Vanderbilt University School of Medicine, Department of Molecular Physiology and Biophysics, Nashville, Tennessee, USA.
Vanderbilt University Medical Center, Division of Surgical Research, Nashville, Tennessee, USA.
JCI Insight. 2019 Feb 26;5(7):126974. doi: 10.1172/jci.insight.126974.
Peripheral hyperinsulinemia resulting from subcutaneous insulin injection is associated with metabolic defects which include abnormal glucose metabolism. The first aim of this study was to quantify the impairments in liver and muscle glucose metabolism that occur when insulin is delivered via a peripheral vein compared to when it is given through its endogenous secretory route (the hepatic portal vein) in overnight fasted conscious dogs. The second aim was to determine if peripheral delivery of a hepato-preferential insulin analog could restore the physiologic response to insulin that occurs under meal feeding conditions. This study is the first to show that hepatic glucose uptake correlates with insulin's direct effects on the liver under hyperinsulinemic-hyperglycemic conditions. In addition, glucose uptake was equally divided between the liver and muscle when insulin was infused into the portal vein, but when it was delivered into a peripheral vein the percentage of glucose taken up by muscle was 4-times greater than that going to the liver, with liver glucose uptake being less than half of normal. These defects could not be corrected by adjusting the dose of peripheral insulin. On the other hand, hepatic and non-hepatic glucose metabolism could be fully normalized by a hepato-preferential insulin analog.
皮下注射胰岛素导致的外周高胰岛素血症与代谢缺陷有关，包括葡萄糖代谢异常。本研究的第一个目的是定量比较胰岛素经外周静脉给药与经内源性分泌途径（肝门静脉）给药时，在夜间禁食清醒犬中肝脏和肌肉葡萄糖代谢的损伤。第二个目的是确定肝靶向胰岛素类似物经外周给药是否可以恢复在进食条件下发生的胰岛素生理反应。这项研究首次表明，在高胰岛素-高血糖状态下，肝脏葡萄糖摄取与胰岛素对肝脏的直接作用相关。此外，当胰岛素注入门静脉时，葡萄糖摄取在肝脏和肌肉之间均等分配，但当胰岛素注入外周静脉时，肌肉摄取的葡萄糖百分比是肝脏的 4 倍，而肝脏葡萄糖摄取量不到正常的一半。这些缺陷不能通过调整外周胰岛素剂量来纠正。另一方面，肝靶向胰岛素类似物可完全使肝和非肝葡萄糖代谢正常化。
