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Results for “Proglucagon”

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At least 19 recordsLinked to original sources

PubMed1992

Alterations in proglucagon processing and inhibition of proglucagon gene expression in transgenic mice which contain a chimeric proglucagon-SV40 T antigen gene.

The proglucagon gene is expressed in A cells of the pancreas and L cells of the large and small intestine. Transgenic mice expressing SV40 large T antigen under the control of proglucagon regulatory sequences develop neuroendocrine carcinoma of the large intestine. To determine the consequences of coexpression of SV40 large T antigen and proglucagon in different cell types, the levels of proglucagon mRNA transcripts and proglucagon-derived peptides were determined in tumor-bearing transgenic mice and in age-matched paired controls. Plasma levels of proglucagon-derived peptides (glicentin, oxyntomodulin, and glucagon, as determined by high pressure liquid chromatography and radioimmunoassay) were markedly elevated in association with tumor growth (p < 0.001). Northern blot analysis demonstrated that the increased concentration of proglucagon-derived peptides was associated with significant inhibition of the endogenous proglucagon gene in pancreas, and to a lesser extent, small intestine. Concomitantly, the concentrations of proglucagon-derived peptides fell to 1-10% of control values in pancreas (p < 0.001) and to 62% of control values in small intestine (p < 0.001). Analysis of proglucagon-derived peptides in mice of different ages demonstrated that tumor growth was associated with a switch in the post-translational processing of proglucagon. Compared with normal mouse intestine, tumors contained increased proportions of glucagon and glucagon-like peptide-1(7-37) relative to glicentin, oxyntomodulin, and glucagon-like peptide-1(1-37). The results of these studies provide evidence for humorally-mediated tissue-specific inhibition of proglucagon gene expression.

Animals↗

PubMed1988

Naturally occurring products of proglucagon 111-160 in the porcine and human small intestine.

Recent studies have revealed that the glucagon gene is expressed in the mammalian intestine. Here it codes for "glicentin" (proglucagon 1-69) and a glucagon-like peptide, proglucagon 78-107, recently isolated from porcine intestine. We studied the fate of the remaining COOH-terminal part of proglucagon (proglucagon 111-160) using radioimmunoassays against proglucagon 111-123 and 126-160. Two peptides were isolated from acid ethanol extracts of porcine ileal mucosa and sequenced: one corresponding to proglucagon 126-158 and one probably corresponding to proglucagon 111-158. By comparing human and porcine proglucagon sequences, Ala117 is replaced by Thr, and Ile138, Ala144, Ile152 and Gln153 are replaced by Val, Thr, Leu, and His. By gel filtration and radioimmunoassay of intestinal extracts it was established that a large part of porcine and virtually all of human proglucagon are processed to release proglucagon 111-123 (designated spacer peptide 2), which, like proglucagon 126-158 must be considered a potential hormonal entity. By isocratic high pressure liquid chromatography human spacer peptide 2 was indistinguishable from synthetic proglucagon 111-122 amide, suggesting that this is the structure of the naturally occurring human peptide.

Amino Acid Sequence↗

PubMed1989

Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine.

Expression of the gene encoding preproglucagon gives rise to different glucagon-related peptides in the pancreas and intestine. Glucagon gene expression is regulated by a protein kinase C-dependent pathway in rat islet cell lines, whereas activation of the adenylate cyclase pathway in islet cell lines is without effect. To elucidate the factors important for the control of proglucagon biosynthesis in the intestine, we have studied proglucagon gene expression and proglucagon biosynthesis in rat intestine. Analysis of intestinal cDNA clones encoding preproglucagon indicated that pancreatic and intestinal glucagon mRNA transcripts were identical. The regulation of proglucagon gene expression in rat intestine differed markedly from that previously observed in islet cell lines. Phorbol esters increased the secretion of glucagon-like immunoreactive peptides (GLI) but had no effect on proglucagon mRNA levels in rat intestinal cells. Bombesin also increased the secretion of GLI without affecting proglucagon mRNA levels or biosynthesis. In contrast, dibutyryl cyclic AMP, forskolin, and cholera toxin increased both proglucagon mRNA levels and GLI biosynthesis and secretion, suggesting that proglucagon gene expression in the intestine is regulated by a cyclic AMP-dependent pathway. These observations suggest that tissue-specific differences in both the regulation of proglucagon gene expression and the posttranslational processing of proglucagon contribute to the diversity of glucagon gene expression.

