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PubMed2001

Proglucagon-derived peptides in intestinal epithelial proliferation: glucagon-like peptide-2 is a major mediator of intestinal epithelial proliferation in rats.

Proglucagon-derived peptides have been implicated in the control of intestinal mucosal cell division. To investigate the actions of these peptides on intestinal cell proliferation, different doses of enteroglucagon, oxyntomodulin, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) were tested in male Wistar rats maintained on total parenteral nutrition. Crypt cell proliferation was assessed by the analysis of arrested metaphases in microdissected crypts. Enteroglucagon and oxyntomodulin had no effect on intestinal weight or cell proliferation. GLP-1 had a slight effect on stomach and small intestinal weights and on epithelial cell proliferation in the small and large intestines. GLP-2 infusion dose-dependently increased the weights of the stomach, small intestine, colon, and cecum and increased crypt cell proliferation in the small and large intestines of parenterally fed rats. In orally fed animals, GLP-2 increased intestinal weight but had little effect on proliferation. Therefore, of the proglucagon-derived peptides, GLP-2 appears to be a major mediator of intestinal epithelial proliferation.

Animals↗
PubMed2005

Biologic actions and therapeutic potential of the proglucagon-derived peptides.

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.

Glucagon↗
PubMed2004

Altered proglucagon processing in an alpha-cell line derived from prohormone convertase 2 null mouse islets.

The endoproteolytic processing of proproteins in the secretory pathway depends on the expression of selected members of a family of subtilisin-like endoproteases known as the prohormone convertases (PCs). The main PC family members expressed in mammalian neuroendocrine cells are PC2 and PC1/3. The differential processing of proglucagon in pancreatic alpha-cells and intestinal L cells leads to production of distinct hormonal products with opposing physiological effects from the same precursor. Here we describe the establishment and characterization of a novel alpha-cell line (alphaTC-DeltaPC2) derived from PC2 homozygous null animals. The alphaTC-DeltaPC2 cells are shown to be similar to the well characterized alphaTC1-6 cell line in both morphology and overall gene expression. However, the absence of PC2 activity in alphaTC-DeltaPC2 leads to a complete block in the production of mature glucagon. Surprisingly, alphaTC-DeltaPC2 cells are able to efficiently cleave the interdomain site in proglucagon (KR 70-71). Further analysis reveals that alphaTC-DeltaPC2 cells, unlike alphaTC1-6 cells, express low levels of PC1/3 that lead to the generation of glicentin as well as low amounts of oxyntomodulin, GLP-1, truncated GLP-1, and N-terminally extended GLP-2. We conclude that alphaTC-DeltaPC2 cells provide additional evidence for PC2 as the major convertase in alpha-cells leading to mature glucagon production and provide a robust model for further analysis of the mechanisms of proprotein processing by the prohormone convertases.

Animals↗
PubMed1998

Short-chain fatty acid-supplemented total parenteral nutrition alters intestinal structure, glucose transporter 2 (GLUT2) mRNA and protein, and proglucagon mRNA abundance in normal rats.

Intestinal adaptation is a complex physiologic process that is not completely understood. Intravenous short-chain fatty acids (SCFAs) enhance intestinal adaptation after 80% enterectomy in rats. The purpose of this study was to examine rapid responses to SCFA-supplemented total parenteral nutrition (TPN) in the normal small intestine. After jugular catheterization, 31 Sprague-Dawley rats (weighing 258 +/- 3 g) were randomly assigned to receive standard TPN or an isoenergetic, isonitrogenous TPN solution supplemented with SCFAs (TPN+SCFA). Intestinal samples were obtained after 24 or 72 h of nutrient infusion. TPN+SCFA for 24 h increased (P < 0.05) the ileal RNA concentration (microg RNA/mg ileum) whereas TPN+SCFA for 72 h increased (P < 0.05) the ileal DNA concentration (microg DNA/mg ileum) and decreased (P < 0.05) the ileal protein concentration (microg protein/mg ileum). Ileal proglucagon mRNA abundance was elevated (P < 0.05) after 24 h of TPN+SCFA infusion and returned to levels seen with control TPN by 72 h. Glucose transporter 2 (GLUT2) mRNA was significantly higher (P < 0.05) in the TPN+SCFA groups at both time points when compared with control TPN groups. Ileal GLUT2 protein abundance in the 72-h TPN+SCFA group was significantly higher (P < 0.05) than that of all other groups. Sodium-glucose cotransporter (SGLT-1) mRNA and protein abundance and uptake of D-fructose and D-glucose did not differ between groups. Jejunal uptake of L-glucose and lauric acid was significantly higher (P < 0.05) after 72 h of TPN+SCFA than after 24 h, whereas the 24- and 72-h TPN groups did not differ. In summary, SCFAs led to rapid changes in ileal proglucagon and glucose transporter expression in rats receiving TPN and provide insights into therapeutic management of individuals with short bowel syndrome or intestinal malabsorption syndromes.

