Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
10
|
| pubmed:dateCreated |
1998-10-9
|
| pubmed:abstractText |
The activity of glucose-6-phosphatase (G-6-Pase) in isolated rat microsomes was inhibited by a new selective inhibitor of the multi-subunit G-6-Pase system, 1-[2-(4-chloro-phenyl)-cyclopropylmethoxy]-3,4-dihydroxy-5-(3-imid azo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid (compound A) with a 50% inhibitory concentration (IC50) of approximately 10 nmol/l. Compound A (500 nmol/l) inhibited the uptake of [14C]glucose-6-phosphate (G-6-P) into intact isolated rat microsomes, confirming that this agent blocks G-6-P translocation, as suggested by previous studies using intact and permeabilized microsomes. The inhibition of microsomal G-6-P transport by compound A was associated with inhibition of the rate of glucose output from rat hepatocytes incubated in the presence of 25 nmol/l glucagon (IC50 approximately 320 nmol/l.) Compound A (1 micromol/l) also inhibited the basal rate of glucose production by rat hepatocytes by 47%. Intraperitoneal administration of compound A to fasted mice lowered circulating plasma glucose concentrations dose-dependently at doses as low as 1 mg/kg. This effect was comparatively short-lived; glucose lowering was maximal at 30 min after dosing with 100 mg/kg compound A (-71%) and declined thereafter, being reversed within 3 h. A similar time course of glycemic response was observed in fasted rats; glucose lowering was maximal 30 min after dosing with 100 mg/kg compound A (-36%) and declined until the effect was fully reversed by 3 h postdose. In rats subjected to compound A treatment, liver glycogen content was increased. G-6-P and lactate levels were maximally elevated 30 min after dosing and declined thereafter. Cumulatively, these results suggest that the mechanism of glucose lowering by compound A was via inhibition of G-6-Pase activity, mediated through inhibition of the T1 subunit of the microsomal G-6-Pase enzyme system. Drug levels measured over the same time course as that used to assess in vivo efficacy peaked within 30 min of administration, then declined, which is consistent with the transient changes in plasma glucose and liver metabolites.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antiporters,
http://linkedlifedata.com/resource/pubmed/chemical/Blood Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclohexanecarboxylic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/Glucose-6-Phosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Glycogen,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoglycemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Monosaccharide Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Slc37a4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Slc37a4 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/glucose 6-phosphate(transporter)
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0012-1797
|
| pubmed:author |
pubmed-author:BurkS HSH,
pubmed-author:CarpinoP APA,
pubmed-author:GantT GTG,
pubmed-author:GiragossianCC,
pubmed-author:KwonYY,
pubmed-author:LeviC RCR,
pubmed-author:MartinW HWH,
pubmed-author:McPhersonR KRK,
pubmed-author:ParkerJ CJC,
pubmed-author:TreadwayJ LJL,
pubmed-author:VanVolkenburgM AMA,
pubmed-author:VestergaardPP
|
| pubmed:issnType |
Print
|
| pubmed:volume |
47
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1630-6
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9753303-Animals,
pubmed-meshheading:9753303-Antiporters,
pubmed-meshheading:9753303-Blood Glucose,
pubmed-meshheading:9753303-Cyclohexanecarboxylic Acids,
pubmed-meshheading:9753303-Enzyme Inhibitors,
pubmed-meshheading:9753303-Glucose,
pubmed-meshheading:9753303-Glucose Tolerance Test,
pubmed-meshheading:9753303-Glucose-6-Phosphate,
pubmed-meshheading:9753303-Glycogen,
pubmed-meshheading:9753303-Hypoglycemic Agents,
pubmed-meshheading:9753303-Kinetics,
pubmed-meshheading:9753303-Liver,
pubmed-meshheading:9753303-Male,
pubmed-meshheading:9753303-Mice,
pubmed-meshheading:9753303-Mice, Inbred C57BL,
pubmed-meshheading:9753303-Mice, Obese,
pubmed-meshheading:9753303-Microsomes, Liver,
pubmed-meshheading:9753303-Molecular Structure,
pubmed-meshheading:9753303-Monosaccharide Transport Proteins,
pubmed-meshheading:9753303-Obesity,
pubmed-meshheading:9753303-Phosphotransferases,
pubmed-meshheading:9753303-Rats,
pubmed-meshheading:9753303-Rats, Sprague-Dawley
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
Plasma glucose levels are reduced in rats and mice treated with an inhibitor of glucose-6-phosphate translocase.
|
| pubmed:affiliation |
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340, USA. janice_c_parker@groton.pfizer.com
|
| pubmed:publicationType |
Journal Article
|