Decreased hepatic futile cycling compensates for increased glucose disposal in the Pten heterodeficient mouse

Jun Xu, Lori Gowen, Christian Raphalides, Katrina K. Hoyer, Jason G. Weinger, Mathilde Renard, Joshua J. Troke, Bhavapriya Vaitheesyaran, W. N Paul Lee, Mohammed F. Saad, Mark W. Sleeman, Michael A. Teitell, Irwin J. Kurland

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Despite altered regulation of insulin signaling, Pten+/- heterodeficient standard diet-fed mice, ∼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.

Original languageEnglish (US)
Pages (from-to)3372-3380
Number of pages9
JournalDiabetes
Volume55
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

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Substrate Cycling
Glucose
Liver
Glucokinase
Insulin
Phenotype
Glucose-6-Phosphatase
Recycling
Isotopes
Fasting
Homeostasis
Diet
Gene Expression

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Decreased hepatic futile cycling compensates for increased glucose disposal in the Pten heterodeficient mouse. / Xu, Jun; Gowen, Lori; Raphalides, Christian; Hoyer, Katrina K.; Weinger, Jason G.; Renard, Mathilde; Troke, Joshua J.; Vaitheesyaran, Bhavapriya; Lee, W. N Paul; Saad, Mohammed F.; Sleeman, Mark W.; Teitell, Michael A.; Kurland, Irwin J.

In: Diabetes, Vol. 55, No. 12, 12.2006, p. 3372-3380.

Research output: Contribution to journalArticle

Xu, J, Gowen, L, Raphalides, C, Hoyer, KK, Weinger, JG, Renard, M, Troke, JJ, Vaitheesyaran, B, Lee, WNP, Saad, MF, Sleeman, MW, Teitell, MA & Kurland, IJ 2006, 'Decreased hepatic futile cycling compensates for increased glucose disposal in the Pten heterodeficient mouse', Diabetes, vol. 55, no. 12, pp. 3372-3380. https://doi.org/10.2337/db06-0002
Xu, Jun ; Gowen, Lori ; Raphalides, Christian ; Hoyer, Katrina K. ; Weinger, Jason G. ; Renard, Mathilde ; Troke, Joshua J. ; Vaitheesyaran, Bhavapriya ; Lee, W. N Paul ; Saad, Mohammed F. ; Sleeman, Mark W. ; Teitell, Michael A. ; Kurland, Irwin J. / Decreased hepatic futile cycling compensates for increased glucose disposal in the Pten heterodeficient mouse. In: Diabetes. 2006 ; Vol. 55, No. 12. pp. 3372-3380.
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