371-P: Hypoglycemia in the Brain Is Required to Augment Counterregulatory Responses to Hypoglycemia when Liver Glycogen Levels Are Enhanced

In a previous study, we showed that elevated hepatic glycogen levels can generate a signal in the liver during insulin (INS)-induced hypoglycemia that is relayed to the brain, resulting in enhanced counterregulatory (CR) hormone secretion and net hepatic glucose output (NHGO). The purpose of this study was to determine whether hypoglycemia in the brain is required for this augmentation to occur. Fasted (18 hour) dogs were studied and each experiment began with a 4h glycogen deposition period in which each animal received somatostatin and basal intraportal infusions of both INS and glucagon (GGN). Plasma glucose (PG) was doubled by an intravenous (IV) glucose infusion and liver glycogen content was enhanced in all animals (76 ± 6 and 68 ± 4 mg/g in Brain EU and HYPO, respectively) by an intraportal infusion of fructose. A 2h control period followed, during which hyperglycemia and basal replacement of hormones were continued but fructose infusion was stopped. In the final 2h hypoglycemic period, somatostatin and GGN infusions were stopped and the plasma INS level was increased 16-fold by an IV infusion of INS. During the final period, whole body PG was clamped at 52 ± 1 mg/dL in one group (HYPO; n=6). In a second group, PG in the head was clamped at 92 ± 3 mg/dL by infusing glucose into the carotid and vertebral arteries (Brain EU; n=8) while the glucose level in the rest of the body remained at 51 ± 1 mg/dL. During the final hour of the hypoglycemic period, NHGO was lower in Brain EU compared to HYPO (0.8 ± 0.2 vs. 2.2 ± 0.4 mg/kg/minute, p<0.01). This decrease in NHGO was associated with a decrease in CR hormone secretion, as GGN (27 ± 6 vs. 53 ± 8 pg/mL, p<0.01) and epinephrine (451 ± 103 vs. 1106 ± 143 pg/mL, p<0.01) were lower when the brain was euglycemic (Brain EU vs. HYPO, respectively). These data suggest that the augmented CR responses that occur during INS-induced hypoglycemia when liver glycogen content is enhanced, require hypoglycemia in the brain. Disclosure S.O. Warner: None. M.S. Smith: None. B. Farmer: None. J.J. Winnick: None. Funding National Institutes of Health