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)

The ability of isoproterenol, glucagon, PGE1 and cholera toxin to stimulate the synthesis of cAMP and protein kinase activity in line of liver cells (BRL) and a line of rat hepatoma cells (H35) has been determined. The concentration of cAMP in BRL cells (approximately 10 pmoles/mg protein) is in the range reported for other cultured cell lines but H35 cells contain extraordinarily low amounts of this cyclic nucleotide (approximately 0.05 pmoles/mg protein). Isoproterenol and PGE1 caused an increase in cAMP content, and protein kinase activation in BRL cells, although glucagon was ineffective. H35 cells, in contrast, were completely insensitive to all hormonal agonists. Despite this fact, cholera toxin was able to produce a marked increase in cAMP content, adenylate cyclase activity and protein kinase activation in H35 cells. binding studies with [125 I]-iodohydroxybenzylpindolol, a specific beta-adrenergic receptor antagonist, revealed that each H35 cell possesses fewer than 10 beta-adrenergic receptors whereas BRL cells contain 2-5,000 receptors per cell. The low level of cAMP in H35 cells appears to result from a combination of totally unstimulated adenylate cyclase and apparently elevated phosphodiesterase activities.
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PMID:Studies of cAMP metabolism in cultured hepatoma cells: presence of functional adenylate cyclase despite low cAMP content and lack of hormonal responsiveness. 20 52

The levels of beta 1- and beta 3-adrenoreceptor mRNAs in several rat tissues were determined simultaneously with a sensitive nuclease protection assay. The beta 1-receptor gene was expressed to varying degrees in most tissues examined. By contrast, high levels of beta 3-receptor mRNA were only found in brown and white adipose tissues, indicating that beta 3-receptor gene expression is essentially adipose tissue specific. Surgical sympathectomy of interscapular brown adipose tissue increased beta 3-receptor mRNA levels by 2.4-fold, but did not affect beta 1-receptor mRNA levels. Exposure of rats to 4 C, which increases sympathetic nerve stimulation of IBAT, reduced beta 3-receptor mRNA levels in intact tissue but did not affect the denervation-induced increase in beta 3-receptor mRNA. Acute treatment of rats with norepinephrine greatly reduced beta 3 mRNA levels in both white and brown adipose tissues, but did not alter beta 1-receptor mRNA levels. These results indicate that beta 1- and beta 3-receptor mRNAs are differentially regulated and that norepinephrine released from sympathetic nerves is an important inhibitory regulator of beta 3-receptor mRNA levels. Injections of the beta-receptor agonist isoproterenol and the beta 3-receptor agonist BRL 26830 each reduced beta 3-receptor mRNA in brown and white fat, whereas injections of glucagon reduced beta 3-receptor mRNA in brown fat only. These data indicate that while stimulation of beta 3-receptors is sufficient to down-regulate beta 3 mRNA, other receptors that stimulate adenylyl cyclase have the same effect. Finally, the agonist-induced down-regulation of beta 3-receptor mRNA was associated with a reduction in beta 3-receptor activation of adenylyl cyclase in white adipose tissue.
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PMID:Differential adrenergic regulation of beta 1- and beta 3-adrenoreceptor messenger ribonucleic acids in adipose tissues. 130 20

The beta 3-adrenoceptor agonist, BRL 26830A, which is not inhibited by either beta 1 or beta 2-selective antagonists, has been shown to possess anti-obesity and anti-diabetic actions. However, the effects of this agent on insulin and glucagon release have not yet been substantiated. Therefore, we tested the hypothesis that BRL 26830A promotes insulin and glucagon secretion via beta 3 receptors on pancreatic islet B and A cells. In ICR mice fasted for 48 h, BRL 26830A significantly stimulated insulin secretion from 5 min after administration, markedly decreased blood glucose levels from 30 min after administration, and significantly increased glucagon secretion from 30 min after administration. The administration of a non-selective beta-receptor antagonist, at a dose of 50 mg/kg, 30 min prior to BRL 26830A injection completely abolished the effects induced by BRL 26830A. However, the administration of a beta 1-selective antagonist at doses of 50 or 100 mg/kg did not produce any significant effects. On the action of BRL 26830A, whereas the administration of a beta 2-selective antagonist at 50 mg/kg, a near maximal effective dose, partially abolished the effects of BRL 26830A. BRL 26830A had no effect on insulin, glucagon, or glucose levels in streptozocin (STZ) diabetic mice fasted for 48 h. These results suggest that, in mice, BRL 26830A may promote insulin secretion mainly via beta 3 receptors and partially via beta 2 receptors on pancreatic-islet B cells, and that glucagon may be secreted as the result of hypoglycemia induced by this agent.
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PMID:Effects of a beta 3-adrenoceptor agonist, BRL 26830A, on insulin and glucagon release in mice. 168 48

