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)

Acetyl-CoA carboxylase has been purified from lactating rat mammary gland using a combination of ammonium sulphate and poly(ethyleneglycol) precipitations. The enzyme was purified from 35--70-fold with a yield of over 50%, the exact figures being difficult to estimate because of activation of the enzyme that occurs during the preparation. The preparation was homogeneous by the criterion of polyacrylamide gel electrophoresis in sodium dodecyl sulphate and had a single subunit of molecular weight 240,000, containing 1.02 +/- 0.04 molecules of biotin and 3.1 +/- 1.7 molecules of alkali-labile phosphate per subunit. The purified enzyme was phosphorylated and inactivated rapidly when incubated in the presence of [gamma 32P]ATP and magnesium ions with the purified catalytic subunit of cyclic-AMP-dependent protein kinase from rabbit skeletal muscle. Both phosphorylation and inactivation are blocked by the heat-stable protein inhibitor of cyclic-AMP-dependent protein kinase, and can be reversed by incubation with purified protein phosphatase-1 from rabbit skeletal muscle. The inactivation by the protein kinase and reactivation by the protein phosphatase correlate with the near-stoichiometric phosphorylation and dephosphorylation of site(s) located in a single tryptic peptide. Phosphorylation does not affect the Km for substrates, but brings about a twofold decrease in V and a twofold increase in the apparent dissociation constant for the allosteric activator, citrate. We also present evidence that the activation of rabbit mammary acetyl-CoA carboxylase by protein phosphatase-1 described previously [Hardie and Cohen (1979) FEBS Lett. 103, 333-338] is due to dephosphorylation at site(s) which are not phosphorylated by either cyclic-AMP-dependent protein kinase or acetyl-CoA carboxylase kinase-2. These results suggest that the rapid inactivation of acetyl-CoA carboxylase, and hence fatty acid synthesis, by adrenaline in adipose tissue, or glucagon in the liver, is due to phosphorylation of the enzyme by cyclic-AMP-dependent protein kinase.
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PMID:Reversible phosphorylation and inactivation of acetyl-CoA carboxylase from lactating rat mammary gland by cyclic AMP-dependent protein kinase. 610 9

Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism. Here we show that hormonal and energy-sensing pathways converge on the coactivator TORC2 (transducer of regulated CREB activity 2) to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK attenuate the gluconeogenic programme by promoting TORC2 phosphorylation and blocking its nuclear accumulation. Individuals with type 2 diabetes often exhibit fasting hyperglycaemia due to elevated gluconeogenesis; compounds that enhance TORC2 phosphorylation may offer therapeutic benefits in this setting.
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PMID:The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. 1614 43

Hepatic gluconeogenesis plays a key role in the maintenance of glucose homeostasis. The hormone glucagon stimulates this process, whereas insulin and adiponectin are inhibitory. In a recent report, Koo et al identify the transcriptional regulator TORC2 (Transducer of Regulated CREB activity 2) as a pivotal component of the gluconeogenic program.1 Both insulin and AMPK increase the phosphorylation of TORC2, while glucagon suppresses it. This in turn regulates the nuclear/cytoplasmic shuttling of TORC2 and its ability to transactivate gluconeogenic genes. Thus, TORC2 might serve as a gluconeogenic "molecular switch" that senses hormones and cellular energy status.
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PMID:More TORC for the gluconeogenic engine. 1647 85

