Rooney D P, Robertson R P
Department of Medicine, University of Minnesota Medical School, Minneapolis, USA.
Diabetes. 1996 Feb;45(2):134-8. doi: 10.2337/diab.45.2.134.
Hyperinsulinemia and peripheral insulin resistance caused by systemic insulin delivery and prednisone therapy are recognized consequences of pancreas transplantation. However, there is little information about insulin action on the liver. To investigate hepatic insulin sensitivity in recipients of pancreas transplants, we devised a staged euglycemic hyperinsulinemic clamp to measure hepatic glucose production (HGP) in 10 type I diabetic pancreas transplant recipients, 10 pair-matched healthy control subjects, and 6 nondiabetic kidney transplant recipients. Clamps were performed in two sequential stages. In stage 1, a 2-h low-dose insulin infusion (0.4 mU.kg-1.min-1) was used to partially suppress HGP. In stage 2, insulin-mediated suppression of HGP was challenged by a 1.5-h glucagon infusion (0.8 ng.kg-1.min-1), while continuing the hyperinsulinemic euglycemic-clamp conditions. During both stages, somatostatin (250 micrograms/h) was infused to suppress endogenous insulin secretion. All subjects underwent stage 1, and all except one pancreas recipient and a respective matched healthy control subject completed stage 2. Fasting HGP was greater in pancreas recipients than in healthy control subjects (15.1 +/- 0.7 vs. 12.0 +/- 0.4 mumol.l-1.kg-1.min-1, P < 0.005) but similar in healthy control subjects and in kidney recipients. During stage 2, both total (706 +/- 28 vs. 469 +/- 31 mumol.l-1.kg-1, P < 0.005) and incremental (62 +/- 20 vs. -21 +/- 16 mumol.l-1.kg-1, P < 0.005) HGP responses to glucagon infusion were significantly greater in pancreas recipients than in healthy control subjects. Changes in HGP in kidney recipients during stage 2 were not significantly different from those in healthy control subjects. In conclusion, fasting HGP is increased in pancreas transplant recipients. Furthermore, recipients have hepatic insulin resistance as demonstrated by an enhanced stimulatory effect of glucagon on HGP during insulin-mediated HGP suppression. Because the magnitude of hepatic insulin resistance was a significant (P < 0.01) predictor of HbA1c level, we suggest that variable hepatic insulin resistance may be responsible for some of the variance observed in glycemic levels after successful pancreas transplantation.
全身胰岛素输注和泼尼松治疗所导致的高胰岛素血症及外周胰岛素抵抗是胰腺移植公认的后果。然而，关于胰岛素对肝脏作用的信息却很少。为了研究胰腺移植受者的肝脏胰岛素敏感性，我们设计了一种分阶段的正常血糖高胰岛素钳夹技术，以测量10例I型糖尿病胰腺移植受者、10例配对的健康对照者以及6例非糖尿病肾移植受者的肝脏葡萄糖生成（HGP）。钳夹分两个连续阶段进行。在第1阶段，采用2小时低剂量胰岛素输注（0.4 mU·kg-1·min-1）来部分抑制HGP。在第2阶段，在持续高胰岛素正常血糖钳夹条件下，通过1.5小时胰高血糖素输注（0.8 ng·kg-1·min-1）来挑战胰岛素介导的HGP抑制作用。在两个阶段中，均输注生长抑素（250微克/小时）以抑制内源性胰岛素分泌。所有受试者都进行了第1阶段，除了一名胰腺受者及其配对的健康对照者外，其他所有人都完成了第2阶段。胰腺移植受者的空腹HGP高于健康对照者（15.1±0.7对12.0±0.4微摩尔·升-1·千克-1·分钟-1，P<0.005），但在健康对照者和肾移植受者中相似。在第2阶段，胰腺移植受者对胰高血糖素输注的总HGP反应（70±28对469±31微摩尔·升-1·千克-1，P<0.005）和增量HGP反应（62±20对-21±16微摩尔·升-1·千克-1，P<0.005）均显著高于健康对照者。肾移植受者在第2阶段HGP的变化与健康对照者无显著差异。总之，胰腺移植受者的空腹HGP升高。此外，在胰岛素介导的HGP抑制过程中，胰高血糖素对HGP的刺激作用增强，表明受者存在肝脏胰岛素抵抗。由于肝脏胰岛素抵抗的程度是糖化血红蛋白水平的一个显著（P<0.01）预测指标，我们认为，成功胰腺移植后血糖水平观察到的一些差异可能与肝脏胰岛素抵抗的变化有关。
