Hypoglycemia-associated autonomic failure (HAAF) is comprised of both a blunted counterregulatory response to hypoglycemia and hypoglycemia unawareness. We previously demonstrated that both these aspects of HAAF can be reversed by treatment with the dopamine receptor antagonist, metoclopramide. These findings suggest that repetitive activation of the dopaminergic system may contribute to HAAF. We now evaluate whether both the blunted counterregulatory response to hypoglycemia and hypoglycemia unawareness are mediated by repeated activation of brain dopaminergic receptors. To test this hypothesis, male Sprague-Dawley rats were randomized to receive either the dopamine receptor agonist, bromocriptine, (Bromo; 20 µg/d) intracerebroventricularly (ICV) for 3 consecutive days or recurrent ICV saline (controls). On the fourth day, all rats underwent either, 1) a hyperinsulinemic (50 mU/kg/min) hypoglycemic (∼50 mg/dl) clamp to assess counterregulation, or 2) had food consumption measured in response to insulin-induced (15 U/kg; SQ) hypoglycemia (∼40 mg/dl) to assess hypoglycemia awareness. In response to hypoglycemia, antecedent Bromo blunted, 1) the epinephrine response by 86%* (see Fig), 2) the glucagon response by 56%§, and 3) hypoglycemia awareness by 37%§, as compared to controls (*p<0.01, §p<0.05). These findings demonstrate that dopaminergic signaling in the central nervous system contributes to the development of HAAF.
A. Vieira de Abreu: None. R. Agrawal: None. E.R. Meier: None. O. Chan: Research Support; Self; Zucara Therapeutics Inc. S. Fisher: None.