Animals↗

PubMed1986

Early O-glycosidic glycosylation of proglucagon in pancreatic islets: an unusual type of prohormonal modification.

Proglucagon from rat islets is identified as a glycoprotein by its binding to soybean lectin and by the biosynthetic incorporation of [14C]galactosamine. Glycosylation can be demonstrated for both forms of proglucagon, i.e. the primary translation product which is detectable as early as 30 s after incubation of isolated islets with radioactive amino acids (proglucagon a), and its conversion product of slightly higher electrophoretic mobility which is formed after 5-10 min of incubation (proglucagon b). This glycosylation is determined to be of the O-glycosidic type by the following criteria: rat proglucagon has previously been shown to lack an acceptor sequence for N-glycosidic linkage of sugars, the sugar bond in rat proglucagon is labile under mild alkaline conditions, glycosylated serine is demonstrated in proteolytic lysates of both the early and the late form of this prohormone. O-glycosidic linkage of sugars has not been reported for other prohormones. Its early formation and the apparent absence of N-glycosidically bound sugars in proglucagon give evidence for an unusual type of protein glycosylation.

Animals↗

PubMed1992

Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection.

To assess potential mediators of adaptive bowel growth, ileal proglucagon messenger RNA (mRNA) ornithine decarboxylase (ODC) mRNA, plasma enteroglucagons, and plasma glucagonlike peptide I (GLP-I) were analyzed in rats soon after jejunoileal resection or control transection. Analyses were performed before and after refeeding to establish whether responses are nutrient dependent. The elevation of ileal proglucagon and ODC mRNAs within 12 hours after resection and before refeeding shows a nutrient-independent component of the adaptive response. The onset of adaptive growth of the ileum required luminal nutrient but occurred very rapidly, within 4 hours of refeeding. The onset of adaptive growth was accompanied by transient elevation of ileal ODC mRNAs. Ileal proglucagon mRNA and plasma GLP-I levels were also elevated, and these increases were sustained up to 8 days after resection. These early and sustained increases in proglucagon mRNA and plasma GLP-I indicate that in addition to the enteroglucagons, other intestinal proglucagon-derived peptides must be considered as potential mediators of adaptive growth after jejunoileal resection.

Adaptation, Physiological↗

PubMed1990

Developmental and tissue-specific regulation of proglucagon gene expression.

The pattern of glucagon gene expression and the posttranslational processing of proglucagon was studied in the fetal and neonatal rat. Pancreatic immunoreactive glucagon (IRG) and glucagon-like immunoreactivity (GLI) were low in both fetal pancreas and intestine, respectively. Immediately after birth, pancreatic IRG rose markedly and reached a peak concentration at postnatal day 7, followed by a gradual return to its adult level. Intestinal GLI was low until postnatal day 7 and rose steadily thereafter to adult levels. The levels of GLI in the hypothalamus were much lower than in intestine, yet the developmental accumulation of hypothalamic GLI resembled the pattern observed in intestine. In contrast, the levels of GLI and IRG in the brain stem were higher in the fetus and neonate, and decreased to adult levels. Proglucagon mRNA transcripts, uniform in size, were detected in RNA isolated from fetal or adult brainstem, pancreas, and intestine. However, fetal proglucagon mRNA transcripts were larger than adult proglucagon mRNA transcripts in pancreas and intestine, but not brainstem. The results of RNAse mapping studies, including analysis of both the 5'- and 3'-ends of the mRNA transcripts, demonstrated that the larger fetal mRNA transcripts could be accounted for by an increase in the length of the polyadenylate tail in the fetal tissues. These observations demonstrate that the developing rat exhibits tissue-specific differences in both proglucagon gene expression and the pattern of posttranslational processing of the prohormone.

Animals↗

PubMed1991

Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine.

We investigated the major products of proglucagon (PG) processing in plasma in the fasting state, after intravenous arginine and after an oral glucose load in noninsulin-dependent diabetics (NIDDM) and in weight matched controls using specific radioimmunoassays and analytical gel filtration. In the fasting state the glucagonlike peptide-1 (GLP-1) immunoreactivity was significantly elevated in the NIDDM group compared with the control group. Both after intravenous arginine and after an oral glucose load a rise in the plasma concentrations of all immunoreactive moieties measured was seen. All integrated incremental responses after intravenous arginine were identical in the two groups. After oral glucose the insulin concentrations in plasma were lower and the concentrations of all proglucagon products were higher in the NIDDM group compared to the control group. The gel filtration analysis showed that arginine stimulated the secretion of pancreatic glucagon (PG 33-61), major proglucagon fragment (PG 72-158) and probably GLP-1 (PG 72-107 amide) in both groups, whereas oral glucose stimulated the secretion of glicentin (PG 1-69) and intestinal GLP-1 (PG 78-107 amide), an insulinotropic hormone. The elevated levels of immunoreactive GLP-1 in diabetics in the fasting state were mainly due to an increased concentration of major proglucagon fragment.

