It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycemia may contribute to the development of counterregulatory failure. We previously showed that treatment with the non-specific β-blocker, carvedilol, can prevent counterregulatory failure in nondiabetic, recurrently hypoglycemic rats. The current study investigated whether carvedilol, can be used to prevent the development of counterregulatory failure in recurrently hypoglycemic diabetic rats. Sprague-Dawley rats were made diabetic with a single injection of streptozotocin (STZ; 60mg/kg; I.P.) One week after the induction of diabetes, carvedilol (4.5mg/kg QID; IP) treatment was started and continued for one week in one subgroup of STZ-diabetic rats. The remaining animals received a saline injection as controls. Three days later, the animals received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 saline injections. On day 14, the animals underwent a hyperinsulinemic-hypoglycemic clamp to assess the counterregulatory hormone responses. Compared to hypoglycemia-naïve STZ Controls, glucose infusion rates were more than doubled in the STZ+RH animals (P<0.001) and this was associated with an ∼50% reduction in the epinephrine response to hypoglycemia. Treatment of STZ+RH animals with carvedilol improved the epinephrine responses to hypoglycemia. Of note, RH did not further diminish the glucagon response in STZ-diabetic rats. Our data suggests that carvedilol may be useful to prevent impairments in the counterregulatory response during recurring episodes of hypoglycemia in diabetic animals.
R. Farhat: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. G. Su: None. E. De Santana Van Vliet: None.
JDRF; National Institutes of Health