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Phosphorylation Barriers to Skeletal and Cardiac Muscle Glucose Uptakes in High-Fat–Fed Mice

Studies in Mice With a 50% Reduction of Hexokinase II

¹ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
² Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, Tennessee
³ A.I. Virtanen Institute and Department of Biochemistry and Biotechnology, University of Kuopio, Kuopio, Finland
⁴ Department of Medicine, University of Kuopio, Kuopio, Finland
⁵ Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

Address correspondence and reprint requests to Patrick T. Fueger, PhD, Duke University Medical Center, Department of Pharmacology and Cancer Biology, 4321 Medical Park Dr., Suite 200, Durham, NC 27704. E-mail: patrick.fueger{at}duke.edu

Abbreviations: [2-³H]DG, 2-deoxy[³H]glucose; [2-³H]DGP, 2-deoxy[³H]glucose-6-phosphate; GIR, glucose infusion rate; HK, hexokinase; ISI, insulin sensitivity index; MGU, muscle glucose uptake; NEFA, nonesterified fatty acid

OBJECTIVE—Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU · kg^–1· min^–1) or exercise with chow or high-fat feeding.

RESEARCH DESIGN AND METHODS—C57BL/6J mice with (HK^+/–) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin clamp or 30 min of treadmill exercise (n = 8–10 mice/group). 2-deoxy[³H]glucose was used to measure R_g, an index of MGU.

RESULTS—Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK^+/–). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by 25% with either high-fat feeding or partial HK II knockout alone but by >50% when the two were combined. Insulin-stimulated R_g was modestly impaired by high-fat feeding and partial HK II knockout independently (15–20%) but markedly reduced by the two together (40–50%). Exercise-stimulated R_g was reduced by 50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two.

CONCLUSIONS—In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat–fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions.

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