Administration, Oral↗

PubMed1988

Proglucagon gene expression and posttranslational processing in a hamster islet cell line.

Expression of the gene encoding glucagon was studied using a BK virus-induced glucagon-producing hamster islet cell line, InR1-G9 cells. Southern blot analysis of InR1-G9 DNA demonstrated that glucagon gene sequences are not amplified, yet appear to be hypomethylated compared to hamster liver or kidney DNA. Northern blot analysis of RNA from InR1-G9 cells detected a single glucagon mRNA species of 1300 basepairs. Phorbol esters and sodium butyrate, agents that increase glucagon gene transcription in RIN1056A cells, have no effect on glucagon mRNA levels in InR1-G9 cells. Posttranslational processing of proglucagon, as analyzed by gel filtration chromatography and RIA, resulted in the liberation of glucagon, glucagon-like peptide I, and glucagon-like peptide II, partially mimicking the processing of proglucagon in pancreas and intestine, yet differing from that previously observed in RIN1056A cells. Secretion of glucagon and the glucagon-like peptides was stimulated 3-fold after 1-h incubations with phorbol esters. These observations suggest that the determinants of glucagon gene expression and the posttranslational processing of proglucagon are highly cell specific and provide a new model for the study of proglucagon biosynthesis.

Animals↗

PubMed1989

Tissue-specific differences in the levels of proglucagon-derived peptides in streptozotocin-induced diabetes.

The synthesis and secretion of proglucagon-derived peptides are regulated in a tissue-specific manner in pancreas, intestine, and brain. We have examined the plasma and tissue levels of these peptides during the first 3 weeks of streptozotocin (STZ)-induced diabetes in the rat. Plasma glucose levels were markedly elevated (P less than 0.0001) within 24 h of STZ administration. The plasma levels of glucagon-like immunoreactive (GLI) peptides were significantly elevated on days 8-22 of diabetes (P less than 0.05-0.001). Ileal GLI peptide concentrations rose in parallel with the plasma levels (r = 0.39; P less than 0.006) to 250% of control levels (P less than 0.001); however, pancreatic GLI peptide content increased only transiently on day 1 (P less than 0.05). No significant differences in the posttranslational processing of proglucagon in normal or diabetic rats could be detected. The increment in ileal GLI peptide content was not associated with increases in intestinal proglucagon mRNA transcripts. In contrast, pancreatic, but not intestinal, somatostatin mRNA levels were increased on day 22 of diabetes. Diabetic rats were found to have small but significant changes in GLI and immunoreactive glucagon peptide content of the hypothalamus and medulla oblongata (P less than 0.05). These observations suggest that STZ-induced diabetes may produce tissue-specific perturbations in the biosynthesis and secretion of the proglucagon-derived peptides.

Animals↗

PubMed1990

Glucagon gene 3'-flanking sequences direct formation of proglucagon messenger RNA 3'-ends in islet and nonislet cells lines.

Glucagon and the glucagon-like peptides are encoded within a larger precursor, proglucagon. Transcription of the glucagon gene in pancreas, intestine, and brain gives rise to identical proglucagon mRNA transcripts, after which tissue-specific post-translational processing produces different profiles of proglucagon-derived peptides in each tissue. The importance of glucagon gene 3'-untranslated and 3'-flanking sequences in the control of glucagon mRNA production was studied by transfecting a series of 3'-deleted glucagon genes into fibroblast and islet cell lines. Glucagon genes containing 2 kilobases of 3'-flanking sequences gave rise to accurately processed mRNA transcripts in both baby hamster kidney fibroblasts and InR1-G9 islet cell lines. Deletion of all but 50 basepairs of 3'-flanking sequence had no effect on glucagon mRNA 3'-end formation. In contrast, additional deletion of 3'-flanking and 3'-untranslated sequences resulted in the production of read-through mRNA transcripts with aberrant 3'-ends. The results of these studies define a 50-basepair region in the 3'-flanking sequence of the glucagon gene important for the accurate processing of proglucagon mRNA transcripts.