Animal Nutritional Physiological Phenomena↗
PubMed1998

Proglucagon and glucose transporter mRNA is altered by diet and disease susceptibility in 30-day-old biobreeding (BB) diabetes-prone and normal rats.

Diet is an important factor influencing the development of diabetes in the Biobreeding (BB) rat. Changes in gut development and absorption of nutrients in the diabetes-prone rat (Bbdp) and the subsequent effect on pancreatic function may play a role in the ultimate development of the disease. BBdp and normal (BBn) dams were fed one of three diets, chow or semipurified diets containing either soy or casein as the protein source. Pups were weaned at 21 d onto the same diet as their respective dam and killed at 30 d. Chow-fed BBn animals weighed significantly more than casein- or soy-fed BBn animals. Chow-fed BBdp had significantly greater small intestine and colon weight when expressed on a per body weight basis than BBn. With all three diets, BBdp animals had significantly lower colonic proglucagon mRNA abundance than did BBn animals. Adjusting for total colonic RNA content resulted in only casein- and soy-fed BBdp animals demonstrating significantly lower colonic proglucagon mRNA abundance than did BBn animals. BBn animals had higher levels of sodium-dependent D-glucose cotransporter (SGLT)-1 and sodium-independent glucose transporter (GLUT) 5 mRNA than did BBdp. Within BBn animals, casein and soy produced significantly lower levels of SGLT-1 and GLUT5 mRNA than did chow. This study demonstrates that BBn and BBdp animals respond differently to chow versus semipurified weaning diets. These differences may explain the differences in growth and intestinal development among the BBdp and BBn strains weaned onto different diets.

Animals↗
PubMed1991

Regulation of intestinal proglucagon-derived peptide secretion by intestinal regulatory peptides.

The physiological regulation of intestinal proglucagon-derived peptide secretion has not been well studied. We have therefore used a fetal rat intestinal cell culture model to investigate the control of secretion of the gut glucagon-like immunoreactive (GLI) peptides by other intestinal regulatory peptides in vitro. Secretion of the intestinal GLI peptides was found to be stimulated in a dose-dependent fashion by the intestinal endocrine peptide, gastric inhibitory peptide (at greater than or equal to 10(-10) M, P less than 0.05), and by the neurocrine peptides, gastrin-releasing peptide (at greater than or equal to 10(-12) M, P less than 0.05), and calcitonin gene-related peptide (at greater than or equal to 10(-8) M, P less than 0.05). Gastrin-releasing peptide and its amphibian equivalent, bombesin were equipotent in stimulating GLI peptide secretion. In contrast, the endocrine and neurocrine intestinal somatostatin-related peptides, somatostatin-28 and -14, inhibited release of the GLI peptides, at concentrations of 10(-10) (P less than 0.01) and 10(-8) (P less than 0.01) M, respectively, with significant differences in potency between the two peptides detected at 10(-10) M (P less than 0.05). The inhibitory effects of both somatostatin-28 and -14 could be blocked by preincubation of the cells with pertussis toxin (P less than 0.05). Dose-dependent stimulation of gut GLI peptide secretion was also detected in response to treatment of cultured cells with sodium oleate (at 10(-4) M; P less than 0.05), or with the cholinergic agonist bethanecol (at greater than or equal to 100 microM; P less than 0.05). Other endocrine [cholecystokinin, glucagon, glucagon-like peptide-1(1-37), glucagon-like peptide-1(7-37), glucagon-like peptide-2, neurotensin, and peptide YY] and neurocrine (vasoactive intestinal peptide) peptides, and the synthetic glucocorticoid, dexamethasone, were without effect on secretion of the gut GLI peptides, at doses of 10(-12) to 10(-6) M. The results of the present study therefore demonstrate that secretion of the intestinal proglucagon-derived peptides is under the regulatory control of a wide variety of intestinal endocrine and neurocrine peptides, as well as nutrients (fats) and neurotransmitters (acetylcholine).

