Herold K C, Nagamatsu S, Buse J B, Kulsakdinun P, Steiner D F
Department of Medicine, Prizker School of Medicine, University of Chicago, Illinois 60637.
Transplantation. 1993 Jan;55(1):186-92. doi: 10.1097/00007890-199301000-00035.
Immunosuppression is currently used for allotransplantation, and is being evaluated for the treatment of insulin-dependent diabetes mellitus and other autoimmune diseases. However, most available agents have a number of side effects that limit their use in clinical situations. It has been shown previously, for example, that cyclosporine may inhibit insulin release from islet tumor cells and rat islets. We have studied the effects of an analog of a newer agent (FK506) termed L-683,590 on insulin secretion by an islet tumor line, beta TC3, and rat islets, and compared the effects of this drug to those of cyclosporine, since both cause similar immunosuppression. L-683,590 and cyclosporine inhibited insulin release by beta TC3 cells by about 50% and 80%, respectively, at doses that inhibit lymphokine production by T cells. The inhibition by L-683,590 and cyclosporine was more pronounced at higher glucose levels, and was not simply attributable to a general toxic effect of the drugs on the cells. Insulin release during long-term (> 48 hr) cultures of isolated rat islets was also inhibited by the drugs. However, there was no effect of either agent on insulin release by islets during the first 4 hr following a glucose stimulus. Both drugs caused reduced levels of insulin mRNA (by 56 +/- 8.1% and 66 +/- 16% in the presence of L-683,590 and cyclosporine, respectively), accounting for reduced rates of insulin biosynthesis that were also seen. Our studies indicate that: (1) both cyclosporine and L-683,590 inhibit insulin release by beta TC3 cells and cultured rat islets after 48 hr (cyclosporine is a more potent inhibitor); (2) neither drug inhibits the release of insulin during the first 4 hr following a glucose stimulus; and (3) their mechanisms of action appear to be similar--both drugs cause reduced levels of insulin mRNA. Although the toxicity of FK506 on human islets in vivo is still unknown, it may be of particular importance in individuals with impaired beta cell function, such as patients with new-onset insulin-dependent diabetes or patients with non-insulin-dependent diabetes mellitus.
免疫抑制目前用于同种异体移植，并且正在评估其用于治疗胰岛素依赖型糖尿病和其他自身免疫性疾病的效果。然而，大多数现有的药物都有一些副作用，这限制了它们在临床中的应用。例如，先前已经表明，环孢素可能抑制胰岛肿瘤细胞和大鼠胰岛释放胰岛素。我们研究了一种新型药物（FK506）的类似物L - 683,590对胰岛肿瘤细胞系βTC3和大鼠胰岛胰岛素分泌的影响，并将该药物的作用与环孢素的作用进行了比较，因为二者都能引起相似的免疫抑制。在抑制T细胞产生淋巴因子的剂量下，L - 683,590和环孢素分别使βTC3细胞的胰岛素释放抑制约50%和80%。在较高葡萄糖水平时，L - 683,590和环孢素的抑制作用更明显，且这并非仅仅归因于药物对细胞的一般毒性作用。分离的大鼠胰岛长期（> 48小时）培养期间的胰岛素释放也受到药物抑制。然而，在葡萄糖刺激后的最初4小时内，两种药物对胰岛的胰岛素释放均无影响。两种药物均导致胰岛素mRNA水平降低（在L - 683,590和环孢素存在的情况下分别降低56±8.1%和66±16%），这也解释了所观察到的胰岛素生物合成速率降低的现象。我们的研究表明：（1）环孢素和L - 683,590在48小时后均抑制βTC3细胞和培养的大鼠胰岛释放胰岛素（环孢素是更强效的抑制剂）；（2）在葡萄糖刺激后的最初4小时内，两种药物均不抑制胰岛素释放；（3）它们的作用机制似乎相似——两种药物均导致胰岛素mRNA水平降低。尽管FK506对体内人胰岛的毒性仍不清楚，但这对于β细胞功能受损的个体可能尤为重要，例如新发胰岛素依赖型糖尿病患者或非胰岛素依赖型糖尿病患者。
