Plasma glucose levels are reduced in rats and mice treated with an inhibitor of glucose-6-phosphate translocase

被引:50
作者
Parker, JC
VanVolkenburg, MA
Levy, CB
Martin, WH
Burk, SH
Kwon, Y
Giragossian, C
Grant, TG
Carpino, PA
McPherson, RK
Vestergaard, P
Treadway, JL
机构
[1] Pfizer Inc, Div Cent Res, Dept Cardiovasc & Metab Dis, Groton, CT 06340 USA
[2] Pfizer Inc, Div Cent Res, Dept Exploratory Med Biol, Groton, CT 06340 USA
[3] Pfizer Inc, Div Cent Res, Dept Drug Metab, Groton, CT 06340 USA
[4] Pfizer Inc, Div Cent Res, Dept Med Chem, Groton, CT 06340 USA
关键词
D O I
10.2337/diabetes.47.10.1630
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-imidazo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid (compound A) with a 50% inhibitory concentration (IC50) of similar to 10 nmol/l. Compound A (500 mol/l) inhibited the uptake of [C-14]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 similar to 320 nmol/l.) Compound A (1 mu mol/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.
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页码:1630 / 1636
页数:7
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