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Decreased Hepatic Futile Cycling Compensates for Increased Glucose Disposal in the Pten Heterodeficient Mouse

¹ Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York
² Regeneron Pharmaceuticals, Tarrytown, New York
³ Department of Pathology, University of California Los Angeles, Los Angeles, California
⁴ Department of Pediatrics, Harbor-University of California Los Angeles Biomedical Institute, Torrance, California
⁵ Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook, New York
⁶ Molecular Biology Institute, University of California Los Angeles, Los Angeles, California
⁷ Departments of Pharmacological Sciences and Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York

Address correspondence and reprint requests to Irwin J. Kurland, SUNY at Stony Brook, HSC T-15 Room 060, Stony Brook, NY 11794-8154. E-mail: irwin.kurland{at}stonybrook.edu

Abbreviations: AUC, area under the curve; G6PDH, glucose-6-phosphate dehydrogenase; GC/MS, gas chromatography–mass spectrometry; glucose-6-P, glucose-6-phosphate; HGP, hepatic glucose production; HR-dGTT, hepatic recycling deuterated glucose tolerance test; HR-GTT, hepatic recycling glucose tolerance test; ipGTT, intraperitoneal glucose tolerance test; ITT, insulin tolerance test; PI3-K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator–activated receptor; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TCA, trichloroacetic acid

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.

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