Hypothalamic glucagon signaling inhibits hepatic glucose production

Patricia I. Mighiu, Jessica T Y Yue, Beatrice M. Filippi, Mona A. Abraham, Madhu Chari, Carol K L Lam, Clair S. Yang, Nikita R. Christian, Maureen J. Charron, Tony K T Lam

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). 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.

Original languageEnglish (US)
Pages (from-to)766-772
Number of pages7
JournalNature Medicine
Volume19
Issue number6
DOIs
StatePublished - Jun 2013

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Glucagon
Glucose
Hypothalamus
Liver
Glucagon Receptors
Cyclic AMP-Dependent Protein Kinases
Rats
Intravenous Infusions
Plasmas
Vagotomy
Clamping devices
High Fat Diet
Nutrition
Medical problems
Knockout Mice
Intravenous Injections
Hyperglycemia
Obesity
Fats
Insulin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mighiu, P. I., Yue, J. T. Y., Filippi, B. M., Abraham, M. A., Chari, M., Lam, C. K. L., ... Lam, T. K. T. (2013). Hypothalamic glucagon signaling inhibits hepatic glucose production. Nature Medicine, 19(6), 766-772. https://doi.org/10.1038/nm.3115

Hypothalamic glucagon signaling inhibits hepatic glucose production. / Mighiu, Patricia I.; Yue, Jessica T Y; Filippi, Beatrice M.; Abraham, Mona A.; Chari, Madhu; Lam, Carol K L; Yang, Clair S.; Christian, Nikita R.; Charron, Maureen J.; Lam, Tony K T.

In: Nature Medicine, Vol. 19, No. 6, 06.2013, p. 766-772.

Research output: Contribution to journalArticle

Mighiu, PI, Yue, JTY, Filippi, BM, Abraham, MA, Chari, M, Lam, CKL, Yang, CS, Christian, NR, Charron, MJ & Lam, TKT 2013, 'Hypothalamic glucagon signaling inhibits hepatic glucose production', Nature Medicine, vol. 19, no. 6, pp. 766-772. https://doi.org/10.1038/nm.3115
Mighiu PI, Yue JTY, Filippi BM, Abraham MA, Chari M, Lam CKL et al. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nature Medicine. 2013 Jun;19(6):766-772. https://doi.org/10.1038/nm.3115
Mighiu, Patricia I. ; Yue, Jessica T Y ; Filippi, Beatrice M. ; Abraham, Mona A. ; Chari, Madhu ; Lam, Carol K L ; Yang, Clair S. ; Christian, Nikita R. ; Charron, Maureen J. ; Lam, Tony K T. / Hypothalamic glucagon signaling inhibits hepatic glucose production. In: Nature Medicine. 2013 ; Vol. 19, No. 6. pp. 766-772.
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