FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.

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TitleFoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.
Publication TypeJournal Article
Year of Publication2015
AuthorsO-Sullivan IS, Zhang W, Wasserman DH, Liew CWee, Liu J, Paik J, DePinho RA, Stolz DBeer, C Kahn R, Schwartz MW, Unterman TG
JournalNat Commun
Volume6
Pagination7079
Date Published2015
ISSN2041-1723
Abstract

FoxO proteins are major targets of insulin action. To better define the role of FoxO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FoxO1 reverses these effects. (13)C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted.

DOI10.1038/ncomms8079
Alternate JournalNat Commun
PubMed ID25963540
Grant ListDK035816 / DK / NIDDK NIH HHS / United States
DK059637 / DK / NIDDK NIH HHS / United States
DK068384 / DK / NIDDK NIH HHS / United States
DK076169 / DK / NIDDK NIH HHS / United States
DK083042 / DK / NIDDK NIH HHS / United States
DK090320 / DK / NIDDK NIH HHS / United States
DK101997 / DK / NIDDK NIH HHS / United States
I01 BX001968 / BX / BLRD VA / United States
P30 DK089503 / DK / NIDDK NIH HHS / United States
R00DK090210 / DK / NIDDK NIH HHS / United States
R24DK097153 / DK / NIDDK NIH HHS / United States
U24 DK059637 / DK / NIDDK NIH HHS / United States