In order to evaluate the role of insulin in chicken, an insulin immuno-neutralization was performed. Fed chickens received 1 or 3 i.v. injections of anti-insulin serum (2-h intervals), while fed or fasted controls received normal serum. Measurements included insulin signaling cascade (at 1 h in liver and muscle), metabolic or endocrine plasma parameters (at 1 and 5 h), and qRT-PCR analysis (at 5 h) of 23 genes involved in endocrine regulation, metabolisms, and transcription. Most plasma parameters and food intake were altered by insulin privation as early as 1 h and largely at 5 h. The initial steps of insulin signaling pathways including insulin receptor (IR), IR substrate-1 (IRS-1), and Src homology collagen and downstream elements: phosphatidylinositol 3-kinase (PI3K), Akt, GSK3, ERK2, and S6 ribosomal protein) were accordingly turned off in the liver. In the muscle, IR, IRS-1 tyrosine phosphorylation, and PI3K activity remained unchanged, whereas several subsequent steps were altered by insulin privation. In both tissues, AMPK was not altered. In the liver, insulin privation decreased Egr1, PPAR gamma, SREBP1, THRSP alpha (spot 14), D2-deiodinase, glucokinase (GK), and fatty acid synthase (whereas D3-deiodinase and IGF-binding protein 1 transcripts were up-regulated. Liver SREBP1 and GK and plasma IGFBP1 proteins were accordingly down- and up-regulated. In the muscle, PPAR beta delta and atrogin-1 mRNA increased and Egr1 mRNA decreased. Changes in messengers were partly mimicked by fasting. Thus, insulin signaling in muscle is peculiar in chicken and is strictly dependent on insulin in fed status. The 'diabetic' status induced by insulin immuno-neutralization is accompanied by impairments of glucagon secretion, thyroid axis, and expression of several genes involved in regulatory pathways or metabolisms, evidencing pleiotropic effects of insulin in fed chicken.
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PMID:Insulin immuno-neutralization in chicken: effects on insulin signaling and gene expression in liver and muscle. 1849 18

The presence of different nutrients regulates the beta-cell response to secrete insulin to maintain glucose in the physiological range and appropriate levels of fuels in different organs and tissues. Glucose is the only nutrient secretagogue capable of promoting alone the release of insulin release. The mechanisms of Insulin secretion are dependent or independent of the closure of ATP-sensitive K(+) channels. In addition, insulin secretion in response to glucose and other nutrients is modulated by several hormones as incretins, glucagon, and leptin. Fatty acids (FAs), amino acids, and keto acids influence secretion as well. The exact mechanism for which nutrients induce insulin secretion is complicated because nutrient signaling shows one of the most complex transduction systems, which exists for the reason that nutrient have to be metabolized. FAs in the absence of glucose induce FA oxidation and insulin secretion in a lesser extent. However, FAs in the presence of glucose produce high concentration of malonyl-CoA that repress FA oxidation and increase the formation of LC-CoA amplifying the insulin release. Long-term exposure to fatty acids and glucose results in glucolipotoxicity and decreases in insulin release. The amino acid pattern produced after the consumption of a dietary protein regulates insulin secretion by generating anaplerotic substrates that stimulates ATP synthesis or by activating specific signal transduction mediated by mTOR, AMPK, and SIRT4 or modulating the expression of genes involved in insulin secretion. Finally, dietary bioactive compounds such as isoflavones play an important role in the regulation of insulin secretion.
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PMID:Nutrient modulation of insulin secretion. 1925 Oct 40

Diabetes is a complex disease involving multiple organs with dysregulation in glucose and lipid metabolism. Hepatic insulin insensitivity can contribute to elevated fasting glucose levels and impaired glucose tolerance in individuals with diabetes. Several currently available therapeutics address defects at the liver. Metformin inhibits glucose production, potentially through effects on AMPK. Thiazolidinediones activate PPAR-gamma and improve hepatic insulin sensitivity, primarily through indirect effects on lipid metabolism. Insulin analogs and secretagogues suppress glucose production and increase liver glucose utilization by both direct and indirect hepatic actions. Incretins, incretin mimetics, and dipeptidyl peptidase-4 inhibitors reduce postprandial hepatic glucose production by increasing insulin secretion and limiting glucagon release, as well as through possible direct effects on the liver. Pramlintide reduces the increase in plasma glucagon that occurs following a meal in individuals with diabetes, and may thereby suppress inappropriate stimulation of liver glucose production. Many other hepatic targets are being considered which may lead to alternative strategies for the treatment of diabetes. This review focuses on currently available therapeutics which target insulin resistance in the liver.
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PMID:Current strategies for the inhibition of hepatic glucose production in type 2 diabetes. 1927 23

