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Hexokinase II Overexpression Improves Exercise-Stimulated But Not Insulin-Stimulated Muscle Glucose Uptake in High-Fat-Fed C57BL/6J Mice

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

The aim of the present study was to determine the specific sites of impairment to muscle glucose uptake (MGU) in the insulin-resistant high-fat-fed, conscious C57BL/6J mouse. Wild type (WT) and hexokinase II overexpressing (HK^Tg) mice were fed either a standard diet or high-fat diet and studied at 4 months of age. A carotid artery and jugular veins had catheters chronically implanted for sampling and infusions, respectively, and mice were allowed to recovery for at least 5 days. Mice were fasted for 5 h and underwent a hyperinsulinemic-euglycemic clamp or saline infusion for 120 min. Separate groups of mice were studied during 30-min sedentary or treadmill exercise periods. A bolus of 2-deoxy[³H]glucose was administered 25 min before the end of each study for determination of R_g, an index of tissue-specific glucose uptake. Fasting blood glucose was increased in high-fat compared with standard diet-fed WT (194 ± 4 vs. 171 ± 4 mg/dl) but not HK^Tg (179 ± 5 vs. 171 ± 3 mg/dl) mice. High-fat feeding created hyperinsulinemia in both WT and HK^Tg mice (58 ± 8 and 77 ± 15 µU/ml) compared with standard diet-fed mice (21 ± 2 and 20 ± 1 µU/ml). R_g was not affected by genotype or diet during either saline infusion or sedentary conditions. HK II overexpression augmented insulin-stimulated R_g in standard diet-fed but not high-fat-fed mice. Exercise-stimulated R_g was impaired by high-fat feeding in WT mice, but this impairment was largely rectified in HK^Tg mice. In conclusion, high-fat feeding impairs both insulin- and exercise-stimulated MGU, but only exercise-stimulated MGU was corrected by HK II overexpression.

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