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)

Semisynthetic N epsilon- acetimidoglucagon was prepared from the [des- His1 ]analogue by coupling the N-hydroxysuccinimide ester of N alpha- tBoc - Nimidazole -DNP-L-histidine to the peptide in dimethylformamide in the presence of 1-hydroxybenzotriazole. The deprotected, purified product was chemically identical to N epsilon- acetimidoglucagon and equipotent to N epsilon- acetimidoglucagon and native glucagon in its ability to activate adenylate cyclase and displace [125I] iodoglucagon from rat liver plasma membranes. Semisynthetic [ Phe1 ]-, [ Ala1 ]-, and [des- His1 ] glucagons prepared similarly achieved 85, 55, and 35% of the maximal activity and 22, 2, and 6% of the binding potency of N epsilon- acetimidoglucagon . The biological assays indicate that the amino group is involved to a greater extent in transduction than in binding, but the aromatic nature and hydrogen bonding capability of the imidazole ring of histidine-1 are important for both binding and transduction. In circular dichroism studies, all derivatives exhibited increased helicity in 2-chloroethanol. The [ Phe1 ] analogue although less soluble behaved similarly to native glucagon, while the [ Ala1 ] and [des- His1 ] derivatives exhibited an increased helical content in 0.01 N HCl as a result of an increased propensity of these derivatives to self-associate in the absence of 2-chloroethanol. The unexpected conformational changes throughout the molecule may have relevance for the functional activity.
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PMID:Semisynthetic derivatives of glucagon. The contribution of histidine-1 to hormone conformation and activity. 654 39

A determination of the spatial structure of the polypeptide hormone glucagon bound to perdeuterated dodecylphosphocholine micelles is described. A map of distance constraints between individually assigned hydrogen atoms of the polypeptide chain was obtained from two-dimensional nuclear Overhauser enhancement spectroscopy. These data were used as the input for a distance geometry algorithm for computing conformations that would be compatible with the experiments. In the region from residues 5 to 29 the mobility of the polypeptide backbone and most of the amino acid side-chains was found to be essentially restricted to the overall rotational tumbling of the micelles. The secondary structure in this region includes three turns of irregular alpha-helix in the segment of residues 17 to 29 near the C terminus, a stretch of extended polypeptide chain from residues 14 to 17, an alpha-helix-like turn formed by the residues 10 to 14 and another extended region from residues 5 to 10. In the N-terminal tetrapeptide H-His-Ser-Gln-Gly- the two terminal residues are highly mobile, indicating that they extend into the aqueous phase, and the mobility of the residues Gln3 and Gly4 appears to be only partially restricted by the binding to the micelle. The absence of long range nuclear Overhauser effects between the peptide segments 5-9 and 11-29, and between 5-16 and 19-29 shows that the polypeptide chain does not fold back on itself and hence that micelle-bound glucagon does not adopt a globular tertiary structure. Previously it was shown that the polypeptide backbone of glucagon is located close to and runs roughly parallel to the micelle surface. Combination of these observations suggests that the overall spatial arrangement of the glucagon polypeptide chain in a lipid-water interphase is largely determined by the topology of the lipid support, in the present case the curvature of the dodecylphosphocholine micelles. The tertiary structure is further characterized by the formation of two hydrophobic patches by the side-chains of Phe6, Tyr10 and Leu14, and the side-chains of Ala19, Phe22, Val23, Trp25 and Leu26, respectively.
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PMID:Conformation of glucagon in a lipid-water interphase by 1H nuclear magnetic resonance. 663 57

