Abstract

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.