Takashi Kadowaki

Objectives: In recent years, with the considerable changes in the therapeutic armamentarium for diabetes, the incidence of hypoglycemia events, especially severe hypoglycemia events, associated with drug treatment in people with diabetes has markedly decreased. We were prompted to evaluate the threshold for each intervention target, especially glycemic control, associated with a minimized risk of the macrovascular complications of diabetes in this setting. Methods: In the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3) conducted by us previously, we recruited 2542 participants and assigned them to a conventional therapy group (n = 1271) and an intensive therapy group (n = 1271; two ineligible participants were removed from all analyses afterwards), and the incidence of severe hypoglycemia events was low in both groups (7 in the intensive therapy group and 4 in the conventional therapy group during a median 8.5 years’ follow-up). Towards the objective of this study, we undertook a landmark analysis with a landmark time-point of 1 year after the baseline of the J-DOIT3 study. Then, using the updated mean values of the glycated hemoglobin (HbA1c), systolic blood pressure, and LDL-cholesterol and HDL-cholesterol levels, we determined the optimal levels of each of these variables associated with the lowest hazard ratios for outcomes, including the primary and cardiovascular outcomes. Results: For glycemic control, our results revealed no clear lower threshold of the glycated hemoglobin associated with the lowest risk of myocardial infarction or all-cause mortality; for other risk factors, it might be an important treatment target to maintain the LDL-cholesterol levels at below 80 mg/dL to minimize the risk of stroke. Conclusions: The present analysis suggested that the treatment target for HbA1c to minimize the risk of all-cause mortality in participants with diabetes with a low incidence of severe hypoglycemia episodes could be < 6.5% (ClinicalTrials.gov, number NCT00300976).

This Perspective argues for a reconceptualization of clinical obesity in Asian populations, moving beyond BMI-centric definitions towards an adiposity-based and function-based framework. Asian populations exhibit a distinctive obesity phenotype, characterized by excess visceral and ectopic adipose tissue accumulation, reduced β-cell reserve, sarcopenic obesity and heightened cardiometabolic risk at lower BMI thresholds than for white European and North American populations, leading to systematic under-recognition of obesity-related disease when conventional criteria are applied. Building on the Lancet Commission's framework for defining and diagnosing clinical obesity, we propose an integrated approach that combines anthropometric measures, body composition assessment, metabolic and organ-specific markers and emerging biomarkers to distinguish preclinical obesity from clinical obesity on the basis of organ dysfunction and functional impairment. This approach improves risk stratification, supports earlier and more precise diagnosis and informs stage-specific management, including lifestyle intervention, pharmacotherapy and metabolic surgery, particularly in Asian populations. We discuss implications for clinical practice, prevention strategies and public health policy, emphasizing the need to align clinical guidelines, reimbursement systems and education with a function-based definition of obesity. Finally, we highlight key research priorities, including validation of biomarker-driven classifications, assessment of long-term clinical and economic outcomes and development of scalable diagnostic tools, to advance precision care and metabolic health equity across diverse Asian populations.

Environmental differences in genetic effect sizes, namely, gene–environment interactions, may uncover the genetic encoding of phenotypic plasticity^1,2,3. We provide a cross-population atlas of gene–environment interactions comprising 440,210 individuals from European and Japanese populations, with replication in 539,794 individuals from diverse populations. By decomposing the contributions from age, sex and lifestyles, we delineate the aetiology of these gene–environment interactions, including a reverse-causality from a disease-related dietary change. Genome-wide analyses uncovered missing heritability and trait–trait relationships connected by the synergistic effects of genome and environments, which systematically affected polygenic prediction accuracy and cross-population portability. Single-cell projection revealed aging shift of pathways and cell types responsible for genetic regulation. Omics-level gene–environment analyses identified multiple sex-discordant genetic effects in lipid metabolism, informing clinical trial failures for genetically supported drug development. Our comprehensive gene–environment study decodes the dynamics of genetic associations, offering insights into complex trait biology, personalized medicine and drug development.

