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Insulin receptor and postbinding defects in KK mouse adipocytes and improvement by ciglitazone
S Taketomi1, T Fujita, K Yokono
1Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Abstract:
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.
Insights
Diabetic KK mice exhibit insulin resistance due to impaired insulin receptors and glucose metabolism. Cures for insulin resistance were observed after ciglitazone treatment, normalizing insulin receptor regulation.
Area of Science:
- Molecular Biology
- Endocrinology
- Metabolic Research
Background:
- Genetic diabetes in KK mice presents alterations in insulin receptor function and glucose metabolism.
- Adipocytes from KK mice demonstrate reduced insulin binding and impaired sensitivity/responsiveness compared to control C57BL/6 mice.
Purpose of the Study:
- To investigate the specific defects in insulin receptor function and glucose metabolism in diabetic KK mouse adipocytes.
- To evaluate the effect of ciglitazone on insulin sensitivity, glucose uptake, and insulin receptor regulation in KK mice.
Main Methods:
- Comparative analysis of adipocytes from KK and C57BL/6 mice regarding insulin binding and glucose metabolism.
- Assessment of insulin's effect on glucose oxidation, glyceride-glycerol synthesis, and fatty acid synthesis.
- Evaluation of ciglitazone's impact on insulin sensitivity and insulin receptor downregulation in KK mouse adipocytes.
Main Results:
- KK adipocytes showed weaker insulin binding and reduced sensitivity/responsiveness in glucose uptake and oxidation.
- Insulin's effects on other metabolic pathways were similar between KK and control mice.
- Ciglitazone treatment improved insulin sensitivity, glucose metabolism, and normalized insulin receptor downregulation in KK adipocytes.
Conclusions:
- Insulin resistance in KK mice is attributed to defects in the insulin receptor and post-binding systems affecting glucose uptake.
- The regulation of the insulin receptor is closely linked to the post-binding system in adipocytes.
- Ciglitazone effectively ameliorates insulin resistance by restoring insulin receptor function and regulation in diabetic models.