Effects of BRL 35135, a beta-adrenoceptor agonist with novel selectivity, on glucose tolerance and insulin sensitivity in obese subjects.

BRL 35135 is a novel oral agent which, when dosed chronically to obese rodents with abnormal glucose tolerance, improves both insulin sensitivity and glucose tolerance. To study its effect in man, 10 obese patients on a weight-maintaining diet received BRL 35135 2 mg four times per day for 5 days and then 6 mg four times per day for 5 days. Oral 100 g glucose tolerance tests were performed 1 day prior to and 12 h after the 10-day treatment with BRL 35135. Simultaneously, energy expenditure, glucose oxidation and glucose storage were measured by open-circuit indirect calorimetry. No significant changes in body weight occurred during the 10-day treatment with BRL 35135. Areas under the curves for glucose and insulin were reduced following treatment with BRL 35135 (1518 +/- 152 to 1277 +/- 132 mmol/1/3 h, P less than 0.001 and 13.8 +/- 1.7 to 9.5 +/- 1.3 U/l/3 h, P less than 0.01) (mean +/- s.e.m.). In addition, plasma glucose concentrations, 2h post-oral glucose, were reduced significantly (8.7 +/- 1.0 mmol/l to 6.7 +/- 0.78, P less than 0.01). There was no effect of the treatment on glucose-induced thermogenesis and glucose oxidation did not change but glucose storage increased significantly. The results suggest that BRL 35135 improves glucose tolerance by an increase in insulin sensitivity that is independent of body weight. Glucose storage accounted for the increased glucose disposal.