Phosphorylation barriers to skeletal and cardiac muscle glucose uptakes in high-fat fed mice: studies in mice with a 50% reduction of hexokinase II.

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 x kg(-1) x 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[(3)H]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 approximately 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 ( approximately 15-20%) but markedly reduced by the two together ( approximately 40-50%). Exercise-stimulated R(g) was reduced by approximately 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.