Animal Nutritional Physiological Phenomena↗
PubMed2005

Role of Cdx-2 in insulin and proglucagon gene expression: a study using the RIN-1056A cell line with an inducible gene expression system.

Although the homeobox gene Cdx-2 was initially isolated from the pancreatic beta cell line HIT-T15, no examination of its role in regulating endogenous insulin gene expression has been reported. To explore further the role of Cdx-2 in regulating both insulin and proglucagon gene expression, we established an ecdysone-inducible Cdx-2 expression system. This report describes a study using the rat insulinoma cell line RIN-1056A, which abundantly expresses both insulin and proglucagon (glu), and relatively high amounts of endogenous Cdx-2. Following the introduction of the inducible Cdx-2 expression system into this cell line and the antibiotic selection procedure, we obtained novel cell lines that displayed dramatically reduced expression of endogenous Cdx-2, in the absence of the inducer. These novel cell lines did not express detectable amounts of glu mRNA or the glucagon hormone, while their insulin expression was not substantially affected. In the presence of the inducer, however, transfected Cdx-2 expression was dramatically increased, accompanied by stimulation of endogenous Cdx-2 expression. More importantly, activated Cdx-2 expression was accompanied by elevated insulin mRNA expression, and insulin synthesis. Cdx-2 bound to the insulin gene promoter enhancer elements, and stimulated the expression of a luciferase reporter gene driven by these enhancer elements. Furthermore, Cdx-2 and insulin gene expressions in the wild-type RIN-1056A cells were stimulated by forskolin treatment, and forskolin-mediated activation on insulin gene expression was attenuated in the absence of Cdx-2. We suggest that Cdx-2 may mediate the second messenger cAMP in regulating insulin gene transcription.

Animals↗
PubMed1985

[Computer bank of amino-acid sequences of protein hormones. Analysis of evolutionary, conformational and physico-chemical properties of the individual sites of sequences in superfamilies of proinsulin and proglucagon].

The correspondence schemes for the amino acid sequence families from different animal species for two superfamilies of protein-peptide hormones and their precursors, i.e., proinsulin-IGF-prorelaxin and proglucagon-pro (PHM-VIP)-prosomatocrinin, were constructed. These schemes were used for the local intra- and interfamilial comparison of the sequences; the average profiles of hypothetical secondary structure of individual sites of these sequences according to Chow and Fasman were obtained, and the profiles of their physico-chemical properties (e. g., hydrophobicity and volume of side amino acid radicals) were computed. An analysis of the profiles obtained demonstrated that despite the apparent similarity of the tertiary structure of IGF and relaxin, on the one hand, and of insulin, on the other, the latter is devoid of the insulin-like receptor (effector) site, whereas in the case of IGF, this site is modified by additional links of the peptide chain. Based on the reciprocal comparison of prosomatocrinin with proglucagon and pro (PHM-VIP), it was assumed that the C-terminal fragment of prosomatocrinin separated from somatocrinin by a single arginine residue is a second glucagon-like peptide in the precursor molecule, which apparently possesses a biological activity.

Amino Acid Sequence↗
PubMed1999

Insulin and proglucagon-derived peptides from the horned frog, Ceratophrys ornata (Anura:Leptodactylidae).