This randomized controlled study aimed to clarify weight loss targets for improving obesity-related disorders in individuals with overweight or obesity. A total of 294 participants with six obesity-related conditions were assigned to either a standard or intensive treatment group, with 12-month weight loss targets of ≥3% and ≥7%, respectively. The standard group followed the Japanese Guidelines for the Management of Obesity Disease 2016. The intensive group received frequent nutritional guidance, enhanced diet and exercise therapy, and additional pharmacotherapy. The primary outcome was weight loss and improvement in at least two obesity-related disorders at 12 months. Secondary outcomes included remission of health disorders, improvement in at least one health disorder, and visceral fat reduction. At 12 months, the weight loss was –2.5% in the intensive group and –1.7% in the standard group, with no significant difference in the primary outcome. However, remission of health disorders was achieved in 16.9% of the intensive group compared with 6.2% of the standard group (adjusted odds ratio 3.079; 95% CI 1.075–8.823; p = 0.036). Visceral fat reduction was greater in the intensive group (–20.46 cm2 vs. –8.9 cm2; p = 0.039). Intensive treatment significantly improved blood pressure early and increased treatment motivation scores by 10.9% (95% CI: 1.2–20.6) at 24 months (p = 0.004). In both groups, ≥60% of the participants showed improvement in at least one disorder. Despite not achieving the target weight loss, resulting in no significant difference in the primary outcome, the intensive treatment increased remission percentages, improved early blood pressure control, and enhanced long-term treatment motivation. The study was registered at UMIN Clinical Trials Registry (UMIN ID: UMIN000031862).

Importance: Prevention of diabetic retinopathy is important to keep vision and quality of life. Objective: To examine the effects of an intensive multifactorial intervention and hypoglycemia on retinopathy in people with type 2 diabetes. Design, Setting, and Participants: J-DOIT3 (Japan Diabetes Optimal Integrated Treatment Study for 3 Major Risk Factors of Cardiovascular Diseases) is a multicenter, open-label, parallel-group randomized clinical trial that examined the efficacy of an intensified multifactorial intervention on cardiovascular outcomes and mortality in people with type 2 diabetes aged 45 to 69 years with hypertension and/or dyslipidemia. The study was conducted at 81 sites in Japan from June 2006 to March 2009, and data analysis was performed from September 2018 to August 2025. Interventions: Participants were randomly assigned to intensive therapy for glucose, blood pressure, and lipids or conventional therapy and were followed up for a median duration of 8.5 years. Main Outcomes and Measures: This study is a secondary analysis of retinopathy events of the secondary outcomes, composed of onset of retinopathy, progression of retinopathy, and loss of vision likely due to retinopathy. Results: Among 2540 total participants (5080 eyes) randomly assigned to intensive therapy or conventional therapy, mean (SD) age was 59.0 (6.3) years, and 965 participants (38.0%) were female. Intensive therapy was associated with a risk reduction in onset of retinopathy (hazard ratio [HR], 0.83; 95% CI, 0.70-0.98; P = .03) but not with progression of retinopathy (HR, 1.02; 95% CI, 0.70-1.49; P = .93). Hemoglobin A _{1 c} (HbA _{1 c} ) at 1 year after randomization was associated with onset (HR, 1.31; 95% CI, 1.13-1.51; P < .001), even after adjustment for baseline risk factors (ie, lower body mass index, longer duration of diabetes, higher fasting plasma glucose, higher blood pressure, and comorbid nephropathy), with no clear HbA _{1 c} threshold observed. Moreover, compared with those without a hypoglycemic episode during the intervention, the risk of onset was higher in those with 0.5 hypoglycemic episodes per year or fewer (HR, 1.25; 95% CI, 1.02-1.53) and even higher in those with more than 1 hypoglycemic episode per year (HR, 1.85; 95% CI, 1.39-2.47). Conclusions and Relevance: This secondary analysis of the J-DOIT3 randomized clinical trial shows that in a randomized clinical trial setting, higher HbA _{1 c} and nonsevere hypoglycemia are associated with higher risk of onset of retinopathy in people with type 2 diabetes, even when good glycemic management, with a very low incidence of severe hypoglycemia, is achieved, suggesting the importance of strict glycemic management without any hypoglycemia. Trial Registration: ClinicalTrials.gov Identifier: NCT00300976

