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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been previously demonstrated that the enteric hormone glucagon-like peptide-1 (7-36 amide) (GLP-1) has acute effects on glucose-induced insulin secretion by RIN 1046-38 cells. In this study, we investigated the effects of extended exposure of RIN 1046-38 cells to GLP-1 and examine the mechanism by which GLP-1 synergizes with glucose in stimulating insulin secretion. Compared with cells cultured with glucose alone, incubation of cells with glucose plus 1 or 10 nM GLP-1 for 12 or 24 h significantly increased insulin release by about 3-fold, intracellular insulin content by 1.5-fold, and insulin messenger RNA (mRNA) by almost 2.5-fold. The insulinotropic effects of GLP-1 on RIN 1046-38 cells were accompanied by an up-regulation of both glucose transporter-1 (GLUT-1) and hexokinase I mRNA by about 2-fold. mRNA levels of GLUT-2 and glucokinase, which were low in controls, were unchanged by GLP-1 treatment. Treatment of cells with a transcription inhibitor, actinomycin D, demonstrated that elevated insulin mRNA levels after a GLP-1 exposure are mainly due to stabilization of the mRNA. In contrast, the elevated mRNA levels of GLUT-1 and hexokinase I are the result of increased transcription stimulated by GLP-1 exposure. Actinomycin D blunted the GLP-1 effect on insulin release but did not affect GLP-1 mediated elevation of insulin mRNA. This suggests that actinomycin D inhibits the transcription of the proteins necessary for insulin biosynthesis and insulin release, such as GLUT-1 and hexokinase I. Our study suggests that the mechanisms by which extended exposure of RIN 1046-38 cells to GLP-1 increases glucose-stimulated insulin secretion include significant up-regulation of glucose-sensing elements.
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PMID:Glucagon-like peptide-1 affects gene transcription and messenger ribonucleic acid stability of components of the insulin secretory system in RIN 1046-38 cells. 758 24

Glucagon-like peptide-1 7-36 amide (GLP-1) has been postulated to be the primary hormonal mediator of the entero-insular axis but evidence has been indirect. The discovery of exendin (9-39), a GLP-1 receptor antagonist, allowed this to be further investigated. The IC50 for GLP-1 receptor binding, using RIN 5AH beta-cell membranes, was found to be 0.36 nmol/l for GLP-1 and 3.44 nmol/l for exendin (9-39). There was no competition by exendin (9-39) at binding sites for glucagon or related peptides. In the anaesthetized fasted rat, insulin release after four doses of GLP-1 (0.1, 0.2, 0.3, and 0.4 nmol/kg) was tested by a 2-min intravenous infusion. Exendin (9-39) (1.5, 3.0, and 4.5 nmol/kg) was administered with GLP-1 0.3 nmol/kg, or saline, and only the highest dose fully inhibited insulin release. Exendin (9-39) at 4.5 nmol/kg had no effect on glucose, arginine, vasoactive intestinal peptide or glucose-dependent insulinotropic peptide stimulated insulin secretion. Postprandial insulin release was studied in conditioned conscious rats after a standard meal. Exendin (9-39) (0.5 nmol/kg) considerably reduced postprandial insulin concentrations, for example by 48% at 15 min (431 +/- 21 pmol/l saline, 224 +/- 32 pmol/l exendin, P < 0.001). Thus, GLP-1 appears to play a major role in the entero-insular axis.
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PMID:Glucagon-like peptide-1 is a physiological incretin in rat. 781 3

Glucagon-like peptide-1-(7-36) amide (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are known incretin hormones, released from enteroendocrine cells in response to food, that enhance insulin secretion, but only in the presence of elevated blood glucose. We used a rat insulinoma cell line, RIN 1046-38, to study the mechanisms underlying the interaction of incretins and glucose. We measured insulin secretion using RIA and the reverse hemolytic plaque assay. GLP-1 stimulates insulin secretion, with a half-maximal concentration of 34 pM. GLP-1 is approximately 2 orders of magnitude more potent than GIP. GLP-1 and GIP have additive effects at submaximal concentrations, but probably not at maximal concentrations, suggesting a common signal transduction pathway. The glucose requirement for GLP-1 action can be replaced by cell membrane depolarization (20 mM KCl in the extracellular medium), suggesting that a rise of intracellular Ca2+ may be an early step required for GLP-1 action. GLP-1 stimulates insulin secretion by significantly increasing the maximum rate of insulin secretion from 10.3 +/- 2.25 to 25.2 +/- 2.94 ng insulin/mg protein.h. GLP-1 acts by recruiting 1.5-fold more cells to secrete insulin as well as enhancing insulin secretion by individual cells. Combinations of stimuli, such as glucose, cell membrane depolarization, and GLP-1, can recruit 90% of RIN 1046-38 cells to secrete insulin.
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PMID:Incretin hormones regulate glucose-dependent insulin secretion in RIN 1046-38 cells: mechanisms of action. 803 7

