Insulin receptor and postbinding defects in KK mouse adipocytes and improvement by ciglitazone.
Alterations of the insulin receptor and of glucose metabolism were examined in adipocytes from genetically diabetic KK mice. Compared with those from control C57BL/6 mice, adipocytes from KK mice showed weaker insulin binding and were less sensitive and less responsive to insulin with respect to 3-O-methylglucose uptake and [1-14C]glucose oxidation. However, insulin had no difference in effect between the two groups of mice with respect to [6-14C]glucose oxidation, glyceride-glycerol synthesis, or fatty acid synthesis from [1-14C]- and [6-14C]glucose. [1-14C]Glucose oxidation of KK cells was also insensitive to insulin mimics such as vitamin K5 and H2O2. When adipose tissues were precultured with insulin or insulin mimics for 24 h, adipocytes from C57BL/6 mice showed decreased insulin binding, but KK cells did not. When administered orally to KK mice for 2 weeks, ciglitazone made adipocytes more sensitive to insulin, more responsive to insulin with respect to glucose uptake and oxidation, and more capable of binding insulin. Impairment of the downregulation at the insulin receptor caused by exposure to insulin or insulin mimics was normalized by ciglitazone treatment in KK cells. In conclusion, KK cells are insulin-resistant due to defects of the insulin receptor and postbinding system in the glucose uptake and pentose pathways. In addition, regulation of the insulin receptor seems to be closely related to the postbinding system.
Taketomi
S
S
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Fujita
T
T
Yokono
K
K
D019325:3-O-Methylglucose; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D007700:Kinetics; D008297:Male; D008757:Methylglucosides / Q000378:metabolism*; D008759:Methylglycosides / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014316:Tritium
D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D008757:Methylglucosides; D008759:Methylglycosides; D013844:Thiazoles; D045162:Thiazolidinediones; D014316:Tritium; D019325:3-O-Methylglucose; D011972:Receptor, Insulin; D005947:Glucose; C039671:ciglitazone