Insulin and peptides derived from the processing of proglucagon have been isolated from an extract of the pancreas of the South American horned frog, Ceratophrys ornata (Leptodactylidae). Ceratophrys insulin is identical to the insulin previously isolated from the toad, Bufo marinus (Bufonidae). Ceratophrys glucagon was isolated in two molecular forms with 29- and 36-amino acid residues in approximately equal amounts. Glucagon-29 is identical to glucagon from B. marinus and from the bullfrog, Rana catesbeiana (Ranidae) and contains only 1 amino acid substitution (Thr29 --> Ser) compared with glucagon from Xenopus laevis (Pipidae). Glucagon-36 comprises glucagon-29 extended from its C-terminus by Lys-Arg-Ser-Gly-Gly-Met-Ser. This extension is structurally dissimilar to the C-terminal octapeptide of mammalian oxyntomodulin and resembles more closely that found in C-terminally extended glucagons isolated from fish pancreata. Ceratophrys glucagon-like peptide-1 (GLP-1) (His-Ala-Asp-Gly-Thr-Tyr-Gln-Asn-Asp-Val10-Gln-Gln-Phe-Leu-Glu- Glu-Lys-Ala-Ala-Lys20-Glu-Phe-Ile-Asp-Trp-Leu-Ile-Lys-Gly- Lys30-Pro-Lys-Lys-Gln-Arg-Leu-Ser) contains 3 amino acid substitutions compared with the corresponding peptide from B. marinus, 8 substitutions compared with GLP-1 from R. catesbeiana, and between 4 and 11 substitutions compared with the three GLP-1 peptides identified in X. laevis proglucagon. GLP-2 was not identified in the extract of Ceratophrys pancreas. The data indicate that, despite its importance in the regulation of glucose metabolism, the primary structure of GLP-1 has been very poorly conserved during evolution, even among a single order such as the Anura.

Amino Acid Sequence↗
PubMed1995

Role of glutamate in regulating hypothalamic proglucagon-derived peptide secretion in vitro.

We have previously demonstrated expression of the proglucagon gene and synthesis and secretion of the proglucagon-derived peptides (PGDPs) in the fetal rat hypothalamus. The excitatory amino acid glutamate has been found to be a key regulator of hypothalamic neuroendocrine hormone secretion. Therefore, the effects of glutamate on hypothalamic PGDP secretion and synthesis were examined in the present study, using the hypothalamic culture model. Glutamate (10 microM) significantly stimulated PGDP secretion (P < 0.01), but had no effect on the total PGDP content of the cultures over 24 hr of incubation. Similarly, the metabotropic/ionotropic glutamate receptor agonist, quisqualic acid (10 microM) stimulated PGDP secretion only ( P < 0.05). In contrast, the ionotropic glutamate receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 10 microM) and antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM), had no effects on either secretion or content of the hypothalamic PGDPs. These findings suggest that excitatory amino acids, and glutamate in particular, regulate secretion but not synthesis of the PGDPs in the hypothalamus.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

Typical Danish Caucasian type 2 diabetic patients do not commonly carry genetic variants in GIP and GLP-1 encoding regions of the proGIP and proglucagon genes.

BACKGROUND: The enteroinsular-axis is abnormal in type 2 diabetics, which contributes to the diabetic phenotype. The effect of the incretin hormone gastric inhibitory polypeptide (GIP) and the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) are thus greatly diminished. The explanation for these changes could be changes in the structure of either of the hormones or their receptors. Thus, the aim of this study was to study the occurrence of genetic variants in the GIP and GLP-1 encoding regions of the proGIP and proglucagon genes in type 2 diabetic patients and matched control subjects. METHODS AND RESULTS: Genomic DNA was extracted from buffy coats from 12 Caucasian type 2 diabetics and 12 healthy subjects, matched with respect to sex, age and BMI. The GIP and GLP-1 sequences were amplified using specific primers using the polymerase chain reaction (PCR). The amplified products were then sequenced. No germ-line mutations were identified in the GIP and the GLP-1 encoding regions of the proGIP and proglucagon genes in either the type 2 diabetic or the control subjects. CONCLUSIONS: The perturbed incretin effect in type 2 diabetics is not commonly caused by genetic variants in either the GIP or the GLP-1 encoding genes in type 2 diabetics.

Aged↗
PubMed1981

Relationship of glicentin to proglucagon and glucagon in the porcine pancreas.