A literature search on the structural aspects of glucagon in dilute aqueous solution has been undertaken. We have found that a compact, well-defined structure must exist and propose a model for that structure. In doing so, care was taken to distinguish between the raw data themselves and the interpretations drawn from them, and to bring about a model consistent with as much of the data as possible. The model building was performed on Corey-Pauling-Koltun (CPK) space-filling models using secondary structure prediction rules, experimental data such as fluorescence quenching, circular dichroism, NMR and high resolution dark field electron microscopy, and was guided by a hierarchy of intramolecular interactions which places hydrophobic bonding first and hydrogen bonding second. This last criterion places a strict requirement on the model-building to maximize contacts among complementary hydrophobic surfaces; this means that no empty spaces are allowed inside the folded molecule. The resultant model is consistent with all the relevant data. Furthermore, as demanded by any structure building exercise, the model suggests structure-function relationships. One of the predictions drawn from the structure--the binding of guanosine-5'-triphosphate (GTP)--has been confirmed by a preliminary experiment (reported elsewhere). Another aspect of the structure suggests a subtle mechanism for allostery.
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PMID:A model for the three-dimensional structure of glucagon. 665 88

The chemical specificity and structural requirements of short-chain fatty acids (SCFAs) in stimulating pancreatic endocrine responses was investigated in conscious sheep. Normal SCFAs with one to eight carbons were injected intravenously at seven doses of 39-2,500 mumol/kg body wt. The isomers or derivatives of SCFAs were administered at 625 mumol/kg body wt. Analysis of dose-response curves showed that n-butyric acid (4 carbons in the molecule) was most effective for both insulin and glucagon secretion among the normal SCFAs tested. In addition, one carboxylic group was absolutely required, since hormone secretion was significantly reduced or abolished with compounds in which the carboxylic element was replaced by other groups and with dicarboxylic acids. The form of the hydrocarbon chain (branched, cyclic, or benzoic ring) also affected hormone secretory activity. Most of the compounds that replaced hydrogen in the hydrocarbon chain by other groups at various positions reduced or abolished the hormone secretory effect obtained by n-butyric acid. In conclusion, a monocarboxylic acid with several numbers of hydrocarbons was required for insulin or glucagon secretion. These results suggest that the pancreatic endocrine system can recognize the chemical structure of SCFAs in detail and induce hormone secretion in sheep.
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PMID:Chemical specificity of short-chain fatty acids in stimulating insulin and glucagon secretion in sheep. 807 2

Sex-dependent stone formation following portacaval shunt (PCS) was investigated in 82 male and 71 female Sprague-Dawley rats. 72.6% of male PCS rats and none of the female PCS rats developed urolithiasis, in 90.2%, potassium-hydrogen-urate stones formed. Hormonal analysis revealed significant alterations in steroid hormones and glucagon postoperatively. Male PCS rats showed a significant decrease in total and free testosterone and an increase in estradiol and glucagon levels. Female PCS rats showed a marked rise in testosterone and glucagon levels as well as a decrease in estradiol plasma levels. Male PCS rats had higher urinary and plasma uric acid concentrations compared to female PCS and sham-operated rats. Loss of testosterone and rise of glucagon in males was correlated with urolithiasis in so far as stone-forming rats had higher concentrations than non-stone-forming PCS rats. Our findings suggest that hormonal alterations might contribute to sex-dependent stone formation in PCS rats.
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PMID:Sex-dependent urolithiasis in the portacaval shunt rat. 2. Hormones and stone formation. 826 10

The effect of Orlistat, a lipase inhibitor used in the treatment of obesity was studied on gastrointestinal transit time, on body composition and on hormones known to be influenced by the degree of hydrolysis of nutritional triglycerides or by reduced nutrient intake and absorption. After a placebo run-in period 14 patients were randomized to a 12-week treatment period on Orlistat 360 mg per day (mean body weight 93.1 +/- 9.8 kg) or placebo (mean body weight 90.7 +/- 10.5 kg). At randomization and after 12 weeks body weight, body composition, thyroid hormones, catecholamines, insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were measured. During 4 hours after consumption of a liquid fat-rich mixed meal containing study medication, 15 g lactulose and 25 g xylose, blood levels of glucose, insulin, c-peptide, glucagon, triglycerides, free fatty acids, cholecystokinin, pancreatic polypeptide and xylose and expiration air levels of hydrogen were measured. Weight loss was 4.2 +/- 3.5 kg in the Orlistat group versus 3.0 +/- 1.9 kg in the placebo group. Fat mass decreased to an equal degree, whereas lean body mass remained stable. No differences were found for thyroid hormones, catecholamines, IGF-I and IGFBP-3 levels. By comparing the areas under the curve (AUC) and the peak levels at randomization (acute effects) of insulin and c-peptide a tendency was found to be increased in the Orlistat group, whereas those of xylose were increased significantly, suggesting faster gastric emptying after Orlistat. No differences were found in the other parameters. By comparing the changes in responses (longer term effects) no significant differences were found. In conclusion, the presence in the gut of undigested and unabsorbed fat does not seem to have a relevant influence on hormonal status and body composition in a small group of moderately obese patients.
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PMID:Lipase inhibition and hormonal status, body composition and gastrointestinal processing of a liquid high-fat mixed meal in moderately obese subjects. 865 34

