Role of dopamine in the development of impaired counterregulation and impaired awareness of hypoglycemia

For people with diabetes, the syndrome of hypoglycemia-associated autonomic failure (HAAF) is composed of a blunted counterregulatory response (CRR) and impaired awareness of hypoglycemia (IAH). The objective herein is to identify a drug that might correct these components of HAAF. A rodent model of HAAF was developed to induce both impaired CRR and IAH (blunted food intake response to hypoglycemia). A drug screen identifies the dopamine antagonist, metoclopramide (MET), that prevents the development of HAAF. Additionally, following the induction of HAAF, MET restores normal awareness and CRRs. Conversely, the dopamine receptor agonist (bromocriptine), when administered centrally, induces HAAF. Finally, dopaminergic modulation of the ventral tegmental area (VTA) induces reciprocal changes in CRR to hypoglycemia with matching changes in VTA dopaminergic gene expression. These data identify dopamine signaling as a critical mediator of HAAF and dopamine antagonism as a potential treatment strategy.