Animals↗

PubMed1991

Proglucagon-derived peptides in the neuroendocrine system.

Using several novel in vitro culture systems, we have examined the tissue-specific regulation of the proglucagon-derived peptides, at the levels of proglucagon gene expression and pGdp synthesis and secretion. Our studies indicate that proglucagon gene expression in intenstine, hypothalamus and pancreas is under the regulatory control of protein kinase A- but not a protein kinase C-dependent pathway. PKA and PKC stimulate secretion of the intestinal pGdp's, whereas only PKA stimulates secretion of the hypothalamic peptides. Pancreatic glucagon secretion in response to PKA is subject to further modulation by prevailing glucose concentrations. This diversity in intracellular regulation of the pGdp's may account for some of the tissue-specific differences in synthesis and secretion of the pGdp's that we have observed in diabetes and during development.

Animals↗

PubMed1989

Proglucagon expression, posttranslational processing and secretion in SV40-transformed islet cells.

HIT T15 is a B cell line derived from SV40 transformation of hamster islets. We describe here a HIT T15 variant, designated HIT T15-G, which appears to have evolved spontaneously and which expresses glucagon. Regulation of glucagon gene expression, posttranslational processing of proglucagon, and secretion of glucagon were studied in this cell line. Glucagon mRNA concentrations were increased approx. 2-fold following incubation of cells for 18 h in 10 microM forskolin but were unaffected by treatment with a phorbol ester (12-O-tetradecanoylphorbol 13-acetate; TPA) or with ionomycin. Proglucagon was processed to glucagon, and several large molecular weight forms of GLP-I and GLP-II which may include the major proglucagon fragment (MPF). The secretion of glucagon was stimulated by forskolin (5-fold), adrenalin (2-fold), arginine (3-fold) and KCl (2-fold) but was unaffected by glucose. These results suggest that the HIT T15-G cells may represent a less differentiated form of the parental HIT T15 cell line in which A cell phenotype is dominant but not complete.

Animals↗

PubMed1988

Pancreatic proglucagon processing: isolation and structures of glucagon and glucagon-like peptide from gene I.

The anglerfish endocrine pancreas expresses two different genes for preproglucagon. The regions of the two proglucagons that correspond to glucagon have different sequences, as do the two glucagon-like peptides (GLPs). The products derived from processing the more abundant proglucagon-II have recently been determined. However, it was not known whether proglucagon-I was processed to similar products. The two major biologically active products of preproglucagon-I processing (glucagon-I and GLP-I) have now been purified to homogeneity. Their structures were determined using automated gas phase Edman degradation, tryptic mapping, and fast atom bombardment mass spectrometry. The preproglucagon-I-processing sites were identified. Glucagon-I represents residues 53-81, and GLP-I corresponds to preproglucagon-I-(91-124) (numbering from the initiator Met).

Amino Acid Sequence↗

PubMed1990

Proglucagon processing similar to normal islets in pancreatic alpha-like cell line derived from transgenic mouse tumor.

A pancreatic alpha-like cell line has been established from a glucagonoma arising in transgenic mice expressing a hybrid gene consisting of the rat glucagon-promoter sequence fused to the sequence encoding the SV40 T-antigen oncoprotein. The alpha-tumor cell 1 (alpha TC1) line maintained many characteristics of differentiated alpha-cells for greater than 40 passages in culture and expressed levels of glucagon mRNA 5- to 10-fold higher than those reported previously in rat and hamster islet cell lines. By radioimmunoassay, the cells synthesized considerable amounts of glucagon, glucagonlike peptide I (GLP-I), the major proglucagon fragment, and small amounts of unprocessed proglucagon but no free GLP-II. This distribution of peptides is similar to that found in extracts of rodent pancreases and is distinct from that seen with other islet cell lines, which process proglucagon in patterns more characteristic of intestinal cells. The GLP-I peptide in the alpha TC1 cell line was in the form of GLP-I-(1-37), which is inactive as a stimulator of insulin secretion, and not GLP-I-7-37) or -(7-36)-amide peptides, both of which are potent insulin secretagogues. The alpha TC1 cell line produced glucagon-related peptides in a relatively uniform pattern by immunocytochemistry, and electron microscopy revealed typical alpha-type (glucagon) secretory granules. Although the cell line was derived from an islet tumor producing only glucagon, the alpha TC1 cell line also produced insulin in addition to the glucagon peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Islet Cell↗

PubMed1988

Truncated glucagon-like peptide-1 (proglucagon 78-107 amide), an intestinal insulin-releasing peptide, has specific receptors on rat insulinoma cells (RIN 5AH).

