Department of Molecular Physiology and Biophysics, Vanderbilt University , Nashville, Tennessee.
Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee.
Am J Physiol Endocrinol Metab. 2019 Jun 1;316(6):E1012-E1023. doi: 10.1152/ajpendo.00501.2018. Epub 2019 Mar 12.
Sepsis costs the healthcare system $23 billion annually and has a mortality rate between 10 and 40%. An early indication of sepsis is the onset of hyperglycemia, which is the result of sepsis-induced insulin resistance in skeletal muscle. Previous investigations have focused on events in the myocyte (e.g., insulin signaling and glucose transport and subsequent metabolism) as the causes for this insulin-resistant state. However, the delivery of insulin to the skeletal muscle is also an important determinant of insulin action. Skeletal muscle microvascular blood flow, which delivers the insulin to the muscle, is known to be decreased during sepsis. Here we test whether the reduced capillary blood flow to skeletal muscle belies the sepsis-induced insulin resistance by reducing insulin delivery to the myocyte. We hypothesize that decreased capillary flow and consequent decrease in insulin delivery is an early event that precedes gross cardiovascular alterations seen with sepsis. This hypothesis was examined in mice treated with either lipopolysaccharide (LPS) or polymicrobial sepsis followed by intravital microscopy of the skeletal muscle microcirculation. We calculated insulin delivery to the myocyte using two independent methods and found that LPS and sepsis rapidly reduce insulin delivery to the skeletal muscle by ~50%; this was driven by decreases in capillary flow velocity and the number of perfused capillaries. Furthermore, the changes in skeletal muscle microcirculation occur before changes in both cardiac output and arterial blood pressure. These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis.
脓毒症每年使医疗系统花费 230 亿美元，死亡率在 10%至 40%之间。脓毒症的早期表现是高血糖的发生，这是由骨骼肌中脓毒症引起的胰岛素抵抗引起的。先前的研究主要集中在肌细胞中的事件（例如胰岛素信号和葡萄糖转运以及随后的代谢）是引起这种胰岛素抵抗状态的原因。然而，胰岛素向骨骼肌的输送也是胰岛素作用的一个重要决定因素。众所周知，脓毒症期间骨骼肌微血管血流减少，将胰岛素输送到肌肉。在这里，我们通过减少胰岛素向肌细胞的输送来测试这种减少的毛细血管血流是否掩盖了脓毒症引起的胰岛素抵抗。我们假设毛细血管流量减少和随之而来的胰岛素输送减少是一个早期事件，先于脓毒症引起的大心血管改变。在接受脂多糖 (LPS) 或多微生物脓毒症治疗的小鼠中，通过对骨骼肌微循环进行活体显微镜检查来检验这一假设。我们使用两种独立的方法计算了胰岛素向肌细胞的输送，并发现 LPS 和脓毒症迅速将胰岛素向骨骼肌的输送减少了约 50%；这是由毛细血管流速和灌注毛细血管数量的减少驱动的。此外，骨骼肌微循环的变化发生在心输出量和动脉血压变化之前。这些数据表明，骨骼肌胰岛素输送的快速减少导致脓毒症期间胰岛素抵抗的诱导。
