University of Pennsylvania School of Medicine, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149, USA.
J Clin Endocrinol Metab. 2010 Mar;95(3):1238-46. doi: 10.1210/jc.2009-2289. Epub 2010 Jan 22.
beta-Cell secretory capacity, a measure of functional beta-cell mass, is often impaired in islet transplant recipients, likely because of a low engrafted beta-cell mass, although calcineurin inhibitor toxicity is often cited as the explanation.
We sought to determine whether use of the calcineurin inhibitor tacrolimus was associated with reduced beta-cell secretory capacity or with increased beta-cell secretory demand independent of engrafted islet mass.
We compared metabolic measures in five intraportal islet recipients vs. 10 normal controls and in seven portally-drained pancreas-kidney and eight nondiabetic kidney recipients vs. nine kidney donor controls. All transplant groups received comparable exposure to tacrolimus, and each transplant group was matched for kidney function to its respective control group.
All participants underwent glucose-potentiated arginine testing where acute insulin responses to arginine (5 g) were determined under fasting (AIR(arg)), 230 mg/dl (AIR(pot)), and 340 mg/dl (AIR(max)) clamp conditions, and AIR(max) gives the beta-cell secretory capacity. Insulin sensitivity (M/I) and proinsulin secretory ratios (PISRs) were assessed to determine whether tacrolimus increased beta-cell secretory demand.
Insulin responses were significantly lower than normal in the islet group for AIR(arg) (P < 0.05), AIR(pot) (P < 0.01), and AIR(max) (P < 0.01), whereas responses in the pancreas-kidney and kidney transplant groups were not different than in the kidney donor group. M/I and PISRs were not different in any of the transplant vs. control groups.
Impaired beta-cell secretory capacity in islet transplantation is best explained by a low engrafted beta-cell mass and not by a deleterious effect of tacrolimus.
β细胞分泌能力是功能性β细胞量的一个衡量指标，在胰岛移植受者中经常受损，可能是由于移植的β细胞量低，尽管钙调神经磷酸酶抑制剂毒性常被认为是解释原因。
我们试图确定钙调神经磷酸酶抑制剂他克莫司的使用是否与β细胞分泌能力降低或β细胞分泌需求增加有关，而与移植的胰岛量无关。
我们比较了门静脉内胰岛移植受者五人与 10 名正常对照者以及门静脉引流胰腺-肾和非糖尿病肾移植受者七人与 9 名肾供体对照者的代谢指标。所有移植组均接受了相似的他克莫司暴露，并且每个移植组都根据其各自的对照组匹配了肾功能。
所有参与者均接受了葡萄糖增强精氨酸测试，其中在空腹（AIR(arg))、230mg/dl(AIR(pot))和 340mg/dl(AIR(max))钳夹条件下测定精氨酸的急性胰岛素反应，并且 AIR(max) 给出了β细胞分泌能力。胰岛素敏感性（M/I)和胰岛素原分泌比（PISRs)被评估以确定他克莫司是否增加了β细胞分泌需求。
与正常对照组相比，胰岛组 AIR(arg)（P<0.05）、AIR(pot)（P<0.01）和 AIR(max)（P<0.01）的胰岛素反应明显降低，而胰腺-肾和肾移植组的反应与肾供体组无差异。在任何移植与对照组之间，M/I 和 PISRs 均无差异。
胰岛移植中β细胞分泌能力受损最好通过低移植β细胞量来解释，而不是通过他克莫司的有害作用来解释。
