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)

Glucagon-like peptide-1 (GLP-1) controls glucose metabolism in extrapancreatic tissues participating in glucose homeostasis, through receptors not associated to cAMP. In rat hepatocytes, activation of PI3K/PKB, PKC and PP-1 mediates the GLP-1-induced stimulation of glycogen synthase. We have investigated the effect of GLP-1 in normal human myocytes, and that of its structurally related peptides exendin-4 (Ex-4) and its truncated form 9-39 (Ex-9) upon glucose uptake, and the participation of cellular enzymes proposed to mediate insulin actions. GLP-1 and both exendins activated, like insulin, PI3K/PKB and p42/44 MAPK enzymes, but p70s6k was activated only by GLP-1 and insulin. GLP-1, Ex-4 and Ex-9, like insulin, stimulated glucose uptake; wortmannin blocked the action of GLP-1, insulin and Ex-9, and reduced that of Ex-4; PD98059 abolished the effect of all peptides/hormones, while rapamycin blocked that of insulin and partially prevented that of GLP-1. H-7 abolished the action of GLP-1, insulin and Ex-4, while Ro 31-8220 prevented only the Ex-4 and Ex-9 effect. In conclusion, GLP-1, like insulin, stimulates glucose uptake, and this involves activation of PI3K/PKB, p44/42 MAPKs, partially p70s6k, and possibly PKC; Ex-4 and Ex-9 both have GLP-1-like effect upon glucose transport, in which both share with GLP-1 an activation of PI3K/PKB--partially in the case of Ex-4--and p44/42 MAPKs but not p70s6k.
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PMID:Effect of GLP-1 on glucose transport and its cell signalling in human myocytes. 1566 68

Several kinases have been implicated in the metabolic response of human and rat myocytes to glucagon-like peptide-1 (GLP-1), exendin-4 (Ex-4) and exendin-9 (Ex-9). We have investigated, in isolated rat adipocytes, the changes caused by GLP-1, Ex-4 and Ex-9 compared with those provoked by insulin or glucagon, upon the activity of phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB), p42/44 MAP kinases (MAPKs) and p70s6 kinase (p70s6k), and the participation of these kinases and protein kinase C (PKC) in their action upon 2-deoxy-d-glucose uptake, lipolysis and lipogenesis. The study was conducted in normal rats, and extended to a streptozotocin-induced type-2 diabetic model (STZ-rats). The participation of distinct kinases was estimated by using potential kinase inhibitors, including wortmannin, PD98059, rapamycin, H-7 and RO31-8220. In normal rat adipocytes, GLP-1 and both exendins share with insulin an increasing action upon the activity of all kinases studied (except PKB), PI3K, p44 and p42 MAPKs and possibly PKC, all being required for their stimulating effect upon glucose uptake. Ex-4 and Ex-9, like GLP-1 and insulin, have lipogenic action, while only Ex-4 shares with GLP-1 its lipolytic effect which is antagonized by Ex-9. MAP kinases and PKC seem to have an essential role in the GLP-1 and Ex-4 lipolytic action, as does PI3K in that of Ex-4. An increase in PI3K and MAPKs activity for the lipogenic effect of Ex-4, Ex-9 and GLP-1 are required, and in the case of Ex-4 and Ex-9, a stimulation of p70s6k activity is also needed. In cells from STZ-rats the magnitude of the above parameters was, in general, comparable to that in normal animals, with some exceptions: basal PI3K activity and lipogenesis were higher, GLP-1, Ex-4 and Ex-9 failed to modify basal lipogenesis but increased PKB activity, insulin failed to affect the activity of MAPKs and the insulin-induced glucose uptake was impaired. The impaired insulin effects upon some of the variables in the STZ-rat, distinct from those of GLP-1 and exendins, adds knowledge to the mechanism of the beneficial action of GLP-1 and Ex-4 in diabetic states.
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PMID:Effects of glucagon-like peptide-1 and exendins on kinase activity, glucose transport and lipid metabolism in adipocytes from normal and type-2 diabetic rats. 1608 19