The aim of the study was to characterize the gastric and mesenteric vascular changes induced by diabetes and the implication of endothelial [nitric oxide (NO) and prostaglandins] and humoral (glucagon) factors in such changes. Diabetes was induced in rats by a single streptozotocin injection. Four weeks later, gastric mucosa, left gastric artery, and superior mesenteric artery blood flows were measured using hydrogen gas clearance and perivascular ultrasonic flowmeter techniques, respectively, in anesthetized and fasted diabetic and control rats. Blood pressure, hematocrit, blood volume, and blood viscosity were also measured. Left gastric (41 +/- 6 vs. 25 +/- 4 ml.min-1.100 g-1) and superior mesenteric artery blood flows (83 +/- 8 vs. 65 +/- 4 ml.min-1.100 g-1) were significantly higher in diabetic than in control rats. The increased blood flow in the left gastric artery was distributed to a hypertrophic mucosa in diabetic rats; therefore, the blood flow per 100 g tissue in the gastric mucosa was not significantly different in diabetic compared with control rats. Pretreatment with indomethacin reduced both increase gastric and mesenteric flows of the diabetic rats to the same levels as in control rats. NG-nitro-L-arginine methyl ester decreased gastric blood flow in a dose-dependent manner and to a similar extent in diabetic and control rats. In contrast, an increased sensitivity to the higher doses of the NO inhibitor was observed in the mesenteric vascular bed of diabetic rats. Glucagon reduction achieved by somatostatin infusion did not influence either gastric or mesenteric blood flow in diabetic rats. In summary, the present study revealed an increase in gastric and mesenteric arterial blood flows in streptozotocin-induced diabetic rats. The gastrointestinal hyperemia seems to be due, at least in part, to the increased demand of a hypertrophic mucosa and is mediated primarily by endogenous prostaglandins. Increased vascular sensitivity to NO may also contribute to the mesenteric vasodilation.
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PMID:Role of prostaglandins and nitric oxide in gastrointestinal hyperemia of diabetic rats. 892 99

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP), retinoic acid, and glucocorticoids stimulate transcription of the PEPCK gene, whereas insulin and phorbol esters have a dominant inhibitory effect. We now show that oxidative and chemical stress (hydrogen peroxide and sodium meta-arsenite, respectively) also produce a dominant inhibitory effect, both on the endogenous PEPCK gene and on a stably transfected PEPCK-chloramphenicol acetyl transferase (CAT) fusion gene. Wortmannin, an inhibitor of 1-phosphatidylinositol 3-kinase (PI 3-kinase), blocks the inhibition of glucocorticoid and cAMP-induced PEPCK gene transcription by insulin; however, it has no effect on the inhibition elicited by oxidative or chemical stress. Thus, the mechanism(s) used by hydrogen peroxide and sodium meta-arsenite to regulate PEPCK gene expression are PI 3-kinase independent. This suggests that these agents operate by a pathway distinct from that used by insulin or that the pathways converge at a point downstream of PI 3-kinase. The reactivating kinase (RK, also known as p38 mitogen activated protein kinase) is induced by insulin, hydrogen peroxide, or sodium meta-arsenite in hepatoma cells, and these effects are blocked by SB203580, a selective inhibitor of RK. However, SB203580 has no effect on the ability of any of these agents to regulate PEPCK-CAT fusion gene expression. Thus, although RK has a role in the regulation of lymphokine gene expression in monocytes, it is not required for the regulation of PEPCK expression by either insulin or oxidative and chemical stress in hepatoma cells.
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PMID:Oxidative and chemical stress mimic insulin by selectively inhibiting the expression of phosphoenolpyruvate carboxykinase in hepatoma cells. 897 Oct 75

