Autonomic nervous system function assessed by heart rate variability and the presence of symptoms affecting activities of daily living in community-dwelling residents with chronic pain: The Hisayama Study.

BACKGROUND: Autonomic nervous system dysfunction has been reported to be associated with impaired activities of daily living (ADL) among patients with chronic pain, but the association has not been fully addressed in general populations. This study cross-sectionally investigated the association between autonomic nervous system function and the presence of subjective symptoms affecting ADL in community-dwelling residents with chronic pain. METHODS: A total of 888 residents with chronic pain, aged 40-79 years, who underwent a health examination in 2017-2018 were included. Based on heart rate variability measured by fingertip pulse wave, the standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR interval differences (RMSSD), low frequency (LF) power, and high frequency (HF) power were calculated. Symptoms affecting ADL were defined as those scoring ≥1 on the modified Rankin Scale. Odds ratios (ORs) and their 95% confidence intervals (CIs) for symptoms affecting ADL were estimated using a logistic regression analysis. RESULTS: The overall prevalence of symptoms affecting ADL was 39.4%. The ORs for symptoms affecting ADL increased significantly per 1-standard-deviation decrement in log-transformed SDNN (OR 1.23 [95% CI 1.06-1.44]), RMSSD (1.25 [1.08-1.45]), LF power (1.29 [1.11-1.52]), and HF power (1.29 [1.11-1.51]) after adjusting for age, sex, education, hypertension, diabetes, serum total cholesterol level, body mass index, past medical history, current smoking, current drinking, exercise, depressive symptoms, and pain intensity. CONCLUSIONS: Decreased heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. SIGNIFICANCE: Decrease in heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. This article could help scientists understand the significance of autonomic nervous system dysfunction in the pathology of chronic pain. Approaches that target autonomic nervous system dysfunction may be an option to relieve or prevent symptoms affecting ADL for chronic pain sufferers.

Serum Mac-2 Binding Protein Glycosylation Isomer Concentrations Are Associated With Incidence of Type 2 Diabetes.

CONTEXT: Serum Mac-2 binding protein glycosylation isomer (M2BPGi) concentrations are known to be an indicator of chronic liver injury and fibrosis. OBJECTIVE: This study aimed to investigate the association between serum M2BPGi concentrations and the development of type 2 diabetes in a Japanese community. METHODS: A total of 2143 community-dwelling Japanese individuals aged 40-79 years without diabetes at baseline were followed up for 7 years. Serum M2BPGi concentrations were divided into quintiles: Q1, ≤0.37 cutoff index (COI); Q2, 0.38-0.49 COI; Q3, 0.50-0.62 COI; Q4, 0.62-0.80 COI; and Q5, ≥0.81 COI. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs for the development of type 2 diabetes. RESULTS: During the follow-up period, 219 individuals developed type 2 diabetes. The age- and sex-adjusted cumulative incidence of type 2 diabetes significantly increased with elevating serum M2BPGi levels (P for trend < .01). This association remained significant after adjustment for potential confounders (P for trend = .04). This significant association attenuated to a nonsignificant level after additionally adjusting for serum high-sensitivity C-reactive protein or homeostasis model assessment of insulin resistance. CONCLUSION: The present study demonstrated that higher serum M2BPGi concentrations were significantly associated with higher risk of diabetes in a Japanese community. Moreover, inflammation and insulin resistance were suggested to contribute to the excess risk of diabetes in individuals with higher serum M2BPGi levels. These findings shed light on the importance of inflammation and insulin resistance when considering the pathogenesis of diabetes.

Secular trends in the prevalence, incidence, and progression of diabetic retinopathy: the Hisayama Study.

PURPOSE: To examine the secular trends in the prevalence, incidence, and progression rates of diabetic retinopathy (DR) in a Japanese community. METHODS: Community-dwelling Japanese residents aged ≥ 40 years with diabetes participated in comprehensive systemic and ophthalmological surveys, including an examination for DR, in 1998 (n = 220), 2007 (n = 511), 2012 (n = 515), and 2017 (n = 560). DR was assessed using colour fundus photographs after pupil dilation according to the modified Airlie House classification system. To compare the frequencies of newly developed or progressed DR between the studied decades, two eye cohorts were established (the 2000s cohort included 145 participants examined in 1998 and 2007; the 2010s cohort included 255 participants examined in 2007, 2012, and 2017). Trends in the prevalence, incidence, and progression rate of DR were tested by logistic regression analysis with a generalised estimating equation. RESULTS: The age-adjusted prevalence of DR among individuals with diabetes decreased significantly with time from 1998 to 2017 (27.4% in 1998, 22.8% in 2007, 12.8% in 2012, and 6.4% in 2017; p for trend < 0.001). During this period, the prevalence of DR was decreasing in every haemoglobin A1c category, but it remained constant in the high systolic blood pressure category. In addition, the rates of new-onset of DR were significantly lower in the 2010s compared to the 2000s (p < 0.001). CONCLUSION: Our findings suggest that the prevalence and incidence of DR among diabetic people significantly decreased with time over the past two decades in a general Japanese population.

Active commuting, commuting modes and the risk of diabetes: 14-year follow-up data from the Hisayama study.