The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), have been suggested to act as beta-cell growth factors and may therefore be of critical importance for the maintenance of a proper beta-cell mass. We have investigated the molecular mechanism of incretin-induced beta-cell replication in primary monolayer cultures of newborn rat islet cells. GLP-1, GIP and the long-acting GLP-1 derivative, liraglutide, increased beta-cell replication 50-80% at 10-100 nM upon a 24 h stimulus, whereas glucagon at a similar concentration had no significant effect. The stimulatory effect of GLP-1 and GIP was efficiently mimicked by the adenylate cyclase activator, forskolin, at 10 nM (approximately 90% increase) and was additive (approximately 170-250% increase) with the growth response to human growth hormone (hGH), indicating the use of distinct intracellular signalling pathways leading to mitosis by incretins and cytokines, respectively. The response to both GLP-1 and GIP was completely blocked by the protein kinase A (PKA) inhibitor, H89. In addition, the phosphoinositol 3-kinase (PI3K) inhibitor wortmannin and the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, both inhibited GLP-1- and GIP-stimulated proliferation. The p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, had no inhibitory effect on either GLP-1 or GIP stimulated proliferation. Cyclin Ds act as molecular switches for the G0/G1-S phase transition in many cell types and we have previously demonstrated hGH-induced cyclin D2 expression in the insulinoma cell line, INS-1. GLP-1 time-dependently induced the cyclin D1 mRNA and protein levels in INS-1E, whereas the cyclin D2 levels were unaffected. However, minor effect of GLP-1 stimulation was observed on the cyclin D3 mRNA levels. Transient transfection of a cyclin D1 promoter-luciferase reporter construct into islet monolayer cells or INS-1 cells revealed approximately a 2-3 fold increase of transcriptional activity in response to GLP-1 and GIP, and a 4-7 fold increase in response to forskolin. However, treatment of either cell type with hGH had no effect on cyclin D1 promoter activity. The stimulation of the cyclin D1 promoter by GLP-1 was inhibited by H89, wortmannin, and PD98059. We conclude that incretin-induced beta-cell replication is dependent on cAMP/PKA, p42 MAPK and PI3K activities, which may involve transcriptional induction of cyclin D1. GLP-1, GIP and liraglutide may have the potential to increase beta-cell replication in humans which would have significant impact on long-term diabetes treatment.
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PMID:Stimulation of pancreatic beta-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways. 1652 28

Nardilysin is a metalloendopeptidase that in vitro cleaves peptides such as dynorphin-A, somatostatin-28, alpha-neoendorphin and glucagon at the N-terminus of arginine and lysine residues in dibasic moieties. The enzyme is highly expressed in many endocrine tissues. Nardilysin has also been found in the brain. Previously, we have detected that nardilysin interacts with brain-specific proteins, i.e. p42(IP4)/centaurin-alpha1 [Stricker R, Chow KM, Walther D, Hanck T, Hersh LB, Reiser G (2006) Interaction of the brain specific protein p42(IP4)/centaurin-alpha1 with the peptidase nardilysin is regulated by the cognate ligands of p42(IP4), PtdIns(3,4,5)P(3) and Ins(1,3,4,5)P(4), with stereospecificity. J Neurochem 98:343-354]. However, very little is known about the distribution of nardilysin in the brain. The aim of the present study was to reveal its regional distribution and cellular localization in developing and adult human brain. Using immunohistochemistry and Western blot analysis we demonstrate that the enzyme is widely, but unevenly, expressed in the human brain. We found high staining intensity in the hypothalamus, neocortex and brain stem nuclei. The cellular localization is almost exclusively confined to neurons. In pre- and perinatal human brain cortex, most neurons express the enzyme. In cortical neurons nardilysin protein was found to be partially co-localized with parvalbumin but not calretinin. No co-expression was seen with somatostatin-28 immunoreactivity. A considerable overlap was revealed between p42(IP4) and nardilysin. Our data support the hypothesis that nardilysin might possibly play a role in brain development, whereas its putative function in brain peptide metabolism remains to be clarified further.
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PMID:Histochemical evidence for wide expression of the metalloendopeptidase nardilysin in human brain neurons. 1744 99

