Fueger Patrick T, Lee-Young Robert S, Shearer Jane, Bracy Deanna P, Heikkinen Sami, Laakso Markku, Rottman Jeffrey N, Wasserman David H
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Diabetes. 2007 Oct;56(10):2476-84. doi: 10.2337/db07-0532. Epub 2007 Jul 16.
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.
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.
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.
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.
肌肉葡萄糖摄取（MGU）受葡萄糖向肌肉的输送、进入肌肉以及在肌肉内磷酸化的调节。本研究的目的是确定在生理胰岛素刺激（4 mU·kg⁻¹·min⁻¹）或进食普通饲料或高脂饲料情况下运动期间，葡萄糖磷酸化受限在MGU控制中的作用。
对有（HK(+/-)）和无（WT）50%己糖激酶（HK）II缺失的C57BL/6J小鼠喂食普通饲料或高脂饲料，并在4月龄时进行120分钟胰岛素钳夹试验或30分钟跑步机运动研究（每组n = 8 - 10只小鼠）。使用2-脱氧[(³)H]葡萄糖测量MGU指标R(g)。
高脂喂养和部分HK II基因敲除（HK(+/-)）使体重和空腹动脉血糖升高。高脂喂养和部分HK II基因敲除均独立导致空腹高胰岛素血症，高脂喂养与HK II基因敲除联合时该反应协同增强。单独高脂喂养或部分HK II基因敲除可使全身胰岛素作用抑制约25%，二者联合时抑制超过50%。胰岛素刺激的R(g)单独受高脂喂养和部分HK II基因敲除影响时轻度受损（约15 - 20%），二者共同作用时则显著降低（约40 - 50%）。单独高脂喂养和部分HK II基因敲除使运动刺激的R(g)降低约50%，二者联合未进一步减弱。
总之，胰岛素刺激期间高脂喂养和部分HK II基因敲除共同导致的全身代谢和MGU损伤具有累加性。相比之下，运动期间高脂喂养和部分HK II基因敲除联合导致的MGU损伤并不比单独两种操作更严重。这表明运动期间高脂喂养导致MGU受损很大程度上是由于葡萄糖磷酸化受限。这些研究共同表明，高脂喂养小鼠在MGU系统的多个步骤存在缺陷，这些缺陷由不同生理状况引发。