We studied binding of 125I-labelled truncated-glucagon-like peptide-1 (proglucagon 78-107 amide) to a cloned rat insulin-producing cell line, RIN 5AH, in monolayer culture. Interaction of the peptide with pancreatic insulinoma cells was saturable and time dependent. Half-maximal binding was obtained when the cells were incubated in the presence of 3.3 x 10(-9) mol/l unlabelled truncated-glucagon-like peptide-1 (proglucagon 78-107 amide). Neither glucagon, full-length glucagon-like peptide-1 (proglucagon 72-107 amide) nor gastric inhibitory peptide competed for binding in concentrations up to 10(-6) mol/l.

Adenoma, Islet Cell↗

PubMed1975

Isolation and partial characterization of anglefish proglucagon.

Evidence is presented that proglucagon from anglefish islets is a single chain polypeptide with 78 amino acid residues and that the glucagon portion of it is liberated after tryptic cleavage. The most striking characteristic in the conversion of the anglerfish proglucagon to glucagon is that the cleaved peptide bonds display enormous sensitivity toward trypsin. Thus, conversion of the prohormone to glucagon occurs very rapidly within 3-10 min with a 1:500-1:1000 molar ratio of enzyme to substrate. Further, trypic cleavage of the anglerfish glucagon requires higher concentrations of trypsin (molar ratio 1:25 enzyme to substrate) and longer incubation time. The behavior of proglucagon and glucagon toward trypsin shows striking similarities with the tryptic conversion of anglerfish proinsulin to insulin.

Amino Acid Sequence↗

PubMed1988

Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach.

We studied the effect of truncated glucagon-like peptide-1 [naturally occurring GLP-1; proglucagon-(78-107) amide], a potent insulinotropic peptide from the pig ileum, on endocrine and exocrine secretion of potential gastrointestinal target organs using isolated perfused preparations of the porcine pancreas, antrum, and nonantral part of the stomach. Truncated GLP-1 significantly increased somatostatin secretion from the pancreas at 10(-10) mol/liter and more than doubled the secretion at 10(-9) mol/liter, but had no effect on either somatostatin or gastrin secretion from the antrum or on somatostatin secretion from the nonantral stomach in concentrations up to 10(-8) mol/liter. Insulin secretion from the pancreas (with 7 mmol/liter glucose in the perfusate) increased 2-fold with truncated GLP-1 at 10(-10) mol/liter and almost 5-fold at 10(-9) mol/liter. Pancreatic glucagon secretion was inhibited by 50% at 10(-10) mol/liter and by 70-80% at 10(-9) mol/liter. Full-length GLP-1 [proglucagon-(72-107)] and GLP-2 [proglucagon-(126-159)] had no effect on hormone secretion from any of the perfused organs. It is concluded that truncated GLP-1 may participate in an entero-insular control of pancreatic endocrine secretion.

Animals↗

PubMed1992

The demonstration of a subset of carcinoid tumours of the appendix by in situ hybridization using synthetic probes to proglucagon mRNA.

Previous studies using immunohistochemistry have shown variable hormone production by carcinoid tumours of the appendix. In order to confirm the existence of a specific subset of these tumours, in situ hybridization using synthetic oligonucleotide probes to detect pre-proglucagon and pre-proinsulin mRNA was performed in formalin-fixed, paraffin-embedded material from eight tubular carcinoids, 12 insulin carcinoids, and two mucinous carcinoids. The results were correlated with standard silver and mucin stains. All tubular carcinoids but none of the insular or mucinous carcinoids contained proglucagon mRNA. Proinsulin mRNA was not detected in any of the tumours. Tubular carcinoids of the appendix constitute a definable subset of appendiceal carcinoids which have a similar distribution and prognosis to typical insular carcinoids and can be diagnosed on haematoxylin and eosin-stained sections confirmed by routine special stains. The main need for recognition is to avoid confusion with mucinous carcinoids, which have a worse prognosis and may require more aggressive treatment.

Appendiceal Neoplasms↗