A role of GLP-1 (glucagon-like peptide-1) in the recovery of the metabolic conditions of morbidly obese patients after bariatric surgery has been proposed. Exendin 4 (Ex-4) and exendin 9 (Ex-9) both have GLP-1-like effects upon glucose metabolism in human myocytes. We investigated in normal human adipocytes the effect of GLP-1, Ex-4 and Ex-9, compared with insulin upon the activity of PI3K, PKB, MAPKs and p70s6 kinases, and the participation of these enzymes in their action upon 2-deoxy-D-glucose transport by using potential inhibitors. The study was extended to morbidly obese patients. In normal subjects, GLP-1, Ex-4 and insulin, but not Ex-9, increased glucose uptake. In addition, GLP-1 and Ex-4 stimulated PI3K and MAPKs, similar to insulin, but not PKB. Ex-9 only enhanced PI3K, while none affected p70s6k. Inhibition of both PI3K and MAPKs blocked the stimulatory action of GLP-1, Ex-4 and insulin upon glucose transport. In obese patients, basal PI3K, PKB and MAPK activity was, as a rule, lower than that in normal subjects, while cells maintained their normal incremental response to GLP-1, Ex-4 or insulin; Ex-9 induced a clear stimulation of p42 MAPK. In summary, in normal human adipocytes, GLP-1 and Ex-4 have a protein kinase-dependent increasing effect upon glucose transport, which is impaired in obese patients. The participation of GLP-1 in the normalization of the metabolic conditions of the obese may occur through its effects on lipid metabolism or through effects upon glucose transport and/or metabolism in the liver and muscle, which in human obesity remain to be investigated.
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PMID:The action of GLP-1 and exendins upon glucose transport in normal human adipocytes, and on kinase activity as compared to morbidly obese patients. 1748 30

Stimulation of numerous G protein-coupled receptors leads to the elevation of intracellular concentrations of cAMP, which subsequently activates the PKA pathway. Specificity of the PKA signaling module is determined by a sophisticated subcellular targeting network that directs the spatiotemporal activation of the kinase. This specific compartmentalization mechanism occurs through high-affinity interactions of PKA with A-kinase anchoring proteins (AKAPs), the role of which is to target the kinase to discrete subcellular microdomains. Recently, a peptide designated "AKAPis" has been proposed to competitively inhibit PKA-AKAP interactions in vitro. We therefore sought to characterize a cell-permeable construct of the AKAPis inhibitor and use it as a tool to characterize the impact of PKA compartmentalization by AKAPs. Using insulin-secreting pancreatic beta-cells (INS-1 cells), we showed that TAT-AKAPis (at a micromolar range) dose dependently disrupted a significant fraction of endogenous PKA-AKAP interactions. Immunoflurescent analysis also indicated that TAT-AKAPis significantly affected PKA subcellular localization. Furthermore, TAT-AKAPis markedly attenuated glucagon-induced phosphorylations of p44/p42 MAPKs and cAMP response element binding protein, which are downstream effectors of PKA. In parallel, TAT-AKAPis dose dependently inhibited the glucagon-induced potentiation of insulin release. Therefore, AKAP-mediated subcellular compartmentalization of PKA represents a key mechanism for PKA-dependent phosphorylation events and potentiation of insulin secretion in intact pancreatic beta-cells. More interestingly, our data highlight the effectiveness of the cell-permeable peptide-mediated approach to monitoring in cellulo PKA-AKAP interactions and delineating PKA-dependent phosphorylation events underlying specific cellular responses.
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PMID:Cell-permeable peptide-based disruption of endogenous PKA-AKAP complexes: a tool for studying the molecular roles of AKAP-mediated PKA subcellular anchoring. 1907 98

Chromatin can exert a regulatory effect on gene transcription by modulating the access of transcription factors to target genes. In the present study, we examined whether nuclear actions of the incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, involve modulation of beta-cell chromatin structure. Stimulation of INS-1(832/13) beta-cells or dispersed mouse islets with glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 resulted in the post-translational modification of core H3 histones, through acetylation and phosphorylation. Both increased histone H3 acetyltransferase and reduced histone deacetylase activities contributed. Subsequent studies demonstrated that incretin-mediated histone H3 modifications involved activation of protein kinase A, p42/44 mitogen-activated protein kinase (MAPK), and p38 MAPK signaling modules, resulting in the activation of mitogen- and stress-activated kinase-1. Additionally, modification of histone H3 increased its association with the transcription factor, phosphorylated cAMP-response element-binding protein (phospho-CREB) and with cAMP-responsive CREB coactivator 2. Incretin-activated CREB-related Bcl-2 transcription was greatly reduced by a histone acetyltransferase inhibitor, demonstrating the functional importance of histone H3 modification. This appears to be the first demonstration of beta-cell chromatin modification in response to the incretins and the studies indicate that their regulatory effects involve coordinated nuclear interactions between specific signaling modules, chromatin-modifying enzymes and transcription factors.
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PMID:Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 modulate beta-cell chromatin structure. 1927


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