Recent studies suggested that glucagon, or blockers of glucagon action, injected into the hypothalamus of rodents can regulate hepatic glucose production (HGP). Direct hepatic glucagon action stimulates HGP but this effect rapidly wanes for reasons that are unclear. To test the hypothesis that this is due to an inhibitory CNS effect of glucagon, as previously proposed, the hormone was administered via a peripheral vein or the head arteries to conscious dogs. After tracer equilibration and basal sampling periods somatostatin was used to disable the endocrine pancreas (0-240 minute) and insulin and glucagon were replaced intraportally at basal rates. Glucagon was also infused either into a leg vein to raise its level at the liver (2.3 ng/kg/minute; CON; n=6) or into the carotid and vertebral arteries (2.8 ng/kg/minute; HEAD; n=6) to create the same increase in glucagon at the liver as in CON, while further increasing brain glucagon exposure. Plasma insulin levels remained basal in both groups. Hepatic glucagon increased from 40±4 to 87±7 and 34±3 to 91±8 pg/ml in CON and HEAD, respectively. The levels of glucagon entering the brain were 85±9 vs. 196±19 pg/ml, respectively, based on jugular vein glucagon levels (brain glucagon extraction was 20%). Hypothalamic cAMP was 2-fold greater in HEAD (140±26 vs. 296±46 pmol/g, respectively). HGP increased from basal (3.0±0.2 and 2.4±0.2 mg/kg/minute in CON and HEAD, respectively) in response to glucagon, peaking rapidly within 30 minutes (6.5±0.5 vs. 6.2±0.4 mg/kg/minute, respectively; P=0.6), quickly declining over the next 30 minute, and then falling slowly to near-basal rates at 240 minute (2.7±0.2 vs. 2.8±0.2 mg/kg/minute, respectively). Arterial plasma glucose levels increased from basal (∼110 mg/dl) and plateaued over the last 3 hours (178±10 vs. 192±5 mg/dl, in CON and HEAD, respectively). Despite the differences in the glucagon level and engagement at the brain, no difference in hepatic glucose metabolism was detected. This suggests that brain glucagon action is not responsible for the waning of its effect on HGP.


D.S. Edgerton: Speaker's Bureau; Self; Novo Nordisk A/S. G. Kraft: Consultant; Self; Metavention. B. Farmer: None. M.S. Smith: None. A.D. Cherrington: Board Member; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Abvance, Boston Scientific Corporation, California Institute for Biomedical Research, Galvani Bioelectronics Limited, MedImmune, Novo Nordisk Inc., Thetis Pharmaceuticals LLC. Research Support; Self; Abvance, Diasome Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; Abvance, Biocon, Fractyl Laboratories, Inc., Metavention, Novo Nordisk Inc., Sensulin, LLC., Thetis Pharmaceuticals LLC, Zafgen, Inc.


National Institutes of Health

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