Bertoldo Alessandra, Pencek R Richard, Azuma Koichiro, Price Julie C, Kelley Carol, Cobelli Claudio, Kelley David E
Department of Information Engineering, University of Padova, Italy.
Diabetes. 2006 Nov;55(11):3028-37. doi: 10.2337/db06-0762.
Skeletal muscle accounts for a large proportion of insulin-stimulated glucose utilization. It is generally regarded that much of the control over rates of uptake is posited within the proximal steps of delivery, transport, and phosphorylation of glucose, with glucose transport as the main locus of control. Whether insulin modulates the distribution of control across these steps and in what manner remains uncertain. The current study addressed this in vivo using dynamic positron emission tomography (PET) imaging of human muscle with sequential injections of three tracers ([(15)O]H(2)O, [(11)C]3-O-methyl glucose [3-OMG], and [(18)F]fluoro-deoxy glucose [FDG]) that enabled quantitative determinations of glucose delivery, transport, and its phosphorylation, respectively. Lean, healthy, research volunteers were studied during fasting conditions (n = 8) or during a euglycemic insulin infusion at 30 mU/min per m(2) (n = 8). PET images were coregistered with magnetic resonance imaging to contrast glucose kinetics in soleus, a highly oxidative muscle, with tibialis anterior, a less oxidative muscle. During fasting conditions, uptake of [(11)C]3-OMG was similar in soleus and tibialis anterior muscles, despite higher delivery to soleus (by 35%; P < 0.01). Uptake of [(18)F]FDG was also similar between muscle during fasting, and glucose transport was found to be the dominant locus of control (90%) for glucose uptake under this condition. Insulin increased uptake of [(11)C]3-OMG substantially and strongly stimulated the kinetics of bidirectional glucose transport. Uptake of [(11)C]3-OMG was higher in soleus than tibialis anterior muscle (by 22%; P < 0.01), a difference partially due to higher delivery, which was again found to be 35% higher to soleus (P < 0.01). The uptake of [(18)F]FDG was 65% greater in soleus compared with tibialis anterior muscle, a larger difference than for [(11)C]3-OMG (P < 0.01), indicating an added importance of glucose phosphorylation in defining insulin sensitivity. Analysis of the distribution of control during insulin-stimulated conditions revealed that most of the control was posited at delivery and transport and was equally divided between these steps. Thus, insulin evokes a broader distribution of control than during fasting conditions in governing glucose uptake into skeletal muscle. This redistribution of control is triggered by the robust stimulation of glucose transport, which in turn unmasks a greater dependence upon delivery and glucose phosphorylation.
骨骼肌在胰岛素刺激的葡萄糖利用中占很大比例。一般认为，对葡萄糖摄取速率的控制大多存在于葡萄糖的输送、转运和磷酸化的近端步骤中，其中葡萄糖转运是主要的控制点。胰岛素是否调节这些步骤中控制的分布以及以何种方式调节仍不确定。本研究使用动态正电子发射断层扫描（PET）成像技术对人体肌肉进行体内研究，依次注射三种示踪剂（[（15）O]H₂O、[（11）C]3 - O - 甲基葡萄糖[3 - OMG]和[（18）F]氟代脱氧葡萄糖[FDG]），分别能够定量测定葡萄糖的输送、转运及其磷酸化。对健康的瘦体型研究志愿者在禁食状态下（n = 8）或在以30 mU/min·m²的速率进行正常血糖胰岛素输注期间（n = 8）进行了研究。PET图像与磁共振成像进行配准，以对比比目鱼肌（一种高度氧化的肌肉）和胫骨前肌（一种氧化程度较低的肌肉）中的葡萄糖动力学。在禁食状态下，比目鱼肌和胫骨前肌对[（11）C]3 - OMG的摄取相似，尽管输送到比目鱼肌的量更高（高35%；P < 0.01）。禁食期间肌肉对[（18）F]FDG的摄取也相似，并且发现葡萄糖转运是此条件下葡萄糖摄取的主要控制点（90%）。胰岛素显著增加了[（11）C]3 - OMG的摄取，并强烈刺激了双向葡萄糖转运的动力学。比目鱼肌中[（11）C]3 - OMG的摄取高于胫骨前肌（高22%；P < 0.01），这种差异部分归因于更高的输送量，再次发现输送到比目鱼肌的量高出35%（P < 0.01）。与胫骨前肌相比，比目鱼肌中[（18）F]FDG的摄取高出65%，这一差异比[（11）C]3 - OMG的差异更大（P < 0.01），表明葡萄糖磷酸化在定义胰岛素敏感性方面具有更大的重要性。对胰岛素刺激条件下控制分布的分析表明，大多数控制存在于输送和转运步骤，并且在这些步骤之间平均分配。因此，在控制骨骼肌对葡萄糖的摄取方面，胰岛素引起的控制分布比禁食状态下更广泛。这种控制的重新分布是由葡萄糖转运的强烈刺激引发的，这反过来又揭示了对输送和葡萄糖磷酸化的更大依赖性。
