Association between self-stigma and diabetic complications in Japanese people with type 2 diabetes: A cross-sectional study

To investigate the association between self-stigma evaluated using the Japanese version of the Self-Stigma Scale (SSS-J) and diabetic complications, such as diabetic retinopathy (DR) and diabetic kidney disease (DKD). Cross-sectional study. One university hospital and one clinic in Fukuoka, Japan. People (age ≥20 years) with type 2 diabetes receiving outpatient care, who were treated by diabetologists, and completed the SSS-J questionnaire (n=259). The primary outcome was the level of self-stigma assessed using the SSS-J. The presence of DR and DKD was evaluated as secondary outcomes. A positive correlation was found between self-stigma and glycated haemoglobin (HbA1c) levels (r=0.132, p=0.034). The mean SSS-J score was significantly higher in people with type 2 diabetes who had DR than in those without DR (p=0.006). There was no significant difference in the mean SSS-J scores of the patients with albuminuria (p=0.318) or a decreased kidney function (p=0.887). Additionally, the relative risk for the presence of DR, as assessed by quartiles of SSS-J scores and a logistic regression analysis, was significantly increased in the Q4 group with the highest SSS-J score after adjustment for sex, age and HbA1c (OR=3.91, 95% CI 1.49 to 10.3, p=0.006). The relative risk for the presence of albuminuria as a DKD significantly increased in the Q4 group immediately after adjustment for sex and age (OR=2.45, 95% CI 1.04 to 5.81, p=0.042). However, this association was attenuated and became non-significant after additional adjustment for HbA1c levels. In contrast, no significant association was observed between the SSS-J score quartiles and decreased kidney function. The presence of DR was more strongly associated with self-stigma than DKD. Although the causality between self-stigma and the presence of DR could not be elucidated due to the cross-sectional nature of the study, the present study suggests that addressing self-stigma may aid in glycaemic management and the prevention of DR, emphasising the need for healthcare providers to recognise self-stigma as a barrier to optimal diabetes care.


Comparison of polygenic risk scores for type 2 diabetes developed from different ancestry groups


Association between coffee and adiponectin according to the obesity status: A cross-sectional analysis of the Japan Multi-Institutional Collaborative Cohort Study in Tokushima, Japan

Coffee may contribute to the prevention of metabolic abnormalities in both obese and normal weight Japanese adults. Although evidence suggests a relationship between coffee and serum adiponectin, stratified analyses according to the obesity status have not yet been reported. This cross-sectional study examined the relationship between coffee intake and serum high molecular weight (HMW)-adiponectin, which is the most active form of adiponectin, according to the obesity status. The baseline data of 606 participants (aged 35-69 years) living in Tokushima prefecture in the Japan Multi-Institutional Collaborative Cohort Study were analyzed. Coffee intake was assessed using a questionnaire. Participants were stratified by the presence or absence of obesity (normal weight: BMI<25 kg/m2; obesity: BMI≥25 kg/m2). Multiple linear regression analyses adjusted for potential confounders were performed to examine the association between coffee intake and HMW-adiponectin or other diabetic factors. Coffee intake was associated with serum HMW-adiponectin in normal weight subjects (Coffee intake ≥3 cups/day, β for model 2 1.02, 95 % CI 0.30, 1.74), but not in obese subjects. Moreover, filtered/instant coffee intake was associated with serum HMW-adiponectin in normal weight subjects (Coffee intake ≥3 cups/day, β for model 2 0.93, 95 % CI 0.21, 1.65), but not in obese subjects. The present study suggests that coffee intake, particularly filtered/instant coffee, is associated with serum HMW-adiponectin in normal weight Japanese adults.

Nutrition, Metabolism, and Cardiovascular Diseases : NMCD


Smoking Behavior-related Genetic Variants and Lung Cancer Risk in Japanese: an Assessment by Mediation Analysis

