Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the influence of and interactions among pancreatic hormones on the secretion of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IG-FBPs) by treating primary hepatocytes from young male Long-Evans rats with insulin or glucagon in combination with rat GH (rGH). The concentration of IGF-I secreted into the medium was estimated by radioimmunoassay after formic acid-acetone cryoextraction, and secreted IGFBPs were analysed by Western ligand blot and immunoblot; accumulation of IGF-I mRNA was analysed by Northern blot. Both insulin (0.1-100 nmol/l) and rGH (0.5, 5 and 50 pmol/l) produced a dose-dependent stimulation of IGF-I secretion over a 24-h incubation period. In contrast, glucagon (0.1-100 nmol/l) inhibited IGF-I production in a dose-related manner. Glucagon (10 nmol/l) also inhibited IGF-I secretion stimulated by rGH (5 pmol/l) and insulin (10 nmol/l). Northern blot analysis of total RNA isolated from rat hepatocytes revealed that rGH (5 pmol/l) elevated IGF-I mRNA levels, glucagon (10 nmol/l) alone had no effect on this parameter, but glucagon significantly reduced IGF-I transcript accumulation in response to rGH. IGFBPs secreted by rat hepatocytes run in two molecular weight ranges on SDS-PAGE: approximately 25 kDa (IGFBP-4) and approximately 29-31 kDa (IGFBP-1 and -2); the predominant hormonally regulated IGFBP was identified as IGFBP-1. Insulin produced a dose-dependent inhibition of production of IGFBP-1, while glucagon was stimulatory; when given together at an equivalent concentration (1 nmol/l), the effects of insulin were dominant to glucagon on IGFBP-1. These observations provide support for significant opposite roles for the pancreatic hormones, insulin and glucagon, in the regulation of liver IGF-I and IGFBP-1 production. As the production of pancreatic hormones is influenced by nutritional status, these polypeptides may mediate the effects of changing nutritional state on the hormonal control of protein anabolism and glucose homeostasis by directly influencing the circulating level of liver-derived IGF-I and its binding proteins.
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PMID:Pancreatic hormones differentially regulate insulin-like growth factor (IGF)-I and IGF-binding protein production by primary rat hepatocytes. 752 61

Regulation of the production of insulin-like growth factor (IGF)-I, IGF-II, IGF binding proteins (IGFBPs), and their related proteins by various hormones was investigated in primary cultures of rat liver parenchymal and nonparenchymal cells. Freshly isolated parenchymal cells contained mRNAs of IGF-I, IGF-II, IGFBP-1, IGFBP-4, growth hormone (GH) receptor, and the acid-labile subunit (ALS), which forms a ternary complex with IGF-I and IGFBP-3; however, parenchymal cells did not express the IGFBP-3 gene. In contrast, nonparenchymal cells contained IGFBP-3 mRNA exclusively, as we reported previously [Takenaka et al. Agric. Biol. Chem., 55, 1191-1193 (1991)]. Cultured rat parenchymal cells produced IGF-I, IGFBP-1, and IGFBP-4 prominently. In these cells, secretion of IGF-I and the content of IGF-I mRNA was greatly increased in the presence of GH in the medium. Insulin also increased the production of IGF-I. Secretion of IGFBP-1 into the medium was enhanced by treatment with glucagon, dibutyrylcyclic AMP (Bu2cAMP), and dexamethasone (Dex) and these enhancements with glucagon and Dex reflected the increase in its mRNA content. Insulin depressed the secretion of IGFBP-1. The content of IGFBP-4 in the parenchymal cells was increased by insulin, Bu2cAMP, and triiodothyronine (T3), thereby enhancing the production of IGFBP-4 and secretion into the medium. Cultured liver nonparenchymal cells of rats produced IGFBP-1, IGFBP-3, and IGFBP-4. Secretion of IGFBP-1 was increased by Bu2cAMP in the medium, that of IGFBP-3 by IGF-I, and that of IGFBP-4 by both IGF-I and Bu2cAMP. Regulation of the production of IGFBP-3 by IGF-I was demonstrated in these investigations. These results suggest that GH increases production of IGF-I in the parenchymal cells and this IGF-I, in turn, increases the production of IGFBP-3 in nonparenchymal cells. As we found GH also increases ALS production in parenchymal cells, by these mechanisms, GH increases the formation of the ternary complex of IGF-I, IGFBP-3, and ALS. This study clearly demonstrates the interrelationship between parenchymal and nonparenchymal cells in the production of IGF-I and IGFBPs in the liver.
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PMID:Production of insulin-like growth factors and their binding proteins in primary cultures of rat liver parenchymal and nonparenchymal cells. 754 2

