Insulinlike activity of new antidiabetic agent CP 68722 in 3T3-L1 adipocytes.
We examined the in vitro effects of CP 68722, a novel antidiabetic agent, in 3T3-L1 adipocytes. CP 68722 stimulated 2-deoxyglucose uptake in the absence of insulin. At least 30 min of incubation were required for stimulation of uptake. This effect increased over 5 h and was sustained up to 72 h. The stimulation of 2-deoxyglucose uptake by CP 68722 could be inhibited approximately 60% by inhibition of protein synthesis with cycloheximide. Half-maximal and maximal responses to CP 68722 at 72 h of incubation were observed at 10 and 100 microM of drug, respectively, with a threefold stimulation of uptake at 100 microM approximating the maximal response of these cells to acute insulin stimulation. CP 68722 was able to overcome insulin resistance induced by dexamethasone in 3T3-L1 cells. The effect of drug, like that of insulin, was primarily to increase the Vmax of 2-deoxyglucose uptake. The stimulation of uptake by CP 68722 or insulin could be prevented by incubating the cells at 10 degrees C, a temperature that impedes translocation of glucose transporters to the plasma membrane. Therefore, it appears that CP 68722, like insulin, stimulates glucose uptake by a mechanism that involves translocation of intracellular glucose transporters to the plasma membrane and de novo protein synthesis. We compared the effect of CP 68722 with the sulfonylureas, the primary drugs used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). CP 68722 was a more potent and effective stimulator of 2-deoxyglucose uptake in 3T3-L1 cells than either first- or second-generation sulfonylureas.(ABSTRACT TRUNCATED AT 250 WORDS)
Kreutter
D K
DK
Department of Metabolic Diseases, Pfizer Central Research, Groton, CT 06340.
Andrews
K M
KM
Gibbs
E M
EM
Hutson
N J
NJ
Stevenson
R W
RW
D000273:Adipose Tissue / Q000166:cytology* / Q000648:ultrastructure; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D010084:Oxidation-Reduction; D011972:Receptor, Insulin / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D013696:Temperature; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D001578:Benzopyrans; D007328:Insulin; D013453:Sulfonylurea Compounds; D013844:Thiazoles; D045162:Thiazolidinediones; D003847:Deoxyglucose; D011972:Receptor, Insulin; D005947:Glucose; C066021:englitazone