Cigarette smoking is one of the most important risk factors for lung cancer. Genetic studies have shown that smoking behavior-related genetic variants are directly associated with lung cancer, independent of smoking behavior, mainly in European populations. A recent genome-wide association study in Japan identified five loci associated with the number of cigarettes smoked per day. This study aimed to evaluate whether these loci are associated with lung cancer risk directly or indirectly through changing smoking behavior. Here, we conducted a case-control study (1427 cases and 5595 controls) and a prospective cohort study (128 incident cases in 10 520 subjects). Using mediation analysis, we decomposed the total effect of the lead single nucleotide polymorphism (SNP) at each locus on lung cancer risk into direct and indirect effects. The results of the two studies were pooled using a random-effects model to estimate summary relative risks (RRs) and their 95% confidence intervals (CIs). Two studies showed that: (a) rs78277894 (EPHX2-CLU, G>A) had a protective direct effect (RR 0.84; 95% CI 0.77-0.93) on lung cancer risk; and (b) rs56129017 (CYP2A6, C>T) had carcinogenic direct and indirect effects on lung cancer risk (RR 1.26; 95% CI 1.15-1.39 and RR 1.01; 95% CI 1.00-1.01, respectively). This mediation analysis revealed that two smoking behavior-related SNPs, EPHX2-CLU rs78277894 and CYP2A6 rs56129017, were associated with lung cancer risk through pathways independent of changing smoking behavior. Our findings may contribute to our understanding of lung carcinogenesis pathways that cannot be addressed by changes in smoking behavior.


Dietary acid load and mortality: Results from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study


Dairy Intake and All-Cause, Cancer, and Cardiovascular Disease Mortality Risk in A Large Japanese Population: A 12-Year Follow-Up of the J-MICC Study

We examined the association between dairy intake and all-cause, cancer, and cardiovascular disease mortality in a cohort of the general population followed up for 12 years across Japan. We conducted a longitudinal cohort study of 79,715 participants from the Japan Multi-Institutional Collaborative Cohort study (57.2% women, mean age 54.7 years old). The amount of dairy (milk and yogurt) intake was determined using a validated short-food frequency questionnaire. The hazard ratio for mortality according to sex-specific tertile of dairy intake was calculated using Cox proportional hazards regression models with adjustment for potential confounding factors and dietary factors by sex. During the follow-up period (932,738 person-years), 3,723 participants died, including 2,088 cancer and 530 cardiovascular disease deaths. The highest tertile of total dairy intake (versus the lowest tertile) was associated with a 19% lower all-cause mortality risk (hazard ratio=0.81, 95% confidence interval: 0.70-0.92; P for trend=0.001) in women. Similarly, we observed inverse associations between milk intake and all-cause and cancer mortality risk in women, yogurt intake and cardiovascular disease risk in women, and yogurt intake and all-cause mortality risk in both sexes. A higher total dairy and milk intakes in women and yogurt intake in both sexes were associated with a reduced risk of all-cause mortality in the general population across Japan during the 12-year follow-up period.

Journal of Atherosclerosis and Thrombosis


The Significance of Comprehensive Metabolic Phenotypes in Cancer Risk: A Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.

The prospective cohort study in a large Japanese population suggested that metabolic phenotypes are important risk factors for total and some site-specific cancers in Japanese adults. Moreover, the risk of each site-specific cancer may differ according to metabolic phenotypes.


Coffee and Metabolic Phenotypes: A Cross-sectional Analysis of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

To date, the relationship between coffee consumption and metabolic phenotypes has hardly been investigated and remains controversial. Therefore, the aim of this cross-sectional study is to examine the associations between coffee consumption and metabolic phenotypes in a Japanese population. We analyzed the data of 26,363 subjects (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Coffee consumption was assessed using a questionnaire. Metabolic Syndrome (MetS) was defined according to the Joint Interim Statement Criteria of 2009, using body mass index (BMI) instead of waist circumference. Subjects stratified by the presence or absence of obesity (normal weight: BMI <25 kg/m; obesity: BMI ≥25 kg/m) were classified by the number of MetS components (metabolically healthy: no components; metabolically unhealthy: one or more components) other than BMI. In multiple logistic regression analyses adjusted for sex, age, and other potential confounders, high coffee consumption (≥3 cups/day) was associated with a lower prevalence of MetS and metabolically unhealthy phenotypes both in normal weight (OR 0.83, 95% CI 0.76-0.90) and obese subjects (OR 0.83, 95% CI 0.69-0.99). Filtered/instant coffee consumption was inversely associated with the prevalence of MetS and metabolically unhealthy phenotypes, whereas canned/bottled/packed coffee consumption was not. The present results suggest that high coffee consumption, particularly filtered/instant coffee, is inversely associated with the prevalence of metabolically unhealthy phenotypes in both normal weight and obese Japanese adults.


