Abstract
Glucagon activates hepatic protein kinase A (PKA) to increase glucose production1,2, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion3,4,5. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver6 and the mediobasal hypothalamus (MBH)7,8. In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor–PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor–PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity.
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Acknowledgements
We thank P.Y.T. Wang for technical assistance and D.J. Drucker from the Samuel Lunenfeld Research Institute for providing the Gcgr−/− and Gcgr+/+ mice. This work was supported by a research grant from the Canadian Diabetes Association. P.I.M. was supported by an Ontario Graduate Scholarship and a scholarship from the University of Toronto Banting and Best Diabetes Centre (BBDC). J.T.Y.Y. is supported by a BBDC and University Health Network postdoctoral fellowship. M.A.A. is supported by a BBDC scholarship. M.C. was supported by an Ontario Graduate scholarship and a BBDC scholarship. C.K.L.L. and C.S.Y. were supported by graduate scholarships from the Canadian Institute of Health Research and the BBDC. T.K.T.L. holds the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity at the Toronto General Research Institute and the University of Toronto.
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P.I.M. and J.T.Y.Y. conducted and designed experiments, performed data analyses and wrote the manuscript. B.M.F. assisted in experiments involving molecular biology techniques. M.A.A., M.C., C.K.L.L., C.S.Y. and N.R.C. assisted in in vivo experiments. M.J.C. generated and provided the Gcgr−/− mice. T.K.T.L. supervised the project, designed experiments and edited the manuscript.
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Mighiu, P., Yue, J., Filippi, B. et al. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 19, 766–772 (2013). https://doi.org/10.1038/nm.3115
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DOI: https://doi.org/10.1038/nm.3115
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