Wataru Nishida1, Masao Nagata, Akihisa Imagawa, Toshiaki Hanafusa, Jun Ohashi, Kenji Takahashi, Tadashi Suehiro, Yuya Yamada, Daisuke Chujo, Eiji Kawasaki, Ryoichi Kawamura, Hiroshi Onuma, Haruhiko Osawa, Hideichi Makino. 1. 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.
Abstract
CONTEXT: 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. OBJECTIVE: The objective of this study was to collect information and characterize insulin-triggered T1DM immunologically and genetically. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
CONTEXT: 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 mellituspatients. OBJECTIVE: The objective of this study was to collect information and characterize insulin-triggered T1DM immunologically and genetically. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.