Sustained improvement in glucose homeostasis in lean and obese mice following chronic administration of the beta 3 agonist SR 58611A.

1. Acute SR 58611A (0.25 mg kg-1), was effective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg-1 glibenclamide in lean mice. 2. Neither brown (BAT) nor white (WAT) adipose tissue lipogenesis was altered by acute SR 58611A (2 - 8 mg kg-1) in lean mice, but both increased significantly at the higher doses in the obese mice. 3. Acute SR 58611A produced a hypoglycaemia 40 min after dosing in lean and obese animals, the duration and potency of which was less than that of glibenclamide. Plasma insulin levels increased 20 min after acute SR 58611A and glibenclamide in lean and obese mice. 4. Chronic treatment (0.25 mg kg-1, 15 days) with SR 58611A increased its effectiveness in improving glucose tolerance, but did not affect the body weight (BW) or food intake of either lean or obese mice. 5. Acute and chronic SR 58611A prolonged the hypoglycaemic effect of exogenous insulin in lean but not obese mice. 6. In fed and fasted lean mice and in fasted obese mice chronic SR 58611A produced an acute hypoglycaemia 30 min post administration which was greater than after a single dose. 7. SR 58611A maintained its effectiveness in improving glucose tolerance in lean and obese mice over a dosing period of 15 days. The improvement in glucose tolerance was achieved at a dose less than that required to stimulate adipose tissue lipogenesis and which did not affect food intake or body weight.