Mechanisms of insulin resistance in experimental hyperinsulinemic dogs
Mechanisms of insulin resistance in experimental hyperinsulinemic dogs
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DOI：
10.1172/jci1256
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发表时间：
1998-01-01
影响因子：
15.9
通讯作者：
Olefsky, JM
中科院分区：
文献类型：
--
作者：
Miles, PDG;Li, SJ;Olefsky, JM
本研究旨在通过外科手术将胰腺静脉从门静脉转移到腔静脉来表征由犬中产生的慢性高胰岛素血症引起的胰岛素抵抗及其机制。与对照组（n = 6）相比，胰静脉转流（PVD，n = 8）引起动脉胰岛素持续升高，门静脉胰岛素持续降低。与对照组相比，PVD组葡萄糖处理率（GDR）的增加明显较少（39.0 ± 5.0 vs，27.9 ± 3.2 μ mol/kg/min，P < 0.01），但胰岛素对肝脏葡萄糖生成的抑制作用在两组中相似。对照组的肌肉胰岛素受体酪氨酸激酶活性（IR-TKA）从6.2+/-0.4增加到20.3+/-2.7，但PVD组从5.8+/-0.5增加到仅12.7+/-1.7 fmol P/fmol IR（P < 0.01），对于外周，两组动脉胰岛素的半最大反应时间（t（1/2）a）相同，而淋巴胰岛素的t（1/2）a（3+/-3 vs，40+/-4分钟，P < 0.05）和GDR慢性高胰岛素血症导致以胰岛素刺激的GDR降低为特征的显著外周胰岛素抵抗，和GDR动力学活化受损，部分原因是IR-TKA减少，跨内皮胰岛素转运受阻，并导致胰岛素抵抗动物中三分之一的动力学缺陷，而GDR的细胞内机制较慢则导致剩余的三分之二。
This study was undertaken to characterize the insulin resistance and the mechanism thereof caused by chronic hyperinsulinemia produced in dogs by surgically diverting the veins of the pancreas from the portal vein to the vena cava. Pancreatic venous diversion (PVD, n = 8) caused a sustained increase in arterial insulin and decrease in portal insulin concentration compared with the control group (n = 6), Hyperinsulinemic euglycemic clamps were conducted 4 wk after surgery. The increase in the glucose disposal rate (GDR) was significantly less in the PVD group (39.0+/-5.0 vs, 27.9+/-3.2 mu mol/kg/min, P < 0.01) compared with the control group, but the suppression of hepatic glucose production by insulin was similar for both groups. Muscle insulin receptor tyrosine kinase activity (IR-TKA) increased from 6.2+/-0.4 to 20.3+/-2.7 in the control group, but from 5.8+/-0.5 to only 12.7+/-1.7 fmol P/fmol IR in the PVD group (P < 0.01), With respect to the periphery, the time to half-maximum response (t(1/2)a) for arterial insulin was the same for both groups, whereas the t(1/2)a for lymph insulin (3+/-3 vs, 40+/-4 min, P < 0.05) and GDR (29+/-3 vs. 66+/-10 min, P < 0.01) were greater for the PVD group, Chronic hyperinsulinemia led to marked peripheral insulin resistance characterized by decreased insulin-stimulated GDR, and impaired activation of GDR kinetics due, in part, to reduced IR-TKA, Transendothelial insulin transport was impeded and was responsible for one third of the kinetic defect in insulin-resistant animals, while slower intracellular mechanisms of GDR were responsible for the remaining two thirds.