Lohmann T, List C, Lamesch P, Kohlhaw K, Wenzke M, Schwarz C, Richter O, Hauss J, Seissler J
Department of Internal Medicine III, University of Leipzig, Germany.
Exp Clin Endocrinol Diabetes. 2000;108(5):347-52. doi: 10.1055/s-2000-8127.
The induction of diabetes has been recognised as adverse effect of the immunsuppressive drug FK506/Tacrolimus. The aim of this study was to clarify whether insulinopenia or insulin resistance dominates and whether islet cell autoantibodies are present in patients treated by FK506. We investigated 58 patients 1-3 years after liver transplantation while under therapy with FK506 or CsA and prednisolone (0-7.5 mg) for basal blood glucose levels and islet-cell specific autoantibodies. A subgroup of 20 patients on FK506, 10 patients on cyclosporin and 15 healthy volunteers were metabolically tested by oGTT. Five patients had diabetes pre-transplantation. After transplantation, 9/28 FK506-treated patients developed newly diagnosed diabetes compared to 0/25 cyclosporin-treated patients (p<0.01). Both patient groups showed significantly higher fasting blood glucose, insulin or C-peptide levels compared to controls. Through the oGTT, FK506-treated patients without diabetes, but not cyclosporin-treated patients, had higher C-peptide levels compared to controls (p<0.05). Five/32 patients on FK506 compared to 0/26 patients on cyclosporin (p<0.05) had islet cell specific autoantibodies, mainly ICA without GAD- or IA2-Ab, a feature described for latent autoimmune diabetes in adults. ICA positivity was correlated to the diabetes associated HLA haplotype DR4/DQ*0302 (p<0.05). Although the interpretation of our metabolic data in patients with concomitant liver disease and prednisolone therapy has limitations, we suggest insulin resistance caused by treatment with FK506. However, manifestation of diabetes was associated with relative insulinopenia rather than insulin resistance in patients on FK506. Immunsuppressive therapy by FK506 was not able to suppress islet cell autoimmunity, and may even induce it in genetically predisposed patients.
糖尿病的诱发已被确认为免疫抑制药物FK506/他克莫司的不良反应。本研究的目的是阐明在接受FK506治疗的患者中，胰岛素缺乏或胰岛素抵抗何者占主导地位，以及是否存在胰岛细胞自身抗体。我们调查了58例肝移植术后1至3年的患者，这些患者正在接受FK506或环孢素及泼尼松龙（0 - 7.5毫克）治疗，检测其基础血糖水平和胰岛细胞特异性自身抗体。对20例使用FK506的患者、10例使用环孢素的患者和15名健康志愿者组成的亚组进行口服葡萄糖耐量试验（oGTT）代谢测试。5例患者移植前患有糖尿病。移植后，28例接受FK506治疗的患者中有9例出现新诊断的糖尿病，而25例接受环孢素治疗的患者中无1例出现（p<0.01）。与对照组相比，两组患者的空腹血糖、胰岛素或C肽水平均显著升高。通过oGTT，未患糖尿病的FK506治疗患者的C肽水平高于对照组，而环孢素治疗患者则不然（p<0.05）。使用FK506的32例患者中有5例（p<0.05）与使用环孢素的26例患者中的0例相比，存在胰岛细胞特异性自身抗体，主要为胰岛细胞抗体（ICA），无谷氨酸脱羧酶抗体（GAD - Ab）或胰岛抗原2抗体（IA2 - Ab），这是成人隐匿性自身免疫性糖尿病的一个特征。ICA阳性与糖尿病相关的人类白细胞抗原（HLA）单倍型DR4/DQ*0302相关（p<0.05）。尽管我们对伴有肝病和泼尼松龙治疗患者的代谢数据的解读存在局限性，但我们认为FK506治疗会导致胰岛素抵抗。然而，在使用FK506的患者中，糖尿病的表现与相对胰岛素缺乏而非胰岛素抵抗有关。FK506免疫抑制治疗无法抑制胰岛细胞自身免疫，甚至可能在遗传易感患者中诱发自身免疫。