In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes.
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PMID:New treatments for patients with type 2 diabetes mellitus. 894 6

Thermogenesis in brown adipose tissue (BAT) is believed to be mediated mainly by beta3 adrenergic receptors. We previously demonstrated that the specific beta3 adrenergic agonist CGP-12177 increases whole body oxygen consumption and BAT GDP binding to a greater extent in young than in senescent rats. In contrast, the forskolin-induced increases were maintained with age, suggesting that early events in beta3 adrenergic signal transduction are impaired with age. To investigate whether beta1 or beta3 adrenergic function is decreased with age, we assessed beta1 and beta3 adrenergic receptor mRNA levels and the ability of beta1 and beta3 adrenergic receptors to activate adenylyl cyclase in BAT membranes from 4- and 24-month-old F-344 rats. Both beta1 and beta3 adrenergic receptor mRNA levels decreased by 50% with age. Adenylyl cyclase stimulated by the nonspecific agonist, isoproterenol, and by the specific beta3 agonist, BRL 37344, also declined by 50% with age, whereas glucagon stimulation decreased by more than 70%. The isoproterenol-stimulated adenylyl cyclase activation curves were resolved by two-site regression analysis to determine the contribution of beta1 and beta3 adrenergic receptors. The Vmax for both beta1 and beta3 adrenergic receptors decreased by 50% with age. However, stimulation of adenylyl cyclase by NaF and forskolin was also diminished by the same amount as beta adrenergic stimulation, suggesting that the activation with age may be limited by the amount of adenylyl cyclase catalytic unit rather than by receptor number. These data suggest both beta1 and beta3 adrenergic receptors and adenylyl cyclase catalytic units are deficient with age in rodent BAT.
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PMID:Effects of age on beta adrenergic subtype activation of adenylyl cyclase in brown adipose tissue. 898 10

Postprandial release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from L cells results from both nutrient transit in the ileal lumen and neural drive of endocrine cells. The adrenosympathetic system and its effectors have been shown to induce secretion of L cells in vivo or in vitro. Because these transmitters act through three receptors, beta, alpha1, alpha2, coupled to different intracellular pathways, we evaluated the responses of L cells to specific agonists, using the model of isolated vascularly perfused rat ileum. General stimulation of adrenergic receptors with epinephrine (10(-7) M) induced significant GLP-1 and PYY secretions (94+/-38 and 257+/-59 fmol/8 min respectively) which were abolished upon propranolol (10(-7) M) pretreatment and strongly decreased upon infusion with 10(-8) M prazosin. Blockade of alpha2-receptors with idazoxan (10(-8) M) did not alter epinephrine-induced peptide secretion. The beta-adrenergic agonist isoproterenol (10(-6) M) infused for 30 min induced a transient release of GLP-1 and PYY (integrated release over the 8 min of the peak secretion: 38+/-16 and 214+/-69 fmol for GLP-1 and PYY respectively, P<0.05). Because terbutaline but not dobutamine or BRL 37,344 (10(-5) M) induced significant GLP-1 and PYY secretions (135+/-30 and 305+/-39 fmol/8 min respectively), isoproterenol-induced secretions are suggested to result mainly from stimulation of the beta2-isoreceptor type. In contrast, the alpha1-agonist phenylephrine (10(-7) M) did not stimulate peptide release. When co-infused with 10(-6) M or 10(-7) M isoproterenol, 10(-7) M phenylephrine raised GLP-1 release to 174+/-53 and 108+/-28 fmol/8 min respectively (vs 38+/-16 and 35+/-10 fmol/8 min for isoproterenol alone, P<0.05) whereas PYY secretion was not significantly increased. Clonidine (10(-7) M), an alpha2-agonist, induced a moderate and delayed increase of GLP-1 and PYY but abolished the isoproterenol-induced peptide secretion. Our results showed that general stimulation of adrenergic receptors stimulates the secretory activity of ileal endocrine L cells. The net peptide secretion results from the activation of the beta2-isoreceptor type. Additionally, GLP-1 and PYY secretions are positively modulated by alpha1-receptor stimulation and inhibited by alpha2-receptor activation upon beta-receptor occupation.
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PMID:Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation. 1042 66

