Nishida Wataru, Nagata Masao, Imagawa Akihisa, Hanafusa Toshiaki, Ohashi Jun, Takahashi Kenji, Suehiro Tadashi, Yamada Yuya, Chujo Daisuke, Kawasaki Eiji, Kawamura Ryoichi, Onuma Hiroshi, Osawa Haruhiko, Makino Hideichi
Department of Diabetes and Molecular Genetics (W.N., R.K., H.On., H.Os., H.M.), Ehime University Graduate School of Medicine, To-on, Ehime 791-0295, Japan; Department of Internal Medicine (M.N.), Kokogawa W City Hospital, Hyogo 675-8611, Japan; Department of Metabolic Medicine (A.I.), Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Internal Medicine (I) (T.H.), Osaka Medical College, Osaka 569-8686, Japan; University of Tsukuba (J.O.), Ibaraki, Japan; 6) Division of Diabetes (K.T.), Department of Internal Medicine, Kurashiki Central Hospital, Kurashiki 710-8602, Japan; Department of Diabetes (T.S.), Kochi Takasu Hospital, Kochi 781-5103, Japan; Sumitomo Hospital (Y.Y.), Osaka 530-0005, Japan; Diabetes Research Center (D.C.), National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Metabolism/Diabetes and Clinical Nutrition (E.K.), Nagasaki University Hospital, Nagasaki 852-8501, Japan; and Shiraishi Hospital Diabetes Center (H.M.), Imabari, Ehime 794-0041, Japan.
J Clin Endocrinol Metab. 2014 Sep;99(9):E1793-7. doi: 10.1210/jc.2014-1759. Epub 2014 Jun 27.
Insulin administration causes various types of immune responses to insulin. We previously reported three cases of type 1 diabetes mellitus (T1DM) triggered by insulin administration in Japanese type 2 diabetes mellitus patients.
The objective of this study was to collect information and characterize insulin-triggered T1DM immunologically and genetically.
Data for six patients (four men and two women) with insulin-triggered T1DM aged 59.5 ± 12.8 years were collected. Serum or urinary C-peptides, islet-related autoantibodies, insulin antibody, human leukocyte antigen, or the insulin gene variable number of tandem repeat genotype were analyzed. Th1- or Th2-associated responses were evaluated using an Enzyme-Linked ImmunoSpot assay.
None of the subjects had received insulin therapy or had an autoantibody to the 65-kDa isoform of glutamic acid decarboxylase before insulin administration. After insulin administration blood glucose control deteriorated acutely without any apparent cause, whereas C-peptide levels rapidly decreased to insulin-deficient levels. The mean duration of insulin administration to the development of T1DM was 7.7 ± 6.1 months. Islet-related autoantibodies became positive, whereas insulin allergy or a high titer of insulin antibody was observed in several cases. All had T1DM high-risk human leukocyte antigen class II (IDDM1) and the insulin gene variable number of tandem repeats genotype (IDDM2). GAD-reactive and insulin peptide-reactive Th1 cells, but not Th2 cells, were identified in two of four cases.
The findings suggest that insulin administration may have triggered TIDM in patients with type 2 diabetes mellitus. IDDM1 and IDDM 2 as well as autoreactive T cells may contribute to the development of T1DM. Developing insulin-triggered T1DM if a patient's blood glucose control acutely deteriorates after insulin administration should be carefully considered.
胰岛素给药会引发多种针对胰岛素的免疫反应。我们之前报道过3例日本2型糖尿病患者因胰岛素给药引发1型糖尿病（T1DM）的病例。
本研究的目的是收集信息，并从免疫学和遗传学角度对胰岛素引发的T1DM进行特征描述。
收集了6例胰岛素引发的T1DM患者（4名男性和2名女性）的数据，年龄为59.5±12.8岁。分析了血清或尿C肽、胰岛相关自身抗体、胰岛素抗体、人类白细胞抗原或胰岛素基因可变串联重复基因型。使用酶联免疫斑点试验评估Th1或Th2相关反应。
在胰岛素给药前，所有受试者均未接受过胰岛素治疗，也没有针对谷氨酸脱羧酶65 kDa异构体的自身抗体。胰岛素给药后，血糖控制在无明显原因的情况下急性恶化，而C肽水平迅速降至胰岛素缺乏水平。从胰岛素给药到发生T1DM的平均持续时间为7.7±6.1个月。胰岛相关自身抗体呈阳性，而在几例患者中观察到胰岛素过敏或高滴度胰岛素抗体。所有患者均具有T1DM高风险人类白细胞抗原II类（IDDM1）和胰岛素基因可变串联重复基因型（IDDM2）。在4例中的2例中鉴定出了GAD反应性和胰岛素肽反应性Th1细胞，但未鉴定出Th2细胞。
研究结果表明，胰岛素给药可能在2型糖尿病患者中引发了TIDM。IDDM1和IDDM 2以及自身反应性T细胞可能促成了T1DM的发生。如果患者在胰岛素给药后血糖控制急性恶化，应仔细考虑是否会发生胰岛素引发的T1DM。
