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R Paul Robertson Nutrition Department of Internal Medicine, Division of Metabolism Endocrinology, University of Washington, Seattle, Washington, USA

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using perifusion experiments. We posited that the lack of periportal blood flow in isolated islet preparations renders the delivery of insulin to downstream alpha cells, and in turn provision of an insulin switch-off signal, impossible. As expected

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Kai-Chun Cheng
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Ying-Xiao Li
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Akihiro Asakawa
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Miharu Ushikai
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Ikuo Kato Department of Psychosomatic Internal Medicine, Department of Bioorganic Chemistry, Department of Medical Research, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

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Yuki Sato Department of Psychosomatic Internal Medicine, Department of Bioorganic Chemistry, Department of Medical Research, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

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Juei-Tang Cheng Department of Psychosomatic Internal Medicine, Department of Bioorganic Chemistry, Department of Medical Research, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan

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Akio Inui
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insulin release and increase glucose sensitivity in terms of insulin secretion, electrical activity, and Ca 2+ signaling for changes in glucose metabolism ( Rajan et al . 1990 , Martín et al . 1999 ). Also, as shown in Fig. 4 , this action of preptin

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Maria H M Lima Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Lílian C Souza Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Luciana C Caperuto Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Estela Bevilacqua Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Alessandra L Gasparetti Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Ricardo Zanuto Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Mario J A Saad Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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Carla R O Carvalho Department of Physiology and Biophysics and
Department of Cellular and Development Biology, Institute of Biomedical Sciences, University of Sao Paulo (USP),
Department of Nursing and
Department of Internal Medicine, Medical Sciences Faculty, University of Campinas (UNICAMP), Brazil

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activation of the extracellular signal-regulated kinase (ERK) pathway (Saltiel & Kahn 2002, Saltiel & Pessin 2002 ). Insulin has a stimulatory effect on steroidogenesis by granulosa cells from cow, rats, and women and interacts with luteinizing

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Thomas Nicholson Institute of Inflammation and Ageing, MRC-ARUK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK

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Chris Church MedImmune, Cardiovascular and Metabolic Disease (CVMD), Milstein Building, Cambridge, UK

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Kostas Tsintzas MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK

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Robert Jones MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK

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Leigh Breen Institute of Inflammation and Ageing, MRC-ARUK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK

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Edward T Davis The Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK

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David J Baker MedImmune, Cardiovascular and Metabolic Disease (CVMD), Milstein Building, Cambridge, UK

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Simon W Jones Institute of Inflammation and Ageing, MRC-ARUK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK

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effect of recombinant human vaspin on insulin signalling and glucose uptake in human skeletal muscle tissue. Materials and methods Human samples Gluteus maximus skeletal muscle, SAT and blood samples were obtained from 21 lean (BMI 22.8 ± 0

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M E Cleasby Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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Q Lau Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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E Polkinghorne Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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S A Patel Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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S J Leslie Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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N Turner Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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G J Cooney Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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A Xu Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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E W Kraegen Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
Department of Veterinary Basic Sciences, Diabetes and Obesity Research Program, Faculty of Medicine, Department of Medicine, Faculty of Medicine, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK

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was abolished by APPL1 down-regulation in these cells ( Mao et al . 2006 ). These data suggest that APPL1 may provide a means for crosstalk between adiponectin and insulin signalling pathways and thus a potential mechanism for the insulin

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L B Hays Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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B Wicksteed Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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Y Wang Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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J F McCuaig Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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L H Philipson Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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J M Edwardson Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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C J Rhodes Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122, USA
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA

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physiologically relevant being glucose ( Lang 1999 ). The proximal signaling mechanism for glucose-stimulated insulin secretion is relatively well defined ( MacDonald 1990 ). Increased glucose metabolism in β-cells leads to an increase in the cytosolic ATP

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Emilio Hirsch Dipartimento di Genetica, Biologia e Biochimica, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy

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Carlotta Costa Dipartimento di Genetica, Biologia e Biochimica, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy

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Elisa Ciraolo Dipartimento di Genetica, Biologia e Biochimica, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino 10126, Italy

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distinct cell types. PI3K signaling in insulin-mediated metabolic control A growing body of evidence indicates that not only is PI3K activation a key step in insulin-mediated control of metabolism but also that PIP 3

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E Bucris Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel

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A Beck Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

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S Boura-Halfon Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

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R Isaac Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

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Y Vinik Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

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T Rosenzweig Department of Molecular Biology and Nutritional Studies, Ariel University, Ariel, Israel

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S R Sampson Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel

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Y Zick Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

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acts as a growth factor that plays an antiapoptotic role and protects cells from death through activation of the PI3-kinase and ERK signaling pathways ( Muller et al . 2006 , Jensen & De Meyts 2009 ), and insulin therapy can protect cells from

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Yu Wu Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Tingting Wu Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Jun Wu Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Lei Zhao Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Qing Li Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Zac Varghese Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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John F Moorhead Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Stephen H Powis Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Yaxi Chen Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Xiong Z Ruan Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Key Laboratory of Metabolism of Lipid and Glucose, John Moorhead Research Laboratory, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

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on alternate days and were culled 14 weeks after the first injection. At termination, blood samples were taken for cytokines and lipid assays, and tissue samples were collected for further detection. For biochemical analysis of insulin signaling

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Kelly D McCall Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Dawn Holliday Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Eric Dickerson Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Brian Wallace Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Anthony L Schwartz Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Christopher Schwartz Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Christopher J Lewis Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Leonard D Kohn Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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Frank L Schwartz Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center

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inflammation and induce insulin resistance via multiple mechanisms including, but not limited to, serine phosphorylation of insulin receptor substrate-1 (IRS-1) and up-regulation of suppressors of cytokine signaling (SOCS; Paz et al . 1997 , Lin et al

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