Glucagon-like peptide-1(7-36)amide (tGLP-1), oxyntomodulin (OXM), and glucagon are posttranslational end products of the glucagon gene expressed in intestinal L-cells. In vivo, these peptides are potent inhibitors of gastric acid secretion via several pathways, including stimulation of somatostatin release. We have examined the receptors through which these peptides stimulate somatostatin secretion using the somatostatin-secreting cell line RIN T3. tGLP-1, OXM, and glucagon stimulated somatostatin release and cAMP accumulation in RIN T3 cells to similar maximum levels, with ED50 values close to 0.2, 2, and 50 nM and 0.02, 0.3, and 8 nM, respectively. Binding of [125I]tGLP-1, [125I]OXM, and [125I]glucagon to RIN T3 plasma membranes was inhibited by the three peptides, with relative potencies as follows: tGLP-1 > OXM > glucagon. Whatever the tracer used, the IC50 for tGLP-1 was close to 0.15 nM and was shifted rightward for OXM and glucagon by about 1 and 2-3 orders of magnitude, respectively. Scatchard analyses for the three peptides were compatible with a single class of receptor sites displaying a similar maximal binding close to 2 pmol/mg protein. In the hamster lung fibroblast cell line CCL39 transfected with the receptor for tGLP-1, binding of [125I]tGLP-1 was inhibited by tGLP-1, OXM, and glucagon, with relative potencies close to those obtained with RIN T3 membranes. Chemical cross-linking of [125I]tGLP-1, [125I]OXM, and [125I]glucagon revealed a single band at 63,000 mol wt, the intensity of which was dose-dependently reduced by all three peptides. These data suggest that in the somatostatin-secreting cell line RIN T3, OXM and glucagon stimulate somatostatin release through a tGLP-1-preferring receptor. This suggests that some biological effects, previously described for these peptides, might be due to their interaction with this receptor.
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PMID:Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line. 810 95

A series of analogs of glucagon-like peptide-1 (GLP-1) was made replacing each amino acid with L-alanine to identify side-chain functional groups required for interaction with the GLP-1 receptor. In the case of L-alanine being the parent amino acid, substitution was made with the amino acid found in the corresponding position in glucagon. Binding assays were performed using the cloned rat GLP-1 receptor, and receptor activation was monitored using RIN 2A18 plasma membranes. The analogs that showed the weakest receptor binding were further compared with native GLP-1 by circular dichroism spectroscopy to investigate possible conformational changes. We conclude that the side chains in positions 7, 10, 12, 13, and 15 are directly involved in the receptor interaction while positions 28 and 29 are important for GLP-1 to adapt the conformation recognized by the receptor.
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PMID:Structure-activity studies of glucagon-like peptide-1. 811 74

PTH-related protein (PTHrP), originally identified through its causative role in human humoral hypercalcemia of malignancy, is now known to be a normal gene product expressed in a wide variety of neuroendocrine, epithelial, and mesoderm-derived tissues. PTHrP gene expression has recently been demonstrated in fetal and adult, benign and malignant, as well as human and rodent pancreatic islets. As in other tissues, the role of PTHrP expression in the normal islet is only beginning to be explored. In the current report, PTHrP expression in the normal rat pancreatic islet was confirmed using an affinity-purified antiserum directed against the N-terminal, biologically active region of the molecule. The effects of PTHrP on the islet were then explored using rat insulinoma (RIN m5F) cells. Synthetic PTHrP-(1-36) bound specifically, but with low affinity (Kd, approximately 10(-7) M) to RIN cell membranes. PTHrP-(1-36) failed to stimulate cAMP production in RIN cells, although RIN cells displayed a normal adenylate cyclase response to glucagon-like peptide-1-(7-36). In contrast, PTHrP-(1-36) induced a rapid dose-dependent rise in intracellular calcium in RIN cells in doses as low as 10(-12)-10(-10) M. These findings 1) confirm that PTHrP is expressed by islet cells, 2) demonstrate that the effects of PTHrP on the pancreatic islet are mediated, as in keratinocytes and lymphocytes, by a receptor related to but distinct from the PTH receptor, and 3) suggest that PTHrP functions in the islet as an autocrine or paracrine factor. Further studies are required to determine the physiological consequences of PTHrP expression by the pancreatic islet.
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PMID:Amino-terminal parathyroid hormone-related protein: specific binding and cytosolic calcium responses in rat insulinoma cells. 838 1

The interaction of glucagon-like peptide-I (GLP-I) and galanin in clonal endocrine pancreatic cells was characterized. By Northern blot analysis the presence of GLP-I receptor mRNA was shown in B (beta TC-1 cells) and D (RIN 1048-38) cells but not in A (INR1 G9) cells, thus confirming functional data demonstrating the absence of active GLP-I receptors on glucagon-producing cells. Galanin receptors were detected on B and D cells but not on A cells. In B and D cells galanin inhibited the GLP-I stimulated adenylate cyclase activity. Treatment of insulin- and somatostatin-producing cells with GLP-I increased intracellular cAMP levels, and this was dampened by galanin, GLP-I stimulated the activity of protein kinase A in B and D cells, which was also inhibited by galanin. Galanin alone did not influence B- and D-cell function. These data show that in the endocrine pancreas B and D cells but not A cells express GLP-I and galanin receptors. The interaction of GLP-I and galanin might act in the endocrine pancreas as a physiological inhibitor of the potent incretin hormone GLP-I. Therefore, we suggest galanin is a 'decretin'.
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PMID:Interaction of glucagon-like peptide-I (GLP-I) and galanin in insulin (beta TC-1)- and somatostatin (RIN T3)-secreting cells and evidence that both peptides have no receptors on glucagon (INR1G9)-secreting cells. 859 Jul 87