Molecular composition of adiponectin in urine is a useful biomarker for detecting early stage of diabetic kidney disease.

We previously developed two immune complex transfer enzyme immunoassays (ICT-EIA) to measure total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) in urine and have verified their usefulness as biomarkers for diabetic kidney disease. In this study, we developed T-AN and H-AN assays using the sandwich EIA (Sand-EIA). The reactivities of Sand-EIAs were compared with ICT-EIAs by measuring size exclusion chromatography (SEC) fractions of urine and adiponectin standard. As a result, ICT-EIAs showed higher macromolecular specificity. We then analyzed the molecular profile of adiponectin in the urine of 5 patients with different eGFR stages by measuring SEC fractions of urine. The results showed that smaller adiponectin correlated relatively well with eGFR stage. Finally, because SEC is time-consuming, we investigated that the ratio of T-ANs by Sand-EIA and ICT-EIA could be a good indicator of the monomer adiponectin. The ratio was evaluated using 77 urine samples from patients with diabetes and showed a significant decrease at an earlier stage compared with other biomarkers. In conclusion, we demonstrated a new index to estimate monomer adiponectin in urine by using Sand-EIA and ICT-EIA, and urinary monomer adiponectin can be a good early indicator of deterioration of renal function in diabetic patients. J. Med. Invest. 70 : 464-470, August, 2023.

The Journal of Medical Investigation : JMI


Associations of metabolic syndrome and metabolically unhealthy obesity with cancer mortality: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

The association between metabolic syndrome (MetS) and the risk of death from cancer is still a controversial issue. The purpose of this study was to examine the associations of MetS and metabolically unhealthy obesity (MUHO) with cancer mortality in a Japanese population. We used data from the Japan Multi-Institutional Collaborative Cohort Study. The study population consisted of 28,554 eligible subjects (14,103 men and 14,451 women) aged 35-69 years. MetS was diagnosed based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the Japan Society for the Study of Obesity (JASSO), using the body mass index instead of waist circumference. The Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to MetS and its components. Additionally, the associations of obesity and the metabolic health status with cancer mortality were examined. During an average 6.9-year follow-up, there were 192 deaths from cancer. The presence of MetS was significantly correlated with increased total cancer mortality when the JASSO criteria were used (HR = 1.51, 95% CI 1.04-2.21), but not when the NCEP-ATP III criteria were used (HR = 1.09, 95% CI 0.78-1.53). Metabolic risk factors, elevated fasting blood glucose, and MUHO were positively associated with cancer mortality (P <0.05). MetS diagnosed using the JASSO criteria and MUHO were associated with an increased risk of total cancer mortality in the Japanese population.


Novel method utilizing bisulfite conversion with dual amplification-refractory mutation system polymerase chain reaction to detect circulating pancreatic β-cell cfDNA.

We developed a novel method for detecting unmethylated insulin DNA in circulation that can be performed using a conventional real-time PCR system. This method would be useful for analyzing dynamic profiles of β-cells in human disease such as type 1 diabetes.


Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index.


Urinary adiponectin excretion is an early predictive marker of the decline of the renal function in patients with diabetes mellitus.

Since diabetes-associated kidney complication changes from diabetic nephropathy to diabetic kidney disease (DKD), more suitable biomarkers than urinary albumin are required. It has been hypothesized that urinary adiponectin (u-ADPN) is associated with the progression of DKD. We therefore evaluated the effectiveness of u-ADPN in predicting the decline of the renal function in patients with diabetes prior to end-stage renal disease. An ultrasensitive immune complex transfer enzyme immunoassay (ICT-EIA) was used to measure total and high molecular weight (HMW) adiponectin separately. We evaluated the relationships between the creatinine-adjusted urinary total-ADPN and HMW-ADPN, albumin (UACR) and liver-type fatty acid binding protein (L-FABP) at baseline and the 2-year change of the estimated glomerular filtration rate (ΔeGFR). This 2-year prospective observational study included 201 patients with diabetes. These patients were divided into three groups according to their ΔeGFR: ≤-10 mL/min/1.73m, >-10 and ≤0 mL/min/1.73m, and >0 mL/min/1.73m. Jonckheere-Terpstra test showed that lower ΔeGFR was associated with higher u-HMW-ADPN (p = 0.045). In logistic regression analysis, u-HMW-ADPN was associated with ΔeGFR after adjusted age, sex, and basal eGFR. Urinary HMW-ADPN could predict a declining renal function in patients with diabetes.

