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 less than .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 less than .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 microU/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/5 min) 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 microU/mL) but no effect was observed in adipocytes from fasted rats (2.57 +/- 0.30 to 2.33 +/- 0.16 nmol glucose/45 min).(ABSTRACT TRUNCATED AT 250 WORDS)
Stevenson
R W
RW
Department of Metabolic Diseases, Pfizer Inc, Groton, CT 06340.
McPherson
R K
RK
Genereux
P E
PE
Danbury
B H
BH
Kreutter
D K
DK
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport; D001786:Blood Glucose / Q000032:analysis*; D050260:Carbohydrate Metabolism; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000096:biosynthesis; D006601:Hexoses / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D050356:Lipid Metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors
D001578:Benzopyrans; D001786:Blood Glucose; D006601:Hexoses; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D006003:Glycogen; C066021:englitazone