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 impact of GLUT2 gene inactivation on the regulation of hepatic glucose metabolism during the fed to fast transition. In control and GLUT2-null mice, fasting was accompanied by a approximately 10-fold increase in plasma glucagon to insulin ratio, a similar activation of liver glycogen phosphorylase and inhibition of glycogen synthase and the same elevation in phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs. In GLUT2-null mice, mobilization of glycogen stores was, however, strongly impaired. This was correlated with glucose-6-phosphate (G6P) levels, which remained at the fed values, indicating an important allosteric stimulation of glycogen synthase by G6P. These G6P levels were also accompanied by a paradoxical elevation of the mRNAs for L-pyruvate kinase. Re-expression of GLUT2 in liver corrected the abnormal regulation of glycogen and L-pyruvate kinase gene expression. Interestingly, GLUT2-null livers were hyperplasic, as revealed by a 40% increase in liver mass and 30% increase in liver DNA content. Together, these data indicate that in the absence of GLUT2, the G6P levels cannot decrease during a fasting period. This may be due to neosynthesized glucose entering the cytosol, being unable to diffuse into the extracellular space, and being phosphorylated back to G6P. Because hepatic glucose production is nevertheless quantitatively normal, glucose produced in the endoplasmic reticulum may also be exported out of the cell through an alternative, membrane traffic-based pathway, as previously reported (Guillam, M.-T., Burcelin, R., and Thorens, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 12317-12321). Therefore, in fasting, GLUT2 is not required for quantitative normal glucose output but is necessary to equilibrate cytosolic glucose with the extracellular space. In the absence of this equilibration, the control of hepatic glucose metabolism by G6P is dominant over that by plasma hormone concentrations.
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PMID:Liver hyperplasia and paradoxical regulation of glycogen metabolism and glucose-sensitive gene expression in GLUT2-null hepatocytes. Further evidence for the existence of a membrane-based glucose release pathway. 1075 92

The first synthesis of the single isomers (3R,4R,5R); (3S,4S,5S): (3R,4R,5S) and (3S,4S,5R) of 5-hydroxymethyl-piperidine-3,4-diol from Arecolin is reported, including the synthesis of a series of N-substituted derivatives of the (3R,4R,5R)-isomer (Isofagomine). The inhibitory effect of these isomers as well as of a series of N-substituted derivatives of the (3R,4R,5R)-isomer and selected hydroxypiperidine analogues on liver glycogen phosphorylase (GP) showed that the (3R,4R,5R) configuration was essential for obtaining an inhibitory effect at submicromolar concentration. The results also showed that all three hydroxy groups should be present and could not be substituted, nor were extra OH groups allowed if sub-micromolar inhibition should be obtained. Some inhibitory effect was retained for N-substituted derivatives of Isofagomine; however, N-substitution always resulted in a loss of activity compared to the parent compound, IC50 values ranging from 1 to 100 microM were obtained for simple alkyl, arylalkyl and benzoylmethyl substituents. Furthermore, we found that it was not enough to assure inhibitory effect to have the (R,R,R) configuration. Fagomine, the (2R,3R,4R)-2-hydroxymethylpiperidine-3,4-diol analogue, showed an IC50 value of 200 microM compared to 0.7 microM for Isofagomine. In addition, Isofagomine was able to prevent basal and glucagon stimulated glycogen degradation in cultured hepatocytes with IC50 values of 2-3 microM.
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PMID:Iminosugars: potential inhibitors of liver glycogen phosphorylase. 1131 Jun 9

Two distinct glycogen phosphorylase inhibitors, 5-chloro-1H-indole-2-carboxylic acid [1-(4-fluorobenzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxoethyl]amide (CP-320,626) and 1,4-dideoxy-1,4-D-arabinitol (DAB), were characterized in vitro with respect to the influence of glucose on their potencies. CP-320,626 has previously been shown to bind to a newly characterized indole site, whereas DAB seems to act as a glucose analogue, but with slightly different properties from those of glucose. When analysed in pig liver glycogen phosphorylase a (GPa) activity assays, the two inhibitors showed very different properties. When GPa activity was measured in the physiological direction (glycogenolysis), DAB was the most potent inhibitor with an IC(50) value of 740+/-9 nM compared with the IC(50) value for CP-320-626 of 2.39+/-0.37 microM. There was no effect of glucose on the inhibitory properties of DAB, whereas a glucose analogue N-acetyl-beta-D-glucopyranosylamine (1-GlcNAc) antagonized the effect of DAB. Likewise, there was no synergistic effect of CP-320,626 and glucose, whereas CP-320,626 and 1-GlcNAc inhibited GPa in synergy. Moreover, the synergistic effect of glucose and CP-320,626 was GPa-isoform-specific, since CP-320,626 and glucose inhibited rabbit muscle GPa in synergy when the GPa activity was measured towards glycogenolysis. When GPa activity was measured towards glycogen synthesis, CP-320,626 showed a synergistic effect with glucose, whereas the effect of DAB was slightly antagonized by glucose in this assay direction. Caffeine was included in the investigation as a control GP inhibitor, and both glucose and 1-GlcNAc potentiated the effect of caffeine independent of the assay direction. In primary cultured rat hepatocytes 1-GlcNAc and CP-320,626 inhibited basal and glucagon-induced glycogenolysis in synergy, whereas the ability of DAB to inhibit basal or glucagon-induced glycogenolysis was unaltered by 1-GlcNAc. Glucose had no effect on either CP-320,626 or DAB inhibition of glycogenolysis in cultured rat hepatocytes. In conclusion, the present study shows that the two GP inhibitors are kinetically very distinct and neither of the inhibitors demonstrates a physiologically relevant glucose dependence in vitro.
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PMID:The effect of glucose on the potency of two distinct glycogen phosphorylase inhibitors. 1209 91

Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.
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PMID:Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. 1619 Jul 45

Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC(50) = 0.4-1.2 microM) and of basal and glucagon-stimulated glycogenolysis (IC(50) = 1-3 microM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.
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PMID:Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition. 1697 Mar 95

A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.
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PMID:Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a. 1843 70

A series of carboxylic acid glycogen phosphorylase inhibitors, which have potential as oral antidiabetic agents, is described. Defining and applying simple physicochemical design criteria was used to assess the opportunity and to focus synthetic efforts on compounds with the greatest probability of success. The study led to compound 17, which exhibits a good balance of properties including potent inhibition of recombinant human liver glycogen phosphorylase in vitro, a good DMPK profile including excellent bioavailability and low clearance and good in vivo activity in a glucagon challenge model of diabetes in Zucker rats.
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PMID:Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors. 2049 91


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