PLASMA-GLUCOSE LEVELS ARE REDUCED IN RATS AND MICE TREATED WITH AN INHIBITOR OF GLUCOSE-6-PHOSPHATE TRANSLOCASE

The activity of glucose-6-phosphatase (G-6-Pase) in isolated rat micro somes was inhibited by a new selective inhibitor of the multi-subunit G-6-Pase system, n-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic ac id (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]glu cose-6-phosphate (G-6-P) into intact isolated rat microsomes, confirmi ng that this agent blocks G-6-P translocation, as suggested by previou s studies using intact and permeabilized microsomes. The inhibition of microsomal G-6-P transport by compound A was associated with inhibiti on 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 wi thin 3 h. A similar time course of glycemic response was observed in f asted rats; glucose lowering was maximal 30 min after dosing with 100 mg/kg compound A (-36%) and declined until the effect was fully revers ed by 3 h postdose. In rats subjected to compound A treatment, liver g lycogen content was increased. G-6-P and lactate levels were maximally elevated 30 min after dosing and declined thereafter. Cumulatively, t hese results suggest that the mechanism of glucose lowering by compoun d A was via inhibition of G-6-Pase activity mediated through inhibitio n of the T1 subunit of the microsomal G-6-Pase enzyme system. Drug lev els 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.