Background: Limited data are available on relative survival (RS) among cancer survivors enrolled in private cancer insurance in Japan. Additionally, the incidence of second primary cancers or recurrences, as applicable, after a certain period remains unclear. Methods: We analyzed 8,846 cancer survivors, including carcinoma in situ, aged 15–79 years, enrolled in private cancer insurance between April 2005 and September 2021, and diagnosed before April 2022. Using the entire insurance-enrolled population as the reference, we estimated sex- and age group-specific RS, conditional RS (CRS), and age-standardized RS (ASR) by cancer type. The cumulative incidence of second primary cancers or recurrences, as applicable, was calculated among cancer-free 3-, 4-, and 5-year survivors. Results: Median ages at first diagnosis were 61.5 years for males and 55.0 years for females. Over median follow-up of 3.40 years, 1,772 deaths (45.4 per 1,000 person-years) occurred. The 5-year RS declined with age: 81.8% for males and 94.8% for females aged 15–39, but 68.5% and 71.8% for those aged 70–79. The 5-year CRS increased with time since diagnosis, exceeding 90% among 5-year survivors in all groups except males aged 70–79. Liver cancer survivors had the highest incidence of second primary cancers or recurrences, predominantly due to recurrences, even after 5 cancer-free years. Conclusion: We estimated sex- and age group-specific RS, CRS, and ASR by cancer type, and the incidence of second primary cancers or recurrences, using a database of private cancer insurance policyholders, though the findings may not be generalizable to the national population.

Coordinated regional action is urgently needed to safeguard insulin access in Asia amid global product realignment. This editorial emphasizes the ethical imperative and policy frameworks required to balance innovation with equitable, uninterrupted diabetes care.

Biological mechanisms underlying multimorbidity remain elusive. To dissect the polygenic heterogeneity of multimorbidity in twelve complex traits across populations, we leveraged biobank resources of genome-wide association studies (GWAS) for 232,987 East Asian individuals (the 1st and 2nd cohorts of BioBank Japan) and 751,051 European individuals (UK Biobank and FinnGen). Cross-trait analyses of respiratory and cardiometabolic diseases, rheumatoid arthritis, and smoking identified negative genetic correlations between respiratory and cardiometabolic diseases in East Asian individuals, opposite from the positive associations in European individuals. Associating genome-wide polygenic risk scores (PRS) with 325 blood metabolome and 2917 proteome biomarkers supported the negative cross-trait genetic correlations in East Asian individuals. Bayesian pathway PRS analysis revealed a negative association between asthma and dyslipidemia in a gene set of peroxisome proliferator-activated receptors. The pathway suggested heterogeneity of cell type specificity in the enrichment analysis of the lung single-cell RNA-sequencing dataset. Our study highlights the heterogeneous pleiotropy of immunometabolic dysfunction in multimorbidity.

Orchestrated hormonal interactions in response to feeding and fasting play a pivotal role in regulating glucose homeostasis. Here, we show that in obesity, the production of follistatin-like 3 (FSTL3), an endogenous inhibitor of Activin B, in adipose tissue is increased in both mice and humans. The knockdown of FSTL3 improves insulin sensitivity and glucose tolerance in diabetic obese db/db mice. Notably, the overexpression of Activin B, a member of the TGFβ superfamily that is induced in liver sinusoidal endothelial cells by fasting, exerts multiple metabolically beneficial effects, including improvement of insulin sensitivity, suppression of hepatic glucose production, and enhancement of glucose-stimulated insulin secretion, all of which are attenuated by the overexpression of FSTL3. Activin B increases insulin sensitivity and reduces fat by inducing fibroblast growth factor 21 (FGF21) while suppressing glucagon action in the liver by increasing phosphodiesterase 4 B (PDE4B), leading to hepatic glucagon resistance and resultant hyperglucagonemia. Activin B-induced hyperglucagonemia enhances glucose-stimulated insulin secretion by stimulating glucagon-like peptide-1 (GLP-1) receptor in pancreatic β-cells. Thus, enhancing the action of Activin B which improves multiple components of the pathogenesis of diabetes may be a promising strategy for diabetes treatment.