for the identification. After the development of the first glucagon radioimmunoassays, Unger and co-workers (2,3) confirmed that intestinal extracts contained peptides that "crossreacted" in the glucagon radioimmunoassay [hence gut "glucagonlike immunoreactivity" (GLI)]. In 1968, the same group discovered that the gut GLIs consisted of at least two peptides, GLI I and II (4), both of which differed immunochemically from pancreatic glucagon and, therefore, necessarily had different chemical structures (4,5). Developments during the last decade in the field of peptide chemistry, particularly improved purification and sequencing techniques, have greatly advanced our knowledge of gut peptides, including the enteroglucagons, and the chemical structure of several of the members of this heterogenous group of peptides is now known. Furthermore, progress in the field of nucleotide and gene technology has also spread to this area of research, and although many problems remain unresolved, the progress made has sufficiently important implications to justify a review of the most recent advances.

Amino Acid Sequence↗
PubMed1983

Molecular forms of glucagon-like immunoreactivity in porcine intestine and pancreas.

Glucagon-related polypeptides in porcine pancreas and intestine were analysed by gel-permeation chromatography and RIA. Three assays were employed: a nonspecific glucagon assay (R59) of 94% cross-reactivity with glicentin; a pancreatic glucagon assay (RCS5) directed against the C-terminal region of glucagon and of less than 0.01% cross-reactivity with glicentin; and a glicentin assay (R64) of less than 0.01% cross-reactivity with glucagon. For extracts of porcine pancreas all three assays gave similar molar concentrations of immunoreactivity. In porcine intestinal extracts immunoreactivity was detected in significant amounts only by the nonspecific glucagon (R59) and the glicentin (R64) assays, again in similar molar concentrations. The immunoreactivities present in pancreas and intestine were chromatographically and immunologically separable into six main peaks, peaks I, II, III, V, and VI being present in the pancreas, and peaks I, II, and IV in the intestine. The different immunoreactivities of the peaks allowed probable identities to be assigned to their main components. Apart from peak I, which consists of void-volume material that may interfere nonspecifically with the assays, the main components of the peaks can be interpreted as glicentin (in peak II) or fragments derived from glicentin. Peak III contains the N-terminal portion of glicentin (glicentin-related pancreatic peptide), peak IV probably contains glucagon with its 8 amino-acid C-terminal extension, peak V is pancreatic glucagon and peak VI contains smaller N-terminal glicentin fragments. These findings fit with the proposition that glicentin fulfills the role of proglucagon in the pancreas, and is the major component of enteroglucagon in the intestine.

Animals↗
PubMed1988

Development of an oxyntomodulin/glicentin C-terminal radioimmunoassay using a "thiol-maleoyl" coupling method for preparing the immunogen.

Oxyntomodulin (OXM) and glicentin, two peptides processed from proglucagon, both contain the glucagon sequence and a C-terminal basic octapeptide, KRNRNNIA extension. A method to produce antibodies, directed specifically toward the C-terminal extension of these two peptides, was developed; it consisted of the use of thioled bovine serum albumin conjugated with the synthetic N-maleoyl C-terminal octapeptide as the immunogen. Three rabbits (FAN, LEG, and PIP) generated antisera with affinity constants close to 5 X 10(10) M-1. In the radioimmunoassay system, these antisera showed a 100% cross-reactivity with OXM, partially purified rat and human glicentin, and the C-terminal 19-37 OXM fragment. They displayed no cross-reactivity toward the glucagon molecule. The cross-reactivity of C-terminal fragments of OXM demonstrated that the epitope involves the C-terminal hexapeptide and that the two last amino acid residues are essential for the binding. The high-performance liquid chromatography elution profiles of human jejunum or rat intestinal extracts obtained by radioimmunoassay with LEG antiserum showed two major peaks which had the same retention times as OXM and glicentin markers. Thus, the major end products in the human and rat small intestine are OXM and glicentin. In human or rat pancreas, the two main peaks detected were glucagon and the C-terminal hexapeptide of OXM/glicentin. Small amounts of OXM were also found in pancreas, whereas no significant quantities of glicentin could be detected. The "thiol-maleoyl" coupling method described here, and applied to produce C-terminal OXM/glicentin specific antisera, might be of general use to obtain antibodies against a well-defined epitope.

