Noso Shinsuke, Chujo Daisuke, Imagawa Akihisa, Kawasaki Eiji, Awata Takuya, Yasuda Kazuki, Abiru Norio, Kodani Noriko, Oikawa Yoichi, Fukui Tomoyasu, Katsuki Takeshi, Kozawa Junji, Nagasawa Kan, Osawa Haruhiko, Takahashi Kazuma, Tsuchiya Kyoichiro, Shimoda Masayuki, Yasuda Hisafumi, Maeda Norikazu, Shimada Akira, Kobayashi Tetsuro, Hanafusa Toshiaki, Kajio Hiroshi, Ikegami Hiroshi
Department of Endocrinology, Metabolism and Diabetes, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Department of Diabetes, Metabolism, and Endocrinology, International University of Health and Welfare, Ichikawa, Japan.
Diabetes Care. 2025 Aug 1;48(8):1438-1445. doi: 10.2337/dc25-0579.
This study aimed to investigate the progression of β-cell dysfunction and its predictors in Japanese patients with type 1 diabetes, using data from the nationwide, multicenter, prospective longitudinal Japanese Type 1 Diabetes Database Study (TIDE-J).
TIDE-J enrolled 314 Japanese individuals with type 1 diabetes, including 165 with acute-onset, 105 with slowly progressive, and 44 with fulminant type 1 diabetes. Clinical data, including C-peptide levels, glycemic control, and autoantibody status, were collected annually for up to 14 years. HLA genotypes were analyzed at study entry. The time to insulin depletion was analyzed using survival curves and Cox proportional hazards models to determine predictive factors.
The rate of undetectable C-peptide varied significantly among subtypes. At 5 years after onset, 43.1% (n = 55) of patients with acute-onset, 9.1% (n = 7) with slowly progressive, and 93.2% (n = 38) with fulminant type 1 diabetes reached undetectable C-peptide. Even within acute-onset type 1 diabetes, a marked interindividual variation was observed in the progression toward β-cell depletion. HLA genotypes influenced progression rates as follows: DRB104:05-DQB104:01/DRB104:05-DQB104:01 (DR4/DR4) carriers exhibited slower β-cell depletion, whereas DR4/DRB108:02-DQB103:02 (i.e., DR4/DR8) and DR4/DRB109:01-DQB103:03 (i.e., DR4/DR9) were associated with a rapid progression. For slowly progressive type 1 diabetes, low BMI, GAD antibody positivity, and absence of the DRB115:01-DQB106:02 or DRB115:02-DQB106:01 (i.e., DR2) haplotype were predictive of progression to insulin dependence.
This study elucidates the heterogeneity in β-cell dysfunction among Japanese individuals with type 1 diabetes and identifies genetic and clinical predictors of disease progression. These findings provide insights for individualized management strategies and future therapeutic interventions.
本研究旨在利用来自全国多中心前瞻性纵向日本1型糖尿病数据库研究（TIDE-J）的数据，调查日本1型糖尿病患者β细胞功能障碍的进展情况及其预测因素。
TIDE-J纳入了314名日本1型糖尿病患者，其中165例为急性起病型，105例为缓慢进展型，44例为暴发性1型糖尿病。每年收集临床数据，包括C肽水平、血糖控制情况和自身抗体状态，最长收集14年。在研究开始时分析HLA基因型。使用生存曲线和Cox比例风险模型分析胰岛素耗竭时间，以确定预测因素。
各亚型中C肽检测不到的发生率差异显著。发病后5年，急性起病型患者中有43.1%（n = 55）、缓慢进展型患者中有9.1%（n = 7）、暴发性1型糖尿病患者中有93.2%（n = 38）的C肽检测不到。即使在急性起病型1型糖尿病患者中，向β细胞耗竭进展的个体间差异也很明显。HLA基因型对进展率的影响如下：DRB104:05-DQB104:01/DRB104:05-DQB104:01（DR4/DR4）携带者的β细胞耗竭较慢，而DR4/DRB108:02-DQB103:02（即DR4/DR8）和DR4/DRB109:01-DQB103:03（即DR4/DR9）与快速进展相关。对于缓慢进展型1型糖尿病，低体重指数、谷氨酸脱羧酶抗体阳性以及不存在DRB115:01-DQB106:02或DRB115:02-DQB106:01（即DR2）单倍型可预测进展为胰岛素依赖。
本研究阐明了日本1型糖尿病患者β细胞功能障碍的异质性，并确定了疾病进展的遗传和临床预测因素。这些发现为个体化管理策略和未来治疗干预提供了见解。
