Effect of a thermogenic agent, BRL 26830A, on insulin receptors in obese mice.

The effect of a new type of antidiabetic agent, BRL 26830A, has been tested in obese mice. Since this drug increases thermogenesis, insulin receptor binding and kinase activity were studied in brown adipose tissue and skeletal muscle of mice made obese by gold thioglucose. At 1 mg.kg-1.day-1, a 3-wk treatment normalized the glycemia and increased the uncoupling protein content of brown adipose tissue. The insulin receptor number and its associated kinase activity increased only in brown adipose tissue. At 2 mg.kg-1.day-1, additional effects, i.e., a 20% reduction in body weight and a normalization of insulin receptor number both in brown adipose tissue and in skeletal muscle, were observed. All those results were obtained even though hyperinsulinemia was not corrected. At the higher drug dosage, insulin receptor kinase activity evolved in direct proportion to the receptor number in brown adipose tissue. By contrast, in skeletal muscle, the receptor kinase activity toward exogenous substrates increased more than the receptor number, suggesting that the alteration of insulin receptor kinase activity previously reported in skeletal muscle of obese mice was partly reversed by BRL 26830A. None of these parameters was modified by the drug in lean mice. These results show that, even without affecting obesity, BRL 26830A improves insulin resistance in obese mice, probably through its effect on insulin receptors. This action prevails in brown adipose tissue, supporting the idea that this tissue plays an important role in glucose homeostasis. Thermogenic drugs could thus be powerful agents for the treatment of noninsulin-dependent diabetics.