145-OR: Counterregulatory Response to Hypoglycemia Is Improved with Serotonin and Norepinephrine Reuptake Inhibitors

Abstract

We previously reported that serotonin and norepinephrine reuptake inhibitors, amitriptyline (AMT) and imipramine (IMP), restored hypoglycemia awareness in rodents. To test the hypothesis that AMT and IMP could prevent the development of an impaired counterregulatory response (CRR) to hypoglycemia, Sprague-Dawley rats (250-350 g) with pre-implanted arterial and jugular cannulae were randomly assigned to one of four treatment groups: 1) recurrent saline controls (RS, n=8); 2) recurrent insulin-induced hypoglycemia (RH, 30-50 mg/dl, n=8); 3) RH + AMT (10 mg/kg IP, n=8); or 4) RH + IMP (5 mg/kg IP, n=8). Following 3-days of RS/RH treatment, all groups underwent 90-minute hyperinsulinemic (50 mU.kg-1.min-1) hypoglycemic (40-45 mg/dL) clamps. Blood glucose was similar for all groups during the clamp. Glucose infusion rates during the last 30-minutes were significantly reduced for both RH+AMT (23.7 mg/kg/min) and RH+IMP (24.8 mg/kg/min) as compared to RH (40.4 mg/kg/min), indicating that both drugs improved the glucoregulatory response to hypoglycemia. In conclusion, these studies identify 1) the involvement of serotonin and norepinephrine neurotransmitter pathways in the development of blunted counterregulatory responses to hypoglycemia, 2) in subjects with blunted CRR, these drugs may be useful therapeutic agents to improve the glucoregulatory response to hypoglycemia. Disclosure E.L.Macon: None. M.H.Devore: None. A.Iles: None. L.A.Schoeder: None. B.Patel: None. M.B.Music: None. S.Fisher: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK118082)