The pancreatic islet hormone, glucagon, stimulates hepatic glucose production and has also been shown to potentiate glucose-induced insulin secretion. Because glucagon is a key regulator of glucose homeostasis, its receptor, which mediates the actions of glucagon, was considered a candidate gene involved in the pathogenesis of NIDDM. We have previously reported that a single heterozygous missense mutation in exon 2 of the glucagon receptor gene, which changes a glycine to a serine (Gly40Ser), is associated with NIDDM in a French population. In the present study, the signaling properties of this mutant receptor were examined in baby hamster kidney cells and rat insulinoma cells (RIN-5AH) stably transfected with either the wild type or Gly40Ser mutant human glucagon receptor cDNAs. Competition assays using (125)I-labeled glucagon were performed, and in both cell types, the Gly40Ser mutant receptor was found to bind glucagon with an approximately threefold lower affinity compared with the wild type receptor. In both cell types, the production of cAMP in response to glucagon was decreased in cells expressing the mutant receptor compared with those expressing the wild type. Finally, glucagon-stimulated insulin secretion by RIN cells expressing the mutant receptor was decreased such that the dose-response curve was shifted to the right in comparison to that obtained with cells expressing the wild type receptor. These results indicate that this single-point mutation located in the extracellular region of the glucagon receptor decreases the sensitivity of target tissues to glucagon.
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PMID:The Gly40Ser mutation in the human glucagon receptor gene associated with NIDDM results in a receptor with reduced sensitivity to glucagon. 863 44

In IDDM, T-cells are postulated to mediate the destruction of pancreatic beta-cells. We analyzed peripheral blood mononuclear cell (PBMC) responses to human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase ICA512, glucagon, membrane preparations of RIN cells and human pancreas, and three control antigens (La = nuclear cell antigen, tetanus toxoid, and phytohemagglutinin). A total of 28 patients with newly diagnosed IDDM, 9 antibody-positive (Ab+) first-degree relatives, and 16 healthy control subjects were included. Increased proliferative responses to pancreatic islet cell antigens were observed in diabetic patients and in Ab+ relatives compared with control subjects, whereas T-cell reactivity to nonpancreatic control antigens was similar between the study groups. The highest differences in the magnitude of proliferative responses were seen for ICA512, followed by membrane preparations of RIN cells, GAD65, and human pancreas. Few subjects reacted with insulin or glucagon. Interestingly, Ab+ relatives showed higher T-cell reactivity with respect to stimulation indexes and prevalences than newly diagnosed diabetic patients, and as many as 89% of Ab+ relatives showed proliferation to more than one islet cell antigen preparation in comparison to 43% of newly diagnosed diabetic patients and none of the control subjects. Statistical analysis revealed significant positive correlation of insulin autoantibody levels with the levels of insulin-specific T-cells in Ab+ relatives, but no relation of PBMC responses to age, sex, or HLA-DR haplotypes. Our results demonstrate the simultaneous existence of various autoreactive T-cells specific for islet cell antigens in the prediabetic period. These T-cells may play a significant role in the pathogenesis of the disease.
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PMID:Cellular immune response to diverse islet cell antigens in IDDM. 863 55

Insulin-like growth factors I and II (IGF-I and IGF-II) are expressed at high levels in the endocrine pancreas during development and tissue regeneration. However, their effects at the endocrine pancreas are poorly understood. We searched for receptors of IGF-I and IGF-II and possible biological effects on clonal insulin-secreting (HIT), glucagon-secreting (INR1G9), and somatostatin-secreting (RIN 1027 B2) cell lines. Our data showed that HIT cells and RIN 1027 B2 cells express specific type I and type 11 IGF receptors. INR1G9 cells possess type II IGF receptors and IGF-I binding sites with the same affinity for both IGF-I and IGF-II. In HIT cells, insulin secretion was not influenced by either peptide. Proinsulin gene transcription was stimulated by IGF-II but not by IGF-I. IGF-I potently inhibited proglucagon gene transcription and glucagon secretion in INR1G9 cells, whereas IGF-II only inhibited glucagon release. In RIN 1027 B2 cells, IGF-I but not IGF-II increased somatostatin output, whereas both stimulated somatostatin gene expression. These data demonstrate the presence of classic type I and type II IGF receptors on insulin-, glucagon-, and somatostatin-secreting cells. Both peptides may be important regulators of endocrine pancreatic function in terms of islet hormone release and gene expression. Therefore, both peptides may be involved in the regulation of intraislet cellular homeostasis.
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PMID:Functional active receptors for insulin-like growth factors-I (IGF-I) and IGF-II on insulin-, glucagon-, and somatostatin-producing cells. 863 52


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