Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs

Christopher J. Ramnanan, Viswanathan Saraswathi, Marta S. Smith, E. Patrick Donahue, Ben Farmer, Tiffany D. Farmer, Doss Neal, Philip E. Williams, Margaret Lautz, Andrea Mari, Alan D. Cherrington, Dale S. Edgerton

Research output: Contribution to journalArticle

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Abstract

In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β(GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP.

Original languageEnglish (US)
Pages (from-to)3713-3723
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number9
DOIs
StatePublished - Sep 1 2011

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Liver Glycogen
Gluconeogenesis
Dogs
Insulin
Glucose
Liver
Brain
Hyperinsulinism
Glucagon
Glycogen
Canidae
Glycogen Synthase Kinase 3
Glycogen Synthase
Phosphatidylinositol 3-Kinases
Blood Glucose
Rodentia
Arteries
Head
Phosphorylation
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

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Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. / Ramnanan, Christopher J.; Saraswathi, Viswanathan; Smith, Marta S.; Donahue, E. Patrick; Farmer, Ben; Farmer, Tiffany D.; Neal, Doss; Williams, Philip E.; Lautz, Margaret; Mari, Andrea; Cherrington, Alan D.; Edgerton, Dale S.

In: Journal of Clinical Investigation, Vol. 121, No. 9, 01.09.2011, p. 3713-3723.

Research output: Contribution to journalArticle

Ramnanan, CJ, Saraswathi, V, Smith, MS, Donahue, EP, Farmer, B, Farmer, TD, Neal, D, Williams, PE, Lautz, M, Mari, A, Cherrington, AD & Edgerton, DS 2011, 'Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs', Journal of Clinical Investigation, vol. 121, no. 9, pp. 3713-3723. https://doi.org/10.1172/JCI45472
Ramnanan, Christopher J. ; Saraswathi, Viswanathan ; Smith, Marta S. ; Donahue, E. Patrick ; Farmer, Ben ; Farmer, Tiffany D. ; Neal, Doss ; Williams, Philip E. ; Lautz, Margaret ; Mari, Andrea ; Cherrington, Alan D. ; Edgerton, Dale S. / Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 9. pp. 3713-3723.
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