Carvedilol Prevents Counterregulatory Failure in Recurrently Hypoglycemic Rats

Abstract

We showed previously that recurring activation of β2-adrenergic receptors in the ventromedial hypothalamus (VMH) leads to the development of counterregulatory failure, in part by increasing local lactate levels. The current study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent the development of counterregulatory failure and improve hypoglycemia awareness (HA) in recurrently hypoglycemic (RH) rats. Sprague-Dawley rats (n=6-10 per group) underwent surgery for the implantation of vascular catheters and intracranial guide cannulas that targeted the VMH. These animals then received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 injections of saline (Controls). A subgroup of RH rats was treated with carvedilol (3mg/kg QID; IP) beginning one day prior to the start of RH and continuing through to the last episode of hypoglycemia. Following the last bout of hypoglycemia, the animals underwent a hypoglycemic clamp with microdialysis to evaluate changes in central lactate and hormone levels. Compared to controls, RH increased VMH lactate by 1.7-fold (P<0.03) and this was associated with an impaired counterregulatory response to hypoglycemia (glucagon and epinephrine responses were reduced by ∼45% and ∼73%, respectively, P<0.04), as expected. Treatment of RH animals with carvedilol restored VMH lactate levels and improved the counterregulatory responses to hypoglycemia. To assess whether carvedilol improved HA, we treated rats that were made “hypoglycemia unaware” with repeated 2-deoxyglucose (2DG; 200mg/kg, SQ) injections with carvedilol and measured food intake in response to insulin-induced hypoglycemia as a surrogate marker for HA. Compared to Controls, 2DG reduced food intake in response to hypoglycemia and treatment with carvedilol increased food intake in 2DG rats (P<0.01). We conclude that carvedilol may be a useful therapeutic strategy to prevent counterregulatory failure and improve HA in RH rats. Disclosure R. Farhat: None. G. Su: None. O. Chan: None.