Decreased hepatic futile cycling compensates for increased glucose disposal in the Pten heterodeficient mouse.
Despite altered regulation of insulin signaling, Pten(+/-) heterodeficient standard diet-fed mice, approximately 4 months old, exhibit normal fasting glucose and insulin levels. We report here a stable isotope flux phenotyping study of this "silent" phenotype, in which tissue-specific insulin effects in whole-body Pten(+/-)-deficient mice were dissected in vivo. Flux phenotyping showed gain of function in Pten(+/-) mice, seen as increased peripheral glucose disposal, and compensation by a metabolic feedback mechanism that 1) decreases hepatic glucose recycling via suppression of glucokinase expression in the basal state to preserve hepatic glucose production and 2) increases hepatic responsiveness in the fasted-to-fed transition. In Pten(+/-) mice, hepatic gene expression of glucokinase was 10-fold less than wild-type (Pten(+/+)) mice in the fasted state and reached Pten(+/+) values in the fed state. Glucose-6-phosphatase expression was the same for Pten(+/-) and Pten(+/+) mice in the fasted state, and its expression for Pten(+/-) was 25% of Pten(+/+) in the fed state. This study demonstrates how intra- and interorgan flux compensations can preserve glucose homeostasis (despite a specific gene defect that accelerates glucose disposal) and how flux phenotyping can dissect these tissue-specific flux compensations in mice presenting with a "silent" phenotype.
Xu
Jun
J
SUNY at Stony Brook, HSC T-15 Room 060, Stony Brook, NY 11794-8154, USA.
Gowen
Lori
L
Raphalides
Christian
C
Hoyer
Katrina K
KK
Weinger
Jason G
JG
Renard
Mathilde
M
Troke
Joshua J
JJ
Vaitheesyaran
Bhavapriya
B
Lee
W N Paul
WN
Saad
Mohammed F
MF
Sleeman
Mark W
MW
Teitell
Michael A
MA
Kurland
Irwin J
IJ
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004435:Eating; D005215:Fasting; D015971:Gene Expression Regulation, Enzymologic; D005941:Glucokinase / Q000235:genetics; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D008066:Lipolysis; D008099:Liver / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics*
D001786:Blood Glucose; D007328:Insulin; D005941:Glucokinase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005952:Glucose-6-Phosphatase