We have previously isolated from porcine small intestine a peptide known as glicentin. The C-terminal portion of glicentin consists of the sequence of glucagon extended at its C terminus by an octapeptide, and differs slightly from the sequence of a proposed fragment of proglucagon. Glicentin-like material has been demonstrated in the pancreatic A cell, wherein it is located in the periphery of the secretory granules, whereas glucagon is located in the centre of the granules. To study the relationship of glicentin to the biosynthesis of glucagon, we have now investigated the glucagon-like and glicentin-like peptides in extracts and perfusates of the porcine pancreas. Our findings that a peptide with glicentin-like immunoreactivity, and intermediate in size between glicentin and glucagon, is secreted synchronously with glucagon suggest that this glicentin-related peptide is a major cleavage product of proglucagon.

Animals↗
PubMed1976

Elevated plasma proglucagon-like component with a glucagon-secreting tumor. Effect of streptozotocin.

To determine the character of the glucagon secretion and its modification by streptozotocin, were studied the plasma of a patient with recurrent pancreatic alpha-cell carcinoma. The plasma immunoreactive glucagon level before treatment of 4.80 ng per milliliter. Biogel column separation of the plasma immunoreactive glucagon revealed four components; the predominant component had a molecular weight of 9000 daltons and was designated as proglucagon-like. This fraction constituted 60 to 90 per cent of the total circulating immunoreactive glucagon, and had a biologic activity of 32 percent of that of an immunoequivalent amount of normal (porcine) pancreatic glucagon. After treatment with streptozocin (1.5 g per square meter) the plasma immunoreactive glucagon level decreased to 0.24 ng per milliliter. Treatment was accompanied by a marked reduction in the proglucagon-like component and the appearance of pancreatic glucagon (molecular weight of 3500 daltons) as the major post-therapy fraction. These findings support the use of streptozotocin in the management of unresectable glucagon-secreting tumors.

Adenoma, Islet Cell↗
PubMed2002

Ancient duplications of the human proglucagon gene.

The human proglucagon gene (GCG) is encoded within a finished 576-kb DNA sequence generated by the Human Genome Project. GCG is flanked by 18 kb and 65 kb of DNA, 5' and 3', respectively, that do not encode genes. The genomic sequence that includes GCG was found to have a long history of gene duplication events. Some members of the glucagon-like family of genes, GCG on chromosome 2 and GIP on chromosome 17, may be products of ancient genome duplications on the early vertebrate lineage. A large genomic tandem duplication event that included DPP4-like and GCG genes occurred before the amphibian-mammal divergence, but one of the duplicated copies of GCG has been lost on the human lineage. Recently, a processed pseudogene of the X-chromosome-linked gene TIMM8A was inserted downstream of GCG. Some ancient duplicates of GCG may retain physiological functions in other vertebrates.

Animals↗
PubMed2004

Protein hydrolysates stimulate proglucagon gene transcription in intestinal endocrine cells via two elements related to cyclic AMP response element.

AIMS/HYPOTHESIS: Protein hydrolysates (peptones) increase not only glucagon-like peptide-1 (GLP-1) secretion but also transcription of the proglucagon ( PG) gene in the intestine. The critical physiological roles of gut-derived GLPs raised hope for their therapeutic use in several disorders, especially GLP-1 in diabetes. We aimed to investigate the molecular mechanisms involved in this nutrient- PG gene interaction. METHODS: Wild-type and mutated PG promoter fragments fused to the luciferase reporter gene were transfected into enteroendocrine STC-1 cells, which were then either treated or not with peptones. Co-transfection with expression vectors of dominant-negative forms of cAMP response element binding protein (CREB) and protein kinase A (PKA) proteins were performed, as well as electrophoresis mobility shift assays. RESULTS: Deletion analysis showed that the promoter region spanning between -350 and -292 bp was crucial for the transcriptional stimulation induced by peptones. Site-directed mutagenesis of the canonical cAMP response element (CRE(PG)) and of the adjacent putative CRE site (CRE-like1) led to a dramatic inhibition of the promoter responsiveness to peptones. Over expression of a dominant-negative mutant of CREB or of PKA produced a comparable and selective inhibitory effect on the activity of transfected promoter fragment containing the -350/-292 sequence. EMSA showed that CREB and fra2 transcription factors bound to CRE(PG) and CRE-like1 elements respectively, independently of peptone treatment. CONCLUSIONS/INTERPRETATION: Our report identified cis- and trans-regulatory elements implicated in the transcriptional control of PG gene by nutrients in enteroendocrine cells. It highlights the role of a previously unsuspected CRE-like1 element, and emphasises the importance of CRE-related sequences in the regulation of PG gene transcription in the intestine.

