Takahiro Ichikawa

Aims: Smoking cessation may transiently increase diabetes risk through weight gain, but its temporal trajectory remains unclear. We evaluated the long‐term effect of smoking cessation on incident diabetes. Materials and Methods: We conducted a target trial emulation using a sequential‐cohort design with repeated annual enrollment. Using annual health checkup data of Japanese employees from 2008 to 2022, we newly enrolled, at each annual assessment, and started follow‐up individuals aged 40 years or older who were currently smoking and free of diabetes. Inverse probability weighting was used to adjust for baseline confounding in every sequential cohort. We estimated cumulative risks for quit‐smoking and persistent‐smoking groups, and their differences and ratios. Results: From 52 880 unique participants, a total of 331 701 participants were followed‐up in the sequential cohorts, with a mean (standard deviation) age of 49.1 (5.7) years, and 25 749 developed diabetes. The risk ratio (95% confidence interval) for diabetes in the quit‐smoking group relative to the persistent‐smoking group was 1.15 (1.07–1.24) at 3 years and 0.95 (0.85–1.06) at 15 years. Per‐protocol analyses showed a similar pattern. Conclusions: Smoking cessation was associated with a short‐term increase in diabetes risk, but this excess risk diminished over time, and no long‐term increase in risk was observed. These findings support sustained smoking cessation as metabolically beneficial in the long term.

Objective: Annual health screening provides repeated measurements of body mass index (BMI) and waist‐based indices, but the implications of short‐term changes in general and central adiposity for cardiometabolic risk remain unclear. We examined whether 1‐year changes in BMI and waist‐to‐height ratio (WHtR) were associated with subsequent cardiometabolic outcomes and cardiovascular–kidney–metabolic (CKM) syndrome progression. Methods: We analysed longitudinal health examination data from 144 394 Japanese employees aged 40–74 years between 2008 and 2023. One‐year changes in BMI and WHtR were calculated from two consecutive annual examinations, and outcomes were assessed during the following year. Outcomes included incident hypertension, dyslipidemia, hyperuricemia, diabetes, major adverse cardiovascular events, all‐cause mortality, and CKM stage progression. Pooled logistic regression with natural cubic splines was used to assess nonlinear associations, with analyses stratified by baseline BMI or WHtR quartiles. Results: Increases in BMI and WHtR were consistently associated with higher risks of hypertension, dyslipidemia, hyperuricemia, and early CKM stage progression across baseline body size categories. For diabetes, increases in BMI and WHtR were associated with higher risk, whereas decreases were also associated with higher risk among leaner individuals. Associations with major adverse cardiovascular events were generally U‐shaped. BMI loss was associated with higher mortality odds, although estimates were imprecise and potentially affected by reverse causation. Conclusions: One‐year changes in BMI and WHtR were associated with subsequent cardiometabolic risk and CKM stage progression. Anthropometric changes, particularly weight loss, may serve as signals for further assessment rather than causal determinants of risk.

Aims: The long‐term cardiometabolic effects of alcohol reduction remain unclear. We evaluated the long‐term associations of sustained alcohol reduction with glycemic, blood pressure, and lipid profiles. Materials and Methods: We conducted a pooled sequential target trial emulation using annual health examination data from Japanese employees (2008–2023). Eligible participants were aged ≥ 40 years and consumed ≥ 20 g/day of ethanol at baseline. Participants subsequently reducing alcohol intake to < 20 g/day formed the intervention group; those maintaining ≥ 20 g/day formed the control group. We applied inverse probability weighting to estimate the per‐protocol effect of sustained alcohol reduction. We used weighted generalized estimating equations to estimate longitudinal trajectories of fasting plasma glucose (FPG), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, high‐density lipoprotein (HDL) cholesterol, and low‐density lipoprotein (LDL) cholesterol. Results: Among 266 699 eligible trial entries, 30 280 and 229 946 trial entries were included in the intervention and control groups, respectively. Alcohol reduction was associated with persistently lower FPG, SBP, DBP, and triglycerides over 15 years. At Year 15, between‐group differences were −1.8 mg/dL for FPG, −3.4 mmHg for SBP, −2.2 mmHg for DBP and −20.4 mg/dL for triglycerides (all p ≤ 0.005). Conversely, HDL cholesterol levels were consistently lower and LDL cholesterol levels modestly higher in the intervention group. Blood pressure‐lowering effects were consistent across genders, and findings were broadly consistent across sensitivity, subgroup, and dose‐transition analyses. Conclusions: Sustained alcohol reduction improved long‐term FPG, blood pressure, and triglycerides. These findings support alcohol reduction as a potentially beneficial lifestyle intervention for improving cardiometabolic profiles.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to dietary fat quality and polyunsaturated fatty-acid metabolism. We evaluated whether dietary n-6 fatty-acid intake, serum dihomo-γ-linolenic acid (DGLA), and desaturase-based indices for Δ5-desaturase (D5D) and Δ6-desaturase (D6D) are associated with MASLD. Methods: We conducted a cross-sectional analysis within the HOZUGAWA health checkup cohort in Japan (n = 289; 100 MASLD, 189 non-MASLD). Participants underwent hepatic ultrasonography, dietary assessment using the Brief Self-Administered Diet History Questionnaire, and fasting serum metabolomics by gas chromatography–mass spectrometry with solid-phase dehydration derivatization. Enzyme indices were defined as the D5D index = arachidonic acid/DGLA and the D6D proxy index = DGLA/linoleic acid (hereafter referred to as the D6D index) because γ-linolenic acid was not measured. Natural-log-transformed D5D index, D6D index, DGLA, and total dietary n-6 fatty-acid intake were entered into multivariable logistic regression models for MASLD adjusted for age, sex, BMI, alcohol intake, and total energy. Results: Compared with non-MASLD, MASLD showed higher serum DGLA, lower D5D index, and higher D6D index (all p ≤ 0.005), with no between-group differences in total energy intake, linoleic acid, total polyunsaturated fatty acids, or total dietary n-6 fatty-acid intake. Higher ln D5D was independently associated with lower odds of MASLD (OR 0.62, 95% CI 0.42–0.86), whereas higher ln D6D index (OR 1.42, 95% CI 1.04–1.95) and ln DGLA (OR 1.62, 95% CI 1.13–2.43) were each positively associated. Total dietary n-6 fatty-acid intake was not independently associated with MASLD. Conclusions: In this Japanese health examination cohort, an imbalance in estimated desaturase activities—lower D5D index and higher D6D index—together with higher serum DGLA was independently associated with MASLD, whereas n-6 intake showed no group difference or independent association. These findings suggest that enzyme-linked endogenous n-6 metabolic status may be more closely related to the MASLD phenotype than intake quantity alone.