The enzyme glucose oxidase was immobilized on the surface of carbon fiber microelectrodes (CFMEs) either by cross-linking in glutaraldehyde vapor or by enzyme entrapment in electropolymerized films of m-phenylenediamine or resorcinol. The cross-linked enzymatic layer was, in the given conditions, covered with an additional membrane of Nafion or cellulose acetate. The prepared glucose sensors were tested using differential normal pulse voltammetry (DNPV, in which the scan comprises successive double pulses ("prepulse and pulse"), the prepulses are of increasing amplitude, and the current measured is the differential of the current existing between each prepulse and pulse). With properly chosen DNPV parameters, the response to glucose presented a peak at a potential of about 1 V versus an Ag/AgC1-reference, owing to the oxidation of enzymatically produced hydrogen peroxide. The calibration curves obtained (peak height/glucose concentration) were linear from 0.3-0.5 up to 1.5-6.5 mM and showed a sensitivity ranging from 1.4 up to 34.5 mA M-1 cm-2, depending on the sensor type. The DNPV response to glucose exhibited an essential insensitivity toward easily oxidizable interfering substances such as ascorbic acid and acetaminophen present at physiological concentrations. Peptides, the interfering species typical of the cerebral medium, were effectively retained by the above additional membranes. Concentration values of glucose in plasma and cerebrospinal fluid, determined in vitro from the DNPV peak height, agreed well with those measured by standard procedures. In the anesthetized rat, extracellular brain concentration of glucose was also monitored during administration of either insulin or glucagon. Under such pharmacological conditions, the changes observed in the peak height were in perfect agreement with the known effects induced by both substances.
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PMID:In vivo brain glucose measurements: differential normal pulse voltammetry with enzyme-modified carbon fiber microelectrodes. 897 23

The different endowment with key enzymes and thus different metabolic capacities of periportal and perivenous cell types led to the model of "metabolic zonation." The periportal and perivenous hepatocytes receive different signals owing to the decrease of substrate concentrations including O2 and hormone levels during passage of blood through the liver sinusoids. These different signal patterns should be important for the short-term regulation of metabolism and also for the long-term induction and maintenance of the different enzyme pathways by control of gene expression. The periportal to perivenous drop in oxygen tension was considered to be a key regulator in the zonated expression of carbohydrate-metabolizing enzymes. In primary hepatocyte cultures, glucagon activated the phosphoenolpyruvate carboxykinase (PCK) gene to higher levels under arterial than under venous oxygen. The insulin-dependent activation of the glucokinase (GK) gene was reciprocally modulated by oxygen. Exogenously added hydrogen peroxide mimicked the effects of arterial oxygen on both the glucagon-dependent PCK gene and the insulin-dependent GK activation. Therefore, the oxygen sensor could be a hydrogen peroxide-producing oxidase which could contain a heme group for "measuring" the O2 tension. This notion was corroborated by the finding that CO mimicked the positive effect of O2 on PCK gene activation. Transfection of PCK promoter-CAT gene constructs into primary hepatocytes showed that the oxygen modulation of the PCK gene activation occurred in the region -281/+69. The modulation by O2 was not mediated by isolated cAMP-responsive elements. Nuclear protein extracts prepared from hepatocytes cultured under venous PO2 as compared to arterial PO2 showed an enhanced binding activity to the promoter fragment -149/-43. Oxidative conditions such as H2O2 reduced the DNA-binding activity, thus supporting the role of H2O2 as a mediator in the O2 response of the PCK and GK genes.
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PMID:Modulation by oxygen of zonal gene expression in liver studied in primary rat hepatocyte cultures. 929 45


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