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)

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.

Cell surface proteins and glycoproteins from biologically different human colon carcinoma cell lines.

Six cultured human colon cancer cell lines possessing different biological characteristics were enzymatically radiolabeled in situ with 125I and 3H, and the labeled cell surface proteins and glycoproteins were compared. The electrophoretic patterns of labeled cell surface material suggest correlations between biological properties and cell surface proteins. Highly aggressive cell lines (as assessed by in vitro parameters) had predominant peaks of 125I-labeled proteins between molecular weights 66,000 and 92,500. The major peak of radioiodinated material from the more indolent cell lines occurred between molecular weights 31,000 and 45,000. The profile of one 125I-labeled intermediately aggressive cell line was similar to the profiles of the more aggressive lines, whereas another intermediate line exhibited a profile different from those of both indolent and aggressive lines. Electrophoresis of tritiated material indicated that essentially all of the recovered labeled glycoprotein was of relatively high molecular weight (92,000-180,000) in the indolent lines, whereas the intermediate and highly aggressive lines had patterns with significant peaks between molecular weights 45,000 and 92,500.

Initiation and characterization of cultures of human colonic carcinoma with different biological characteristics utilizing feeder layers of confluent fibroblasts.

The tissue culture of human colonic carcinoma with and without feeder layers of confluent C3H 10T1/2 mouse fibroblast was compared. In a series of 27 different tumor specimens, 21 long-term cultures (6 mos. or more) were obtained by utilizing feeder layers. Only 3 long-term cultures were obtained from the same set of specimens when feeder layers were not employed. Several of the long-term cultures were established as cell lines weaned from fibroblast feeder layers. These lines could be classified into 3 groups based upon their expression of several biological properties including tumorigenicity in nude mice, degree of differentiation of the tumors growing in nude mice, growth in semisolid medium, morphology in vitro and production of carcinoembryonic antigen in vitro.