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Publication
Regulation of endogenous glucose production in glucose transporter 4
over-expressing mice
Authors Berglund ED, Li CY, Ayala JE, McGuinness OP, Wasserman DH
Submitted By Fran Tripp on 3/5/2013
Status Published
Journal PLoS ONE
Year 2012
Date Published 12/17/2013
Volume : Pages 7 : e52355
PubMed Reference 23285006
Abstract Strategies to amplify whole-body glucose disposal are key therapies to treat
type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in
skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting
glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also
exhibit improved insulin-stimulated suppression of endogenous glucose production
even though Glut4 is not present in the liver. It is unclear, however, if
hepatic gluco-regulation is altered in G4Tg mice in the basal,
non-insulin-stimulated state. The current studies were performed to examine
fasting hepatic glucose metabolism in G4Tg mice and to determine whether
gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To
test this question, phloridzin-glucose clamps were used to match blood glucose
and pancreatic hormone levels while tracer dilution techniques were used to
measure glucose flux. These techniques were performed in
chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and
wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen
content, and hepatic glucokinase (GK) activity/expression as well as higher
endogenous glucose production, glucose disposal, arterial glucagon, and hepatic
glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT
controls. Clamping blood glucose for 90 min at ~115 mg/dLin G4Tg and WT mice
normalized nearly all variables. Notably, however, net hepatic glycogen
synthetic rates were disproportionately elevated compared to changes in blood
glucose. In conclusion, these studies demonstrate that basal improvements in
glucose tolerance due to increased uptake in extra-hepatic sites provoke
important gluco-regulatory adaptations in the liver. Although changes in blood
glucose underlie the majority of these adaptations, net hepatic glycogen
synthesis is sensitized. These data emphasize that anti-diabetic therapies that
target skeletal muscle, heart, and/or adipose tissue likely positively impact
the liver.




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