Effects of BRL 26830, a novel beta-adrenoceptor agonist, on glucose tolerance, insulin sensitivity and glucose turnover in Zucker (fa/fa) rats.

Zucker fa/fa rats exhibit glucose intolerance in comparison with lean Fa/? littermates. A single acute dose of BRL 26830 (2.9 mg/kg p.o.) improved glucose tolerance in Fa/? littermates but exacerbated glucose intolerance in the fa/fa rats. This latter effect occurred in spite of an increase in the plasma insulin concentration. Chronic treatment of Zucker fa/fa rats with BRL 26830 (2.9 mg/kg) for 24 days or more produced a significant reduction in the area under the glucose tolerance curve. In addition, the glucose decay rate (k%) following the administration of insulin intravenously was significantly increased in the BRL 26830-treated rats suggesting that tissue insulin sensitivity was increased. Glucose turnover measurements show that chronic treatment of Zucker fa/fa rats with BRL 26830 produced a significant increase in the rate of glucose utilization integrated over a 3 hr period, but this increase was, in part, off-set by an increase in the endogenous rate of glucose production. The ultimate fate of the extra glucose that is metabolized is not known but it is suggested that it might be used to support the thermogenic response that is also activated by BRL 26830.

Anti-hyperglycaemic action of BRL 26830, a novel beta-adrenoceptor agonist, in mice and rats.

BRL 26830, (R*,R*)-(+/-)-methyl 4-[2-[(2-hydroxy-2-phenylethyl)amino] propyl] benzoate, is a new orally active anti-hyperglycaemic agent. In 24 hr-fasted rats and mice, BRL 26830 decreased the blood glucose concentration following the administration of a subcutaneous glucose load. It also improved oral and intravenous glucose tolerance in 24 hr-fasted rats and decreased the post-prandial blood glucose concentration following the consumption of the complete, milk-based, meal "Nutrament". BRL 26830 produced a dose-related increase in the plasma insulin concentration and since it was inactive in lowering blood glucose in streptozotocin-diabetic rats, it is likely that its acute action on glucose tolerance was through the stimulation of insulin secretion. In contrast to the sulphonylurea, glibenclamide, BRL 26830 had no effect on the blood glucose concentration in 5 hr-fasted rats and only produced a transient reduction in 24 hr-fasted rats. BRL 26830 did not improve glucose tolerance when given acutely to hyperinsulinaemic C57BL/6 ob/ob mice. However, chronic treatment of these mice with BRL 26830 for 14-43 days resulted in a significant improvement in glucose tolerance.

Glucose metabolism in the obese hyperglycaemic (C57B1/6 ob/ob) mouse: the effects of fasting on glucose turnover rates.

Rates of glucose turnover and of glucose-carbon recycling in fed and fasted C57B1/6 ob/ob mice were measured using D-[6(-3)H/U-14C]-glucose. In both the fed and fasted state, obese mice had significantly higher blood glucose concentrations than their lean littermates. This hyperglycaemia was a consequence of elevated rates of glucose synthesis and of glucose-lactate (Cori cycle) recycling.

Defective activation by glucose of hepatic glycogen synthesis in the obese hyperglycaemic mouse.

The administration of an oral glucose load to 24 h-starved lean (+/?) male C57BL/6 mice produced a rapid, 7-fold increase in the rate of hepatic glycogen synthesis and a sustained activation of glycogen synthase. In contrast, glucose produced only a small (4.5-fold), short-lived increase in hepatic glycogen synthesis in genetically obese (ob/ob) mice and no activation of glycogen synthase.