Actions of novel antidiabetic agent englitazone in hyperglycemic hyperinsulinemic ob/ob mice.
The effects of CP 68722 (racemic englitazone) were examined in ob/ob mice, in adipocytes and soleus muscles from ob/ob mice, and in 3T3-L1 adipocytes. Administration of englitazone at 5-50 mg.kg-1.day-1 lowered plasma glucose and insulin dose dependently without producing frank hypoglycemia in either the diabetic or nondiabetic lean animals. The glucose-lowering effect in ob/ob mice preceded the reduction in hyperinsulinemia. On cessation of drug, plasma insulin returned to untreated levels within 48 h, whereas plasma glucose rose slowly over 5 days. Englitazone (50 mg/kg) for 11 days lowered plasma glucose (22.2 +/- 1.4 to 14.0 +/- 1.9 mM), insulin (7.57 +/- 0.67 to 1.64 +/- 0.60 nM), nonesterified fatty acids (1813 +/- 86 to 914 +/- 88 microM), glycerol (9.20 +/- 0.98 to 4.94 +/- 0.03 mM), triglycerides (1.99 +/- 0.25 to 1.03 +/- 0.11 g/L), and cholesterol (6.27 +/- 0.96 to 3.87 +/- 0.57 mM), but no effects were observed 3 h after a single dose. Basal and insulin-stimulated lipogenesis were enhanced in adipocytes from ob/ob mice treated with 50 mg/kg englitazone for 11 days compared with lipogenesis in cells from vehicle-treated controls. Treatment of ob/ob mice with 50 mg/kg englitazone reversed the defects in insulin-stimulated glycolysis (from [3-3H]glucose) and glycogenesis and basal glucose oxidation (from [1-14C]glucose) in isolated soleus muscles. Englitazone (30 microM) stimulated 2-deoxy-D-glucose transport in 3T3-L1 adipocytes from 0.37 +/- 0.03 to 0.65 +/- 0.06 and 1.53 nmol.min-1.mg-1 protein at 24 and 48 h, respectively. Thus, englitazone has 1) insulinomimetic and insulin-enhancing actions in vitro and 2) glucose-, insulin-, triglyceride-, and cholesterol-lowering properties in an animal model of non-insulin-dependent diabetes mellitus (NIDDM) in which sulfonylureas have little or no effect. Thus, this new agent may have beneficial effects including a reduced risk of hypoglycemia in patients with NIDDM.
Stevenson
R W
RW
Department of Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340.
Hutson
N J
NJ
Krupp
M N
MN
Volkmann
R A
RA
Holland
G F
GF
Eggler
J F
JF
Clark
D A
DA
McPherson
R K
RK
Hall
K L
KL
Danbury
B H
BH
D020155:3-Hydroxybutyric Acid; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D005990:Glycerol / Q000097:blood; D006885:Hydroxybutyrates / Q000097:blood; D006943:Hyperglycemia / Q000097:blood*; D006946:Hyperinsulinism / Q000097:blood*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D012016:Reference Values; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000097:blood
D001578:Benzopyrans; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D005934:Glucagon; D002784:Cholesterol; D005990:Glycerol; D020155:3-Hydroxybutyric Acid; C066021:englitazone