Aims: Despite the reported success of low‐carbohydrate diets in improving glycemic control in the Western countries, no studies have investigated the effects of such diets in Asians. We aimed to conduct a systematic review and meta‐analysis of randomized controlled trials to examine the effects of low‐carbohydrate diets on glycemic control in East Asian adults.Materials and Methods: We systematically searched the PubMed, Cochrane Library, and Embase databases from inception to June 28, 2023, to identify randomized controlled trials examining the efficacy of low‐carbohydrate diets in patients with type 2 diabetes (PROSPERO number CRD 42023453007). The primary outcome was the difference in glycated hemoglobin levels between the low‐carbohydrate diet and control groups. The secondary outcome was the difference in body mass index, fasting blood glucose level, blood pressure, and lipid profile.Results: Six randomized controlled trials met the eligibility criteria. The study duration ranged from 3 to 18 months, with five studies conducted within 6 months. The results showed that low‐carbohydrate diets were more beneficial in lowering glycated hemoglobin levels and body mass index than control diets. The risk of bias for the six studies was minimal for two and moderate for four. The heterogeneity among the studies was low.Conclusions: Low‐carbohydrate diets improved glycated hemoglobin levels and body mass index in East Asians compared with control diets. Therefore, carbohydrate restriction may be effective for glycemic management in East Asians with type 2 diabetes for at least 6 months.

This study explores the impact of royal jelly (RJ) on small intestinal epigenomic changes. RJ, produced by honeybees, is known for its effects on metabolic diseases. The hypothesis is that RJ induces epigenomic modifications in small intestinal epithelial cells, affecting gene expression and contributing to metabolic health. Male db/m and db/db mice were used to examine RJ’s effects through mRNA sequencing and CUT&Tag methods. This study focused on histone modifications and gene expression changes, with statistical significance set at p < 0.05. RJ administration improved insulin sensitivity and lipid metabolism without affecting body weight. GO and KEGG pathway analyses showed significant enrichment in metabolic processes, cellular components, and molecular functions. RJ altered histone modifications, increasing H3K27me3 and decreasing H3K23Ac in genes associated with the G2M checkpoint. These genes, including Smc2, Mcm3, Ccnd1, Rasal2, Mcm6, and Mad2l1, are linked to cancer progression and metabolic regulation. RJ induces beneficial epigenomic changes in small intestinal epithelial cells, improving metabolic health and reducing cancer-associated gene expression. These findings highlight RJ’s potential as a therapeutic agent for metabolic disorders. Further research is needed to fully understand the mechanisms behind these effects and their implications for human health.

Aims/Introduction: Efficacy of long‐term low‐carbohydrate diets (LCD) to improve glycemic management for type 2 diabetes remains controversial. Thus, we investigated the association between long‐term LCD and glycemic control in individuals with type 2 diabetes.Materials and Methods: We searched PubMed, Embase and the Cochrane Database for articles published up to June 2023, and included randomized controlled trials conducted on LCD interventions for >12 months in adults with type 2 diabetes. Primary outcome was the difference in glycated hemoglobin between long‐term LCD and control groups. Additionally, we evaluated the differences in changes in systolic and diastolic blood pressure, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglyceride, and weight between long‐term LCD and control groups.Results: Six studies were identified and met the inclusion criteria. This study did not show significant differences in changes in glycated hemoglobin between long‐term LCD and control diets (standardized mean difference −0.11, 95% confidence interval −0.33 to 0.11, P = 0.32). As with glycemic control, there were no significant differences in the changes in weight loss, blood pressure, and low‐density lipoprotein cholesterol between long‐term LCD and control diets. However, long‐term LCD were associated with greater elevation in high‐density lipoprotein cholesterol (standardized mean difference 0.22, 95% confidence interval 0.04–0.41; P = 0.02) and decrease in triglyceride (standardized mean difference −0.19; 95% confidence interval −0.37 to 0.02; P = 0.03) than that in control diets.Conclusions: Our findings suggest efficacy of long‐term LCD in treating dyslipidemia in individuals with type 2 diabetes, but do not recommend long‐term LCD for glycemic control in the individuals.