Carpentier A, Patterson B W, Uffelman K D, Giacca A, Vranic M, Cattral M S, Lewis G F
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Diabetes. 2001 Jun;50(6):1402-13. doi: 10.2337/diabetes.50.6.1402.
Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n = 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n = 7) and healthy control subjects (n = 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite approximately 35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization during the euglycemic-hyperinsulinemic clamp was approximately 40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an approximately 50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no elevation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.
将胰腺静脉与体循环（KPT-S）或门静脉循环（KPT-P）吻合的联合肾胰腺移植（KPT）提供了一种人体模型，借此可以研究门静脉与体循环胰岛素输送对葡萄糖和极低密度脂蛋白（VLDL）代谢的慢性影响。尽管血浆葡萄糖和C肽水平相似，但与KPT-P组（n = 7）和健康对照受试者（n = 15）相比，KPT-S组（n = 9）的空腹和静脉内葡萄糖刺激后的血浆胰岛素水平大约升高了两倍。与对照受试者相比，两个移植组的血浆游离脂肪酸（FFA）水平均升高，但KPT-S组将血浆FFA降低50%所需的血浆胰岛素升高幅度比KPT-P组和对照受试者高约两倍。KPT-S组和KPT-P组的内源性葡萄糖生成相似，尽管后者的肝脏胰岛素水平大约高35%，并且在正常血糖-高胰岛素钳夹期间，KPT-S组的内源性葡萄糖生成比KPT-P组受到更大程度的抑制。在正常血糖-高胰岛素钳夹期间，KPT-S组的全身葡萄糖利用率比KPT-P组低约40%，表明KPT-S组相对于KPT-P组存在外周组织而非肝脏胰岛素抵抗。与对照受试者相比，两个移植组富含甘油三酯（TG）的脂蛋白载脂蛋白B（apoB）和脂质水平大约升高了两倍。两个移植组中VLDL-apoB和VLDL-TG的升高完全是由于与健康对照受试者相比，VLDL清除率大约降低了50%。在FFA负荷增加但不存在肝脏胰岛素过量和明显肝脏胰岛素抵抗的情况下，KPT-S组与KPT-P组和对照受试者相比，VLDL分泌没有升高。这些发现表明，慢性全身性高胰岛素血症和外周组织胰岛素抵抗以及随之而来的血浆FFA通量升高本身不足以导致VLDL过度产生，而其他因素，如肝脏高胰岛素血症和/或严重胰岛素抵抗，可能是胰岛素抵抗综合征常见形式中VLDL过度产生发病机制的重要先决条件。