Animals↗
PubMed1996

Role of prohormone convertases in the tissue-specific processing of proglucagon.

Proglucagon (proG) is processed in a tissue-specific manner to glucagon in the pancreas and to gilcentin, oxyntomodulin, glucagon-like peptide (GLP)-1, and GLP-2 in the intestine. Recombinant vaccinia virus (vv) vectors were used to infect prohormone convertase 1 (PC1) or PC2 into nonendocrine (BHK-proG) cells, which stably express proG. Similarly, endocrine (GH3, AtT-20) cells were coinfected with proG along with PC1 or PC2 alone, or in combination with furin, PACE4, PC5a, or PC5b. Cell extracts were analyzed for various proG-derived peptides by RIA of fractions obtained from HPLC. Upon infection of BHK-proG cells with either vv: furin or vv:PC1, glicentin was produced, while vv: PC2 did not process proG. In GH3 and AtT-20 cells, vv:PC1 produced glicentin, oxyntomodulin, GLP-1(1-37), GLP-1(7-37), and GLP-2. All other enzymes tested produced only glicentin. Interestingly, no enzyme or combination produced glucagon. Coinfection of GH3 cells with vv:PC2 and members of the chromogranin family of peptides, including chromogranin A and B and secretogranin II, as well as the PC2-binding protein 7B2, did not result in processing to glucagon. It is concluded that: 1) PC1 is responsible for the processing of proG to produce the intestinal peptides glicentin, oxyntomodulin, GLP-1(1-37), GLP-1(7-37), and GLP-2, and 2) PC2 processes proG to glicentin but does not produce glucagon, alone or in combination with other enzymes or with known molecular chaperones.

Animals↗
PubMed1986

The biological significance of "enteroglucagon." Present status.

"Enteroglucagon" refers to glucagon-like peptides present in intestine that cross react with N-terminally directed antiglucagon antisera but not with C-terminally directed antisera. Two peptides having these features have been isolated from the lower small intestine: glicentin (69 amino acids) and oxyntomodulin (37 amino acids). The sequence of the pancreatic preproglucagon gene suggests that glucagon, glicentin and oxyntomodulin derive from the same translational pathway, each individual peptide being produced by different posttranslational processing. Both glicentin and oxyntomodulin contain the glucagon sequence that bears the N-terminal epitope and are C-terminally extended by the same octapeptide masking the C-terminal epitope. The N-terminal 32 amino acid extension of glicentin renders the molecule unable to bind to hepatic glucagon receptors, unlike glucagon and oxyntomodulin. An original tissue specificity of oxyntomodulin, mediated by a novel type of receptor, has been observed in acid secreting gastric oxyntic glands. Oxyntomodulin and glicentin containing the C-terminal octapeptide, as well as the octapeptide itself, are able to inhibit gastric acid secretion. This biological activity is likely to represent the main physiological regulatory pattern in which "Enteroglucagon" is involved.

Animals↗
PubMed1984

Immunocytochemical study of the gastroenteropancreatic endocrine cells of the sheep.

The gastroenteropancreatic (GEP) endocrine cells of the sheep were studied immunocytochemically and their distribution and frequency were determined. Eleven types of endocrine cells were revealed. In the abomasum, somatostatin-, gastrin-, glucagon- and glicentin-immunoreactive cells were detected with the highest frequency in the pyloric region. In the small intestine, somatostatin-, gastrin-, CCK-, motilin-, neurotensin-, secretin-, substance P-, glucagon-, glicentin- and BPP-immunoreactive cells were found and were most numerous in the duodenum except for neurotensin-, glucagon- and glicentin-immunoreactive cells which were more concentrated in the ileum. In the large intestine, somatostatin-, substance P-, glucagon-, glicentin- and BPP-immunoreactive cells were localized with the last three cell types being more concentrated in the rectum. In the pancreas, somatostatin-, glucagon-, glicentin-, BPP- and insulin-immunoreactive cells predominated within the islets and were also scattered in the exocrine portion and rarely detected in duct epithelial cells. The differences between the distribution and frequency of the GEP endocrine cells of the sheep and those of monogastric species are discussed.

