New genetic clues explain speed of insulin depletion in Japanese patients with type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune condition where the immune system destroys insulin-producing β-cells in the pancreas. Yet, not all patients lose insulin function at the same pace. Understanding this variation is especially important in Japanese populations, who tend to experience faster and more complete loss of insulin secretion than their Western counterparts.

In a groundbreaking nationwide study with a follow-up period of up to 14 years, researchers in Japan addressed this knowledge gap by unraveling why some individuals with T1D lose their insulin-producing capacity faster than others. This study was made available online on DDMMYY, and was published in Volume ___ Issue ___ of the journal Diabetes Care Journal on DDMMYY.  Professor Shinsuke Noso from the Department of Endocrinology, Metabolism and Diabetes at Kindai University Faculty of Medicine, Japan, played a central role in analyzing data from the Japanese Type 1 Diabetes Database Study (TIDE-J) to identify genetic and clinical predictors of β-cell depletion—a key driver of disease progression and long-term management in T1D. This research was actively conducted in collaboration with Dr. Hiroshi Kajio and Dr. Noriko Kodani from the National Center for Global Health and Medicine, Japan Institute for Health Security, as well as Professor Hiroshi Ikegami from the Kindai University, who also serves as Chair of the Type 1 Diabetes Research Committee of the Japan Diabetes Society.

In the TIDE-J study, researchers enrolled 314 Japanese individuals across three T1D subtypes: acute-onset (165 patients), slowly progressive (SP; 105 patients), and fulminant (44 patients). Through detailed annual tracking of C-peptide levels (a marker of insulin secretion), autoantibodies, glycemic control, and specific immune system genes known as human leukocyte antigens (HLA), the team documented how β-cell function evolved over time.

They found that 5 years after T1D onset, 43% of acute-onset, 9% of SP, and 93% of patients with fulminant, had reached undetectable insulin secretion. Remarkably, even among those within the same subtype, there was substantial variability. Genetic analysis revealed that individuals carrying the DR4/DR4 genotype (a double dose of the DRB1*04:05-DQB1*04:01 haplotype) retained β-cell function significantly longer—earning them the label of “slow progressors.” In contrast, heterozygous DR4/DR8 and DR4/DR9 carriers experienced rapid insulin depletion and were classified as “rapid progressors.”

“Certain HLA genotypes that influence susceptibility to T1D also affect how quickly the disease worsens,” explains Prof. Noso. “This adds a new layer to precision medicine—moving from predicting disease risk to forecasting its trajectory.”

The researchers also identified key clinical predictors beyond genetics. For the SP subtype, which is similar to latent autoimmune diabetes in adults, a low body mass index, positivity for glutamic acid decarboxylase autoantibodies, and absence of the DR2 haplotype (a known protective factor) were associated with a faster transition to insulin dependence. In fulminant T1D, although over 90% of patients lost insulin secretion within 5 years, genetic predictors were less distinct—possibly due to the subtype’s inherently aggressive course and the limited sample size, which constrained further exploration of the factors underlying heterogeneity in disease progression.

These findings provide an immediate and practical clinical implication. Knowing a patient’s HLA genotype could help physicians estimate how fast they are likely to lose insulin production, enabling the timely use of technologies like automated insulin delivery systems and interventions such as anti-CD3 antibody therapies aimed at preserving β-cell function. “By integrating HLA genotyping with early diagnostic tools—like islet autoantibody screening or glucose tolerance testing in at-risk relatives—we can better time immunotherapies and improve clinical outcomes,” says Prof. Noso.

The TIDE-J study also represents a major milestone in Japan’s public health landscape. It is the country's first and only comprehensive, multicenter cohort study on T1D, launched in 2010 through a joint effort by the National Center for Global Health and Medicine and the Japan Diabetes Society. “TIDE-J is not just an academic study—it’s a national initiative to understand and transform diabetes care in Japan,” says Prof. Noso. “It reflects a decade-long commitment to tracking and improving outcomes of people with T1D, while also providing critical insights into the natural history and progression of the disease.”

Overall, this study offers crucial insights that could enable earlier interventions, delay disease onset, and even help preserve long-term insulin production in some patients. The TIDE-J study stands as a powerful example of how combining genetic science with real-world data can advance personalized care and improve long-term outcomes for people living with T1D.