Glucagon-like peptide (GLP)-1 is a potent glucose-dependent insulinotropic gut hormone released from intestinal L cells. Our previous studies showed that berberine increased GLP-1 secretion in streptozotocin-induced diabetic rats. The aim of this study was to investigate whether berberine affected GLP-1 release in normal rats and in NCI-H716 cells. Proglucagon and prohormone convertase 3 genes regulating GLP-1 biosynthesis were analyzed by RT-PCR. Effects of pharmacological inhibitors on berberine-mediated GLP-1 release were studied. In vivo, 5-week treatment of berberine enhanced GLP-1 secretion induced by glucose load and promoted proglucagon mRNA expression as well as L cell proliferation in intestine. In vitro, berberine concentration-dependently stimulated GLP-1 release in NCI-H716 cells. Berberine also promoted both prohormone convertase 3 and proglucagon mRNA expression. Chelerythrine (inhibitor of PKC) concentration-dependently suppressed berberine-mediated GLP-1 secretion. Compound C (inhibitor of AMPK) also inhibited berberine-mediated GLP-1 secretion. But only low concentrations of H89 (inhibitor of PKA) showed inhibitory effects on berberine-mediated GLP-1 release. The present results demonstrated that berberine showed its modulation on GLP-1 via promoting GLP-1 secretion and GLP-1 biosynthesis. Some signal pathways including PKC-dependent pathway were involved in this process. Elucidation of mechanisms controlling berberine-mediated GLP-1 secretion may facilitate the understanding of berberine's antidiabetic effects.
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PMID:Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. 1994 41

NAD-dependent deacetylase SIRT1 is known to be activated by caloric restriction and is related to longevity. A natural polyphenolic compound resveratrol is also shown to increases SIRT1 activity and extends lifespan. However, the transcriptional regulation of SIRT1 gene has not completely examined in the context of metabolism. Thus, in this study, we characterized the 5' -flanking region of human SIRT1 gene. We first found that representative metabolic hormones and related factors (glucocorticoid, glucagon/cAMP, and insulin) did not show significant effect on SIRT1 gene transcription. PPARalpha and PPARgamma1 without/with their specific ligands did not have significant effect as well. In contrast, expression of PPARbeta/delta (PPARdelta markedly increased the 5' -promoter activity of SIRT1 gene, which was further amplified by the addition of GW501516, a selective PPARdelta agonist. Deletion/mutation mapping analyses failed to identify PPAR binding element but revealed the presence of canonical Sp1 binding site, which was conserved among species. The Sp1 site is functional, because Sp1 overexpresson significantly enhanced SIRT1 promoter activity, and the binding of Sp1 to the element was confirmed by EMSA and ChIP assays. Interestingly, specific Sp1 antagonist mithramycin completely abolished the PPARdelta-mediated induction of SIRT1 gene transcription. Altogether, our data suggest the predominant role of PPARdelta in the transcriptional regulation of SIRT1 gene. Furthermore, the effects of PPARdelta seem to be mediated by Sp1. We assume that, in vivo, starvation increases lipolysis-derived free fatty acid and activates PPARdelta and the resultant increase in SIRT1 expression, in addition to the activation by NAD and AMPK, facilitates the deacetylation of a variety of proteins involved in mitochondrial beta-oxidation pathway and cell survival.
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PMID:PPARbeta/delta regulates the human SIRT1 gene transcription via Sp1. 2016 Mar 99

In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism.
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PMID:Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs. 2108 54

Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (fourth i.c.v.) GLP-1R activation by Exendin-4 (Ex-4) increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Ex-4, as inhibitors RpcAMP and U0126 (fourth i.c.v.), respectively, attenuated Ex-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (fourth i.c.v.). The PKA, MAPK, and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.
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PMID:Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. 2707 83


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