Year-end Sale % OFF 
Abstract
Insulin signaling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin despite lack of autonomous liver insulin signaling. These data indicate that, in the absence of Foxo1, insulin signals via an intermediary extra-hepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR-Akt-Foxo1 axis exists to regulate glucose production.
Highlights
Insulin signalling and nutrient levels coordinate the metabolic response to feeding in the liver
In contrast to the major metabolic abnormalities reported in the congenital its receptor (IR) liver knockout mouse (LIRKO)[18], L-Insulin Receptor KO mice displayed normal fasting glucose levels (Fig. 1b) and modest postprandial hyperglycaemia following 4 h of refeeding (Fig. 1c)
In this study, we used genetic loss of function experiments in mice to test the requirement for hepatic insulin action for the insulin-dependent regulation of glucose metabolism and transcription in mouse liver
Summary
Insulin signalling and nutrient levels coordinate the metabolic response to feeding in the liver. Liver-specific deletion of Foxo[1] (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin, despite lack of autonomous liver insulin signalling. These data indicate that in the absence of Foxo[1], insulin signals via an intermediary extrahepatic tissue to regulate liver glucose production. L-AktFoxo1TKO mice adapt appropriately to the postprandial state despite lacking canonical liver insulin signalling[17] These data are inconsistent with the established model of hepatic insulin action and suggest Akt is not an obligate intermediate for insulin action under all conditions. At least two alternative mechanisms can be formulated to explain the insulin effects in L-AktFoxo1TKO mice: (1) insulin acts directly on the liver via the IR–Irs pathway; a bifurcation occurs before Akt thereby activating an unidentified parallel pathway independent of Akt to suppress HGP19; or (2) insulin acts non-autonomously via a peripheral tissue to regulate HGP
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