The hormonal regulation of insulin-like growth factor binding protein (IGFBP)-1 and -4 mRNA was compared in serum-free primary rat hepatocyte cultures. The combination of dexamethasone and glucagon (Dex/Gluc) strongly increased IGFBP-1 and IGFBP-4 mRNA levels. Insulin suppressed Dex/Gluc-stimulated IGFBP-1 but not IGFBP-4 mRNA levels. In contrast, the peroxovanadium compound, bisperoxovanadium 1,10-phenanthroline (bpV(phen)), completely abrogated Dex/Gluc induction of both IGFBP mRNA species. Wortmannin and rapamycin blocked the inhibitory effect of insulin but not that of bpV(phen) on Dex/Gluc-stimulated IGFBP mRNA. Thus, although phosphatidylinositol 3'-kinase and p70s6k are necessary for insulin-mediated transcriptional inhibition of the IGFBP-1 gene, a signaling pathway, independent of phosphatidyloinositol 3'-kinase and p70s6k, is activated by bpV(phen) and mediates IGFBP-1 as well as IGFBP-4 mRNA inhibition. Mitogen-activated protein (MAP) kinase activity induced by insulin was suppressed to below basal levels in the presence of Dex/Gluc, whereas in response to bpV(phen), MAP kinase activity was high and unaffected by Dex/Gluc, consistent with a role of MAP kinases in bpV(phen)-mediated inhibition of IGFBP mRNA. The specific MAP kinase kinase (MEK) inhibitor, PD98059, inhibited insulin but not bpV(phen)-stimulated MAP kinase activity, suggesting that MAP kinases can be activated in a MEK-independent fashion. Peroxovanadium compounds are strong inhibitors of tyrosine phosphatases, which may inhibit specific tyrosine/threonine phosphatases involved in the negative regulation of MAP kinases.
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PMID:Phosphatidylinositol 3'-kinase and p70s6k are required for insulin but not bisperoxovanadium 1,10-phenanthroline (bpV(phen)) inhibition of insulin-like growth factor binding protein gene expression. Evidence for MEK-independent activation of mitogen-activated protein kinase by bpV(phen). 899 39

The IGFs are mitogenic agents which are closely linked to regulatory processes in carbohydrate metabolism. Because limited information is available on the occurrence of the IGF system in the pancreatic beta-cell milieu, we evaluated the presence of IGFs, IGF receptors, and IGF-binding proteins (IGFBPs) in the beta-cell lines beta TC3 and HIT T-15. Serum-free conditioned media (SFCM) from beta TC3 cells contained IGF-II at concentrations greater than 100 ng/ml. High (15 kDa) and low (7.5 kDa) molecular weight IGF-II were detected both by column chromatography followed by RIA and by immunoblotting. GH (10-1000 ng/ml) conditioning of beta TC3 cells stimulated IGF-II secretion in a dose-dependent manner. IGF-II mRNA was detected in beta TC3 cells using Northern blots, and also showed a GH-dependent relationship. IGF-II peptide was detected in SFCM from HIT cells, albeit at lower concentrations. To evaluate the presence of IGF receptors in beta-cell lines, affinity cross-linking studies were performed on beta TC3 cells, demonstrating type I IGF receptors which bound iodinated IGF-II with high affinity, iodinated IGF-I with lesser affinity, and had minimal appreciable binding to iodinated insulin. Type II IGF receptors were not detected. SFCM from beta TC3 and HIT cells was subjected to Western ligand blotting, which disclosed the presence of two major IGFBPs of 29 kDa and 24 kDa, characteristic of IGFBP-2 and IGFBP-4. The identity of the specific IGFBPs was confirmed by immunoprecipitation and Northern blotting. Varying the glucose concentration had no significant effect on the levels of IGFBPs, nor did preconditioning with GH, IGF-I, IGF-II, insulin, or glucagon. Levels of both IGFBPs in beta TC3 cell-conditioned media increased in the presence of dexamethasone at concentrations of 10(-6) M or greater. In summary, we present evidence that beta-cell lines comprise an environment for GH and IGF action. We speculate that IGFs, their receptors and binding proteins function as a complex interactive system which regulates beta-cell growth and function.
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PMID:IGF-II, IGF-binding proteins and IGF receptors in pancreatic beta-cell lines. 907 67

Local vascular expression and action of insulin-like growth factor-I (IGF-I) appear to be important in the biologic events that follow arterial wall injury. Octreotide, a long-acting somatostatin analog, is a potent inhibitor of the growth hormone/IGF-I axis. We examined the effects of octreotide on the vascular IGF-I and IGF-binding proteins (IGFBP), gene regulation, smooth muscle cell proliferation, and neointimal thickening after arterial wall injury. Treatment with octreotide selectively decreased IGF-I mRNA expression in normal rat arteries by 70% and prevented the induction of the IGF-I gene after balloon injury. Because up-regulation of platelet-derived growth factor-A gene was not affected, and because there was no change in plasma growth hormone, IGF-I, and glucagon levels, it appears that this effect is selective and mediated locally. Of the IGFBP, IGFBP-4 was modestly up-regulated after balloon injury, whereas treatment with octreotide had no effect on IGFBP-4 expression. The inhibitory effects of octreotide on vascular IGF-I were associated with a decrease in the number of proliferating cell nuclear antigen-positive cells and an up to 90% reduction in neointimal thickening after balloon injury in a dose-dependent fashion.
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PMID:Direct effects of somatostatin analog octreotide on insulin-like growth factor-I in the arterial wall. 912 Nov 16