Animals↗
PubMed1997

Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1.

Proglucagon is processed differentially in pancreatic alpha-cells and intestinal endocrine L cells to release either glucagon or glucagon-like peptide-1-(7-36amide) (tGLP-1), two peptide hormones with opposing biological actions. Previous studies have demonstrated that the prohormone convertase PC2 is responsible for the processing of proglucagon to glucagon, and have suggested that the related endoprotease PC3 is involved in the formation of tGLP-1. To understand better the biosynthetic pathway of tGLP-1, proglucagon processing was studied in the mouse pituitary cell line AtT-20, a cell line that mimics the intestinal pathway of proglucagon processing and in the rat insulinoma cell line INS-1. In both of these cell lines, proglucagon was initially cleaved to glicentin and the major proglucagon fragment (MPGF) at the interdomain site Lys70-Arg71. In both cell lines, MPGF was cleaved successively at the monobasic site Arg77 and then at the dibasic site Arg109-Arg110, thus releasing tGLP-1, the cleavages being less extensive in INS-1 cells. Glicentin was completely processed to glucagon in INS-1 cells, but was partially converted to oxyntomodulin and very low levels of glucagon in AtT-20 cells in the face of generation of tGLP-1. Adenovirus-mediated co-expression of PC3 and proglucagon in GH4C1 cells (normally expressing no PC2 or PC3) resulted in the formation of tGLP-1, glicentin, and oxyntomodulin, but no glucagon. When expressed in alphaTC1-6 (transformed pancreatic alpha-cells) or in rat primary pancreatic alpha-cells in culture, PC3 converted MPGF to tGLP-1. Finally, GLP-1-(1-37) was cleaved to tGLP-1 in vitro by purified recombinant PC3. Taken together, these results indicate that PC3 has the same specificity as the convertase that is responsible for the processing of proglucagon to tGLP-1, glicentin and oxyntomodulin in the intestinal L cell, and it is concluded that this enzyme is thus able to act alone in this processing pathway.

Animals↗
PubMed1998

Proglucagon processing in an islet cell line: effects of PC1 overexpression and PC2 depletion.

Proglucagon (proG) is differentially processed in the A cells of the pancreas to yield glucagon, and in the L cells of the intestine to generate glicentin, oxyntomodulin, the incretin glucagon-like peptide (GLP)-1(7-36NH2) and the intestinotropin GLP-2. To establish roles for the prohormone convertases PC1 and PC2 in proG processing within the context of a physiological model, we created stable cell lines from an islet-derived cell line, InR1-G9. These cells express proG and PC2, but not PC1, messenger RNA (mRNA). InR1-G9 cells were stably transfected with PC1 or antisense PC2. Selection was carried out in G418 (InR1-G9/PC1) or Zeocin (InR1-G9/ASPC2). Both PC1 mRNA and protein were highly expressed in InR1-G9/PC1 cells (P < 0.01-0.001) compared with wild-type (WT) cells. Cells transfected with ASPC2 demonstrated significant decreases in both PC2 mRNA (P < 0.001) and protein (P < 0.05) levels. ProG-derived peptides in WT, control, InR1-G9/PC1, and InR1-G9/ASPC2 cells were identified by HPLC and RIA. Overexpression of PC1 in InR1-G9 cells resulted in increased processing to glicentin (P < 0.01), oxyntomodulin (P < 0.05), and GLP-2 (P < 0.05). Interestingly, processing to GLP-1(7-36NH2) did not increase upon transfection of PC1. Transfection of InR1-G9 cells with ASPC2 resulted in the disappearance of glicentin (P < 0.05). However, production of glucagon was not altered by antisense deletion of PC2. Surprisingly, GLP-1(7-36NH2) production appeared to be augmented (P < 0.05) in InR1-G9/ASPC2 cells, whereas GLP-2 production was not altered. In conclusion, these studies establish the role of PC1 in the processing of proG to the intestinal proG-derived peptides. This study also establishes a role for PC2 in the production of glicentin; however, the liberation of glucagon appears to be mediated by another, yet to be identified, convertase.

Animals↗