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Decreased Hepatic Futile Cycling Compensates for Increased Glucose Disposal in the Pten Heterodeficient Mouse Jun Xu 1 , Lori Gowen 2 , Christian Raphalides 2 , Katrina K. Hoyer 3 , Jason G. Weinger 3 , Mathilde Renard 3 , Joshua J. Troke 3 , Bhavapriya Vaitheesyaran 1 , W.N. Paul Lee 4 , Mohammed F. Saad 5 , Mark W. Sleeman 2 , Michael A. Teitell 3 6 and Irwin J. Kurland 1 7 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 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. 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 Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 6, 2006. Received January 2, 2006. DIABETES

The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury.