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.