The objective was to evaluate whether norepinephrine (NE) and other hormonal factors have direct effects on protein degradation in brown fat cells. NE inhibited proteolysis by 35-45% in mouse brown adipocytes differentiated in culture. Insulin also inhibited protein degradation but significantly less than NE, whereas glucagon and leptin had no effect. The inhibitory effect of NE was partially antagonized by propranolol but not by prazosin, and dose-response curves with BRL-37344 (a beta(3)-agonist), isoproterenol (a beta(1)/beta(2)-agonist) and dobutamide (a beta(1)-agonist) were consistent with the involvement of a beta(3)-adrenergic receptor. Furthermore, forskolin mimicked the effects of NE, whereas additions of A-23187 or phorbol esters had no effect, alone or in combination with NE or forskolin. Thus inhibition of proteolysis by NE likely involves a beta(3)-adrenergic receptor-mediated increase in cAMP. In contrast, NE, BRL-37344, and dobutamide had no effect on proteolysis in preadipocytes. Inhibition of proteolysis by NE was due at least in part to inhibition of autophagy. Thus inhibition of proteolysis by NE and insulin in mature brown adipocytes is likely an important process contributing to brown fat growth and atrophy under many physiological or pathological conditions.
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PMID:Differentiation-dependent inhibition of proteolysis by norepinephrine in brown adipocytes. 1044 15

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, adalimumab, adefovir dipivoxil, alefacept, alemtuzumab, 3-AP, AP-12009, APC-8015, L-Arginine hydrochloride, aripiprazole, arundic acid, avasimibe; Bevacizumab, bivatuzumab, BMS-181176, BMS-184476, BMS-188797, bortezomib, bosentan, botulinum toxin type B, BQ-123, BRL-55730, bryostatin 1; CEP-1347, cetuximab, cinacalcet hydrochloride, CP-461, CpG-7909; D-003, dabuzalgron hydrochloride, darbepoetin alfa, desloratadine, desoxyepothilone B, dexmethylphenidate hydrochloride, DHA-paclitaxel, diflomotecan, DN-101, DP-b99, drotrecogin alfa (activated), duloxetine hydrochloride, duramycin; Eculizumab, Efalizumab, EKB-569, elcometrine, enfuvirtide, eplerenone, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, exatecan mesilate, ezetimibe; Fenretinide, fosamprenavir calcium, frovatriptan; GD2L-KLH conjugate vaccine, gefitinib, glufosfamide, GTI-2040; Hexyl insulin M2, human insulin, hydroquinone, gamma-Hydroxybutyrate sodium; IL-4(38-37)-PE38KDEL, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; KRN-5500; LY-544344; MDX-210, melatonin, mepolizumab, motexafin gadolinium; Natalizumab, NSC-330507, NSC-683864; 1-Octanol, omalizumab, ortataxel; Pagoclone, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, phenoxodiol, pimecrolimus, plevitrexed, polyphenon E, pramlintide acetate, prasterone, pregabalin, PX-12; QS-21; Ragaglitazar, ranelic acid distrontium salt, RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, repinotan hydrochloride, rhEndostatin, rh-Lactoferrin, (R)-roscovitine; S-8184, semaxanib, sitafloxacin hydrate, sitaxsentan sodium, sorafenib, synthadotin; Tadalafil, tesmilifene hydrochloride, theratope, tipifarnib, tirapazamine, topixantrone hydrochloride, trabectedin, traxoprodil, Tri-Luma; Valdecoxib, valganciclovir hydrochloride, vinflunine; Ximelagatran; Ziconotide.
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PMID:Gateways to clinical trials. 1514 27