ANTIDIABETIC AGENT ENGLITAZONE ENHANCES INSULIN ACTION IN NONDIABETIC RATS WITHOUT PRODUCING HYPOGLYCEMIA

The new antihyperglycemic agent englitazone (CP-68,722) was examined in nondiabetic rats. Administration of englitazone at 50 mg/kg/d for 8 days did not produce overt hypoglycemia but it lowered basal plasma insulin by 59% and 41% in rats fed ad libitum and fasted overnight on the last day, respectively. Drug treatment also lowered (P <.05) plasma nonesterified fatty acids (1.09 ± 0.05 to 0.36 ± 0.05 mmol/L) and cholesterol (2.41 ± 0.08 to 2.06 ± 0.07 mmol/L) in fasted rats, and glycerol (0.25 ± 0.02 to 0.14 ± 0.02 mmol/L) in fed rats but had no effect on 3-hydroxybutyrate or lactate levels despite the hypoinsulinemia. Disposition of an oral glucose load (1 g/kg) in drug-treated fed rats was identical to that in control rats despite a 40% reduction in the area under the plasma insulin curve. Insulin-stimulated 2-deoxy-D-3H-glucose uptake was significantly (P < .05) enhanced in adipocytes prepared from both fasted and fed drug-treated rats (0.56 ± 0.07 to 0.84 ± 0.03 and 0.79 ± 0.02 to 1.00 ± 0.02 nmol 5 min, respectively, at insulin concentration of 2,500 μU/mL). There was also a significant increase in the basal rate of 2-deoxyglucose uptake ( 0.07 ± 0.01 to 0.24 ± 0.07 nmol 5min) in adipocytes from fasted rats only. Insulin-stimulated lipogenesis from 3H-2-glucose was enhanced in adipocytes from drug-treated fed rats ( 7.72 ± 0.09 to 10.19 ± 0.10 nmol glucose 45 min at insulin concentration of 2,500 μU/mL) but no effect was observed in adipocytes from fasted rats ( 2.57 ± 0.30 to 2.33 ± 0.16 nmol glucose 45 min). Thus, englitazone (1) enhances insulin action in nondiabetic rats without producing overt hypoglycemia, (2) exhibits insulinomimetic activity with respect to hexose transport in adipocytes from drug-treated fasted rats, and (3) enhances insulin action in adipocytes from drug-treated fasted and fed rats, but (4) prevents the excess glucose entering the cells from fasted rats from being converted to triglyceride. © 1991.