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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.
Affiliation
  • Mighiu PI; Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
Nat Med ; 19(6): 766-72, 2013 Jun.
Article in En | MEDLINE | ID: mdl-23685839
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Glucagon / Signal Transduction / Glucose / Hypothalamus / Liver Limits: Animals Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2013 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Glucagon / Signal Transduction / Glucose / Hypothalamus / Liver Limits: Animals Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2013 Document type: Article Affiliation country:
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