Journal of Diabetes and its Complications


Circulating FGF23 is not associated with cardiac dysfunction, atherosclerosis, infection or inflammation in hemodialysis patients.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone regulating serum inorganic phosphate (Pi) concentration. FGF23 is also involved in the development of chronic kidney disease (CKD)-mineral and bone disorder. Serum FGF23 concentration begins to increase early in the progression of CKD and can be remarkably high in hemodialysis patients with end-stage renal disease. It has been reported that high FGF23 concentration is a risk factor for cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. FGF23 was also shown to induce cardiac hypertrophy directly acting on cardiomyocytes. However, it is still controversial whether high FGF23 is causing cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. In the current study, we investigated whether FGF23 concentration is associated with cardiac dysfunction, atherosclerosis, infection or systemic inflammation in Japanese hemodialysis patients. We recruited 119 hemodialysis patients and examined the association between serum FGF23 concentration and several parameters concerning mineral metabolism, cardiac dysfunction, atherosclerosis, infection, and systemic inflammation. Serum FGF23 concentration was independently associated with serum calcium and Pi concentration (β = 0.276, p < 0.001; β = 0.689, p < 0.001). However, serum FGF23 concentration was not associated with parameters of cardiac dysfunction, atherosclerosis, infection, and systemic inflammation, either. Our results do not support the hypothesis that high FGF23 in dialysis patients is the cause of cardiac dysfunction, atherosclerosis, infection or systemic inflammation.


Development of fully automated and ultrasensitive assays for urinary adiponectin and their application as novel biomarkers for diabetic kidney disease.

Glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) are used to diagnose and classify the severity of chronic kidney disease. Total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) assays were developed using the fully automated immunoassay system, HI-1000 and their significance over conventional biomarkers were investigated. The T-AN and H-AN assays had high reproducibility, good linearity, and sufficient sensitivity to detect trace amounts of adiponectin in the urine. Urine samples after gel filtration were analyzed for the presence of different molecular isoforms. Low molecular weight (LMW) forms and monomers were the major components (93%) of adiponectin in the urine from a diabetic patient with normoalbuminuria. Urine from a microalbuminuria patient contained both high molecular weight (HMW) (11%) and middle molecular weight (MMW) (28%) adiponectin, although the LMW level was still high (52%). The amount of HMW (32%) and MMW (42%) were more abundant than that of LMW (24%) in a diabetic patient with macroalbuminuria. T-AN (r = - 0.43) and H-AN (r = - 0.38) levels showed higher correlation with estimated GFR (eGFR) than UAER (r = - 0.23). Urinary levels of both T-AN and H-AN negatively correlated with renal function in diabetic patients and they may serve as new biomarkers for diabetic kidney disease.


Circulating osteocalcin as a bone-derived hormone is inversely correlated with body fat in patients with type 1 diabetes.

The objective of the present study was to investigate the correlations between serum undercarboxylated osteocalcin (ucOC) or osteocalcin (OC) concentrations and %body fat, serum adiponectin and free-testosterone concentration, muscle strength and dose of exogenous insulin in patients with type 1 diabetes. We recruited 73 Japanese young adult patients with childhood-onset type 1 diabetes. All participants were receiving insulin replacement therapy. The correlations between logarithmic serum ucOC or OC concentrations and each parameter were examined. Serum ucOC and OC concentrations were inversely correlated with %body fat (r = -0.319, P = 0.007; r = -0.321, P = 0.006, respectively). Furthermore, multiple linear regression analyses were performed to determine whether or not serum ucOC or OC concentrations were factors associated with %body fat. Serum ucOC and OC concentrations remained significant factors even after adjusting for gender, HbA1c, body weight-adjusted total daily dose of insulin and duration of diabetes (β = -0.260, P = 0.027; β = -0.254, P = 0.031, respectively). However, serum ucOC and OC concentrations were not correlated with serum adiponectin or free-testosterone concentrations, muscle strength or dose of exogenous insulin. In conclusion, our study demonstrates the inverse correlation between serum ucOC or OC concentrations and body fat in patients with type 1 diabetes.


