Diabetes, Vol 47, Issue 10 1630-1636, Copyright © 1998 by American Diabetes Association

ARTICLES

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

JC Parker, MA VanVolkenburg, CB Levy, WH Martin, SH Burk, Y Kwon, C Giragossian, TG Gant, PA Carpino, RK McPherson, P Vestergaard and JL Treadway
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340, USA. janice_c_parker@groton.pfizer.com

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.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. W. Sloop, A. D. Showalter, A. L. Cox, J. X. C. Cao, A. M. Siesky, H. Y. Zhang, A. R. Irizarry, S. F. Murray, S. L. Booten, E. A. Finger, et al. Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease J. Biol. Chem., June 29, 2007; 282(26): 19113 - 19121. [Abstract] [Full Text] [PDF]

				N. Ercan-Fang, M. R. Taylor, J. L. Treadway, C. B. Levy, P. E. Genereux, E. M. Gibbs, V. L. Rath, Y. Kwon, M. C. Gannon, and F. Q. Nuttall Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E366 - E372. [Abstract] [Full Text] [PDF]

				S. Metzger, S. Nusair, D. Planer, V. Barash, O. Pappo, J. Shilyansky, and T. Chajek-Shaul Inhibition of Hepatic Gluconeogenesis and Enhanced Glucose Uptake Contribute to the Development of Hypoglycemia in Mice Bearing Interleukin-1{beta}- Secreting Tumor Endocrinology, November 1, 2004; 145(11): 5150 - 5156. [Abstract] [Full Text] [PDF]