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.