INCREASE IN INSULIN ACTION AND FAT OXIDATION AFTER TREATMENT WITH CL-316,243, A HIGHLY SELECTIVE BETA(3)-ADRENOCEPTOR AGONIST IN HUMANS

Stimulation of beta(3)-adrenoceptors by selective agonists improves in sulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta(3)-adrenocepto r stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta(3)-adrenoceptor agonist on ins ulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment w ith either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Ins ulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal(N OGD), oxidative glucose disposal(OGD) (indirect calorimetry), and spla nchnic glucose output (SGO; 3-[H-3]glucose) were determined during a 1 00-min hyperinsulinemic-euglycemic glucose clamp (40 mU.m(-2).min(-l)) before and after 4 and 8 weeks of treatment. The 24-h energy expendit ure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rate s of fat and carbohydrate were determined in a respiratory chamber bef ore and after 8 weeks. After 4 weeks, treatment with CL 316,243 increa sed IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner ( r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 3 16,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and le ptin were unaffected by treatment, while free fatty acid concentration s increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 3 16,243 had no effect on heart rate or blood pressure and caused no cas es of tremors. We conclude that treatment of lean male subjects with C L 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrat e unequivocal metabolic effects of a highly selective beta(3)-adrenoce ptor agonist in humans.