Animals↗
PubMed1999

Comparison of the postprandial release of peptide YY and proglucagon-derived peptides in the rat.

Endocrine L-cells of the distal intestine synthesize both peptide YY (PYY) and proglucagon-derived peptides (PGDPs), whose release has been reported to be either parallel or selective. Here we compare the release mechanisms of PYY, glucagon-like peptide-1 (GLP-1), and oxyntomodulin-like immunoreactivity (OLI) in vivo. Anaesthetized rats were intraduodenally (ID) given either a mixed semi-liquid meal or oleic acid, or they received oleic acid or short chain fatty acids (SCFA) intracolonically (IC). The ID meal released the three peptides with a similar time-course (peak at 30 min); ID oleic acid produced a progressive release of PYY and OLI, while GLP-1 release was less. IC oleic acid or SCFA released smaller (but significant) amounts of PYY but no OLI or GLP-1. Hexamethonium inhibited most of the response to the ID meal and ID oleic acid, but did not change the PYY response to IC oleic acid. NG-nitro-l-arginine methyl ester (l-NAME, a nitric oxide synthase inhibitor) inhibited meal-induced PYY release and left OLI and GLP-1 unaffected. BW10 (a gastrin-releasing peptide antagonist) had no effect on the meal-induced release of either peptide. These results suggest a parallel initial release of PYY, OLI and GLP-1 after the ID meal, or oleic acid, by an indirect mechanism triggered in the proximal bowel, using nicotinic synapses, and involving nitric oxide release for PYY and an unknown mediator for PGDPs. For PYY there is a later phase of peptide release, probably induced by direct contact between nutrients and colonic L-cells.

Animals↗
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↗
PubMed1987

Glucagon, glicentin, proglucagon, PYY, PP and proPP-icosapeptide immunoreactivities of rectal carcinoid tumors and related non-tumor cells.

Glucagon/PP-related peptides were detected immunohistochemically in 18 out of 22 cases of rectal tumors investigated. The reactive tumors showed prevalence of trabecular or mixed trabecular-acinar structure and moderate staining with Grimelius' silver and lead-hematoxylin. Three of the remaining 4 cases were characterized by reactivity for 5-hydroxytryptamine only, prevalence of a solid nest structural component and intense staining with Grimelius' silver technique and lead-hematoxylin. Fifteen of the 18 glucagon/PP-reactive cases were investigated immunohistochemically with a series of 6 sera directed against different sequences of glucagon, glicentin and proglucagon, and of 7 sera directed against PP, PYY and proPP-icosapeptide. A large spectrum of glucagon-related immunoreactivities, including C-terminus and mid-portion glucagon-immunoreactivity, N- and C-terminus glicentin-immunoreactivity, GLP1- and GLP2-immunoreactivity, were detected in human rectal L cells and most rectal carcinoids. With the exception of a few scattered cells in the rectal mucosa and in 3 tumors, C-terminus glucagon-immunoreactivity was obtained only after trypsin or subtilisin treatment of tissue sections. Both PYY and PP/proPP-like peptide(s) were detected in rectal L cells and carcinoids, with prevalence of PYY in normal cells and PP/proPP-like peptides in tumor cells. It is concluded that the same or closely related hormone/prohormone sequences are synthesized and stored in rectal endocrine cells and carcinoid tumors although differences of quantitative expression, post-translational cleavage or reactivity to antibodies may occur. The usefulness of protease treatments of tissue sections to unmask immunoreactivities of uncleaved propeptides or fixative-denatured peptides is outlined.

Animals↗