Association of accumulated advanced glycation end-products with a high prevalence of sarcopenia and dynapenia in patients with type 2 diabetes.

Advanced glycation end-products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so-called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. We recruited 166 patients with type 2 diabetes aged 30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m ; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes.


Nutrient-derived dietary patterns and their association with metabolic syndrome in a Japanese population

Nutrients have been proposed to be related to metabolic syndrome (MetS). The aims of this study were to identify dietary patterns that correlated with several nutrients using reduced rank regression (RRR) and to examine the association between extracted dietary patterns and prevalence of MetS in a Japanese population. The study population comprised 1,092 Japanese men and women (35-69 years old) who had participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study in Tokushima Prefecture. Dietary patterns were derived with RRR using 46 food items as predictors and six established nutrients (potassium, calcium, vitamin D, vitamin C, insoluble dietary fiber, and carotene) as response variables. Associations between extracted dietary patterns and MetS were then examined with logistic regression models. Among the six dietary patterns, dietary pattern 1 (DP1) explained the largest proportion (60.1%) of variance in the six nutrients. Therefore, only DP1 was selected for further analysis. DP1 was characterized by high intake frequency of vegetables, fruits, fish and small fish, natto (fermented soybeans), and deep-fried tofu. After adjustment for potential confounders, significant inverse associations were found between DP1 score and MetS (odds ratio [OR] for each quartile: 1.00, 0.58, 0.60, 0.52; P = 0.02); DP1 and high blood pressure (P = 0.0002); and DP1 and high blood glucose (P = 0.02). A dietary pattern characterized by high intake of vegetables, fruits, fish and small fish, natto, and deep-fried tofu was associated with reduced prevalence of MetS in a Japanese population.


Dietary calcium intake is associated with serum high-sensitivity C-reactive protein level in the general Japanese population

The beneficial effects of dietary calcium intake on high-sensitivity C-reactive protein levels, a risk factor of cardiovascular disease, have not been fully elucidated. This study investigated the associations between dietary calcium intake and serum high-sensitivity C-reactive protein levels in the general Japanese population. We analyzed the data of 2,019 subjects (1,194 men and 825 women) aged 35 to 69 years in a cross-sectional study of the Japan Multi-Institutional Collaborative Cohort Study. Nutrients intake including calcium were estimated using a validated food-frequency questionnaire. Analysis using a general linear model revealed that dietary calcium intake was inversely associated with serum high-sensitivity C-reactive protein levels ( for trend <0.001) after adjustment for age, sex, research group, leisure-time physical activity, smoking habit, drinking habit, dietary intakes (energy, dietary fiber, saturated fatty acids and vitamin D) and menopausal status. The association was slightly attenuated after additional adjustment for body mass index; however, remained significant ( for trend = 0.008). There were no significant interactions between dietary calcium intakes and sex, body mass index, or vitamin D intake for high-sensitivity C-reactive protein levels. This study have demonstrated that dietary calcium intake was inversely associated with serum high-sensitivity C-reactive protein levels in the general population.

Journal of Clinical Biochemistry and Nutrition


Systemic inflammation and family history in relation to the prevalence of type 2 diabetes based on an alternating decision tree

To investigate unknown patterns associated with type 2 diabetes in the Japanese population, we first used an alternating decision tree (ADTree) algorithm, a powerful classification algorithm from data mining, for the data from 1,102 subjects aged 35-69 years. On the basis of the investigated patterns, we then evaluated the associations of serum high-sensitivity C-reactive protein (hs-CRP) as a biomarker of systemic inflammation and family history of diabetes (negative, positive or unknown) with the prevalence of type 2 diabetes because their detailed associations have been scarcely reported. Elevated serum hs-CRP levels were proportionally associated with the increased prevalence of type 2 diabetes after adjusting for probable covariates, including body mass index and family history of diabetes (P for trend = 0.016). Stratified analyses revealed that elevated serum hs-CRP levels were proportionally associated with increased prevalence of diabetes in subjects without a family history of diabetes (P for trend = 0.020) but not in those with a family history or with an unknown family history of diabetes. Our study demonstrates that systemic inflammation was proportionally associated with increased prevalence of type 2 diabetes even after adjusting for body mass index, especially in subjects without a family history of diabetes.