To determine if the hormonal effects on insulin-like growth factor binding protein (IGFBP) production differed between granulosa and thecal cells, both cell types were collected and cultured in serum-free medium with various hormone treatments, arranged in three experiments. Following treatment, cells were enumerated and media were collected, concentrated 10-fold and subjected to ligand blotting. Experiment 1 revealed that > or =1.5 x 10(5) viable cells at plating were needed for maximal IGFBP production by granulosa and thecal cells. The major forms of IGFBPs produced were a 27-34-kDa IGFBP (IGFBP-2 and -5), and a 20-22-kDa IGFBP (IGFBP-4) by the granulosa cells and a 40-44-kDa IGFBP (IGFBP-3), 34-kDa IGFBP (IGFBP-2), 27-29-kDa IGFBP (IGFBP-5) and a 20-22-kDa IGFBP (IGFBP-4) by the thecal cells. In Experiment 2A, insulin stimulated production of IGFBP-5 by thecal cells, and basic fibroblast growth factor (bFGF) inhibited the insulin-induced increase in IGFBP-5 production; epidermal growth factor (EGF) and luteinizing hormone were without effect. The small amounts of IGFBP-2 and -3 produced by thecal cells of Experiment 2A were not affected by treatment. Production of IGFBP-2/-5 by granulosa cells in Experiment 2B was inhibited by insulin, with EGF and bFGF further enhancing insulin's inhibitory effect; follicle-stimulating hormone was without effect. In Experiment 3A, insulin enhanced production of IGFBP-5 by thecal cells whereas glucagon blocked insulin's stimulatory effect. In contrast, insulin or glucagon alone had no effect on production of the IGFBP-4 by thecal cells but when combined inhibited IGFBP-4 production. The small amounts of IGFBP-2 and -3 produced by thecal cells of Experiment 3A were not affected by treatment. In Experiment 3B, production of IGFBP-2/-5 by granulosa cells was attenuated in the presence of cortisol with or without insulin and insulin plus glucagon; glucagon and cortisol decreased production of IGFBP-4 by granulosa cells. These results suggest that production of IGFBP-2, -4, and -5 by granulosa and thecal cells are differentially affected by hormonal stimuli, and that IGFBP-3 is more consistently produced by thecal cells than granulosa cells of cattle although its production was not hormonally regulated.
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PMID:Hormonal control of ovarian cell production of insulin-like growth factor binding proteins. 1150 Feb 40

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone that stimulates the growth of the intestinal epithelium. We have previously demonstrated that GLP-2 exerts its intestinotropic effect through an indirect mechanism that requires both IGF-1 and the intestinal epithelial IGF-1 receptor. However, the biological activity of IGF-1 is modulated by IGF binding proteins (IGFBPs), including IGFBP-4, which is highly expressed in the intestine. To determine the role of IGFBP-4 in the tropic effects of GLP-2, IGFBP-4 knockout (KO) and control mice were treated with degradation-resistant GLP-2 or vehicle for 10 days. Comparable levels of IGFBP-1-3/5-7 mRNAs were observed in the intestinal mucosa of all animals. IGFBP-4 KO mice had greater small intestinal weight and length, and deeper crypts (P < .05) as compared with controls, suggesting that IGFBP-4 has an inhibitory role in basal intestinal growth. However, small intestinal weight, crypt-villus height and crypt cell proliferation increased in response to GLP-2 in control mice (P < .05), and these changes were abrogated with IGFBP-4 KO. In contrast, pregnancy-associated plasma protein-A KO mice, which have increased levels of circulating IGFBP-4, demonstrated a normal intestinotropic response to GLP-2. Finally, GLP-2 treatment of control mice significantly increased IGFBP-4 mRNA expression in the jejunal mucosa (P < .05), a finding that was recapitulated by GLP-2 treatment of fetal rat intestinal cells in culture (10(-8)M for 2 h; P < .05). Collectively, these results indicate that the IGF-I-modulating protein, IGFBP-4, exerts a negative effect on basal intestinal growth but plays a positive regulatory role in the intestinotropic actions of GLP-2.
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PMID:IGF binding protein-4 is required for the growth effects of glucagon-like peptide-2 in murine intestine. 2551 89

Glucagon-like peptide (GLP)-2 stimulates intestinal epithelial proliferation by acting, in part, via IGF release from sub-epithelial myofibroblasts. The response of myofibroblasts to GLP-2 remains incompletely understood. We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs.
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PMID:Glucagon-like petide-2 acts on colon cancer myofibroblasts to stimulate proliferation, migration and invasion of both myofibroblasts and cancer cells via the IGF pathway. 2836 95