AIMS/INTRODUCTION: We aimed to investigate the association of active commuting (cycling or walking to work), as well as the association of the individual commuting modes, with the risk of diabetes in a prospective cohort of community-dwelling adults in Japan. MATERIAL AND METHODS: A total of 1,270 residents aged 40-79 years were followed up for a median of 14 years. Active commuting was defined as either cycling or walking to work. A Cox proportional hazards model was used to examine the association of active commuting with the risk of diabetes. Associations for different forms of active commuting (cycling, walking and mixed modes of cycling or walking with non-active components) were also examined. RESULTS: During the follow-up period, 191 participants developed diabetes. Active commuting was associated with a lower risk of diabetes than non-active commuting after adjustment for potential confounders (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.31-0.92). With regard to the commuting modes, the risk of diabetes was significantly lower in individuals who commuted by cycling alone (HR 0.46, 95% CI 0.22-0.98), and tended to be lower in individuals who commuted by walking alone (HR 0.14, 95% CI 0.02-1.02) compared with that in individuals with non-active commuting. Meanwhile, no significant associations were observed for the mixed mode of walking and non-active commuting (HR 1.69, 95% CI 0.77-3.71). CONCLUSIONS: Active commuting, particularly that consisting exclusively of cycling or walking, was associated with a reduced risk of diabetes. Our findings support a public health policy that promotes the choice of active commuting for the prevention of diabetes.

Comparison of the contributions of impaired beta cell function and insulin resistance to the development of type 2 diabetes in a Japanese community: the Hisayama Study.

AIMS/HYPOTHESIS: Our aim was to compare the contributions of impaired beta cell function (IBF) and insulin resistance with the development of type 2 diabetes in a Japanese community. METHODS: A total of 2094 residents aged 40-79 years without diabetes underwent a health examination including a 75 g OGTT in 2007. Participants were divided into four groups according to the presence or absence of IBF (insulinogenic index/HOMA-IR ≤28.5) and insulin resistance (HOMA-IR ≥1.61) and were followed up for 7 years (2007-2014). Cox's proportional hazards model was used to estimate HRs and 95% CIs for type 2 diabetes. The population attributable fractions (PAFs) due to IBF, insulin resistance, and their combination were calculated. RESULTS: At baseline, the prevalence of isolated IBF, isolated insulin resistance, and both IBF and insulin resistance were 5.4%, 24.1% and 9.5%, respectively. During the follow-up period, 272 participants developed type 2 diabetes. The multivariable-adjusted HRs (95% CI) and PAFs (95% CI) for type 2 diabetes were 6.3 (4.3, 9.2) and 13.3% (8.7, 17.7) in the participants with isolated IBF, 1.9 (1.3, 2.7) and 10.5% (4.0, 16.6) in those with isolated insulin resistance, and 8.0 (5.7, 11.4) and 29.3% (23.0, 35.1) in those with both IBF and insulin resistance, respectively, compared with the participants without either. CONCLUSIONS/INTERPRETATION: The present study suggests that the combination of IBF and insulin resistance makes the main contribution to the development of type 2 diabetes in Japanese communities.

The Association of Small Dense Low-Density Lipoprotein Cholesterol and Coronary Heart Disease in Subjects at High Cardiovascular Risk.

AIM: The present study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in subjects at high cardiovascular risk. METHODS: A total of 3,080 participants without prior cardiovascular disease (CVD), aged ≥ 40 years, were followed up for a median of 8.3 years, which were divided into two groups, those with serum sdLDL cholesterol levels of ＜35 mg/dL or ≥ 35 mg/dL. Then, subjects were stratified by the status of diabetes, CVD-related comorbidities (defined as the presence of diabetes, chronic kidney disease, or peripheral artery disease), and the CVD risk assessment according to the Japan Atherosclerosis Society Guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using a Cox proportional hazards model. RESULTS: During the follow-up, 79 subjects developed CHD. The risk for incident CHD was higher in subjects with serum sdLDL cholesterol of ≥ 35 mg/dL than those with sdLDL cholesterol of ＜35 mg/dL (HR 2.09, 95%CI 1.26-3.45) after adjusting for traditional risk factors. In the subgroup analyses, the multivariable-adjusted HR for incident CHD increased significantly in those with serum sdLDL cholesterol of ≥ 35 mg/dL among subjects with diabetes (HR 2.76, 95%CI 1.09-7.01), subjects with CVD-related comorbidities (HR 2.60, 95%CI 1.21-5.58), and high-risk category defined as the presence of CVD-related comorbidities or a Suita score of ≥ 56 points (HR 1.93, 95%CI 1.02-3.65). CONCLUSIONS: Elevated serum sdLDL cholesterol was associated with the development of CHD even in subjects at high cardiovascular risk.

30-minute postload plasma glucose levels during an oral glucose tolerance test predict the risk of future type 2 diabetes: the Hisayama Study.

INTRODUCTION: To investigate the associations of 30 min postload plasma glucose (30 mPG) levels during an oral glucose tolerance test (OGTT) with the risk of future diabetes in a general Japanese population. RESEARCH DESIGN AND METHODS: A total of 2957 Japanese community-dwelling residents without diabetes, aged 40-79 years, participated in the examinations in 2007 and 2008 (participation rate, 77.1%). Among them, 2162 subjects who received 75 g OGTT in a fasting state with measurements of plasma glucose level at 0, 30, and 120 min were followed up for 7 years (2007-2014). Cox's proportional hazards model was used to estimate HRs and their 95% CIs of each index for the development of type 2 diabetes using continuous variables and quartiles with adjustment for traditional risk factors. The influence of 30 mPG on the predictive ability was estimated with Harrell's C-statistics, integrated discrimination improvement (IDI), and the continuous net reclassification index (cNRI). RESULTS: During follow-up, 275 subjects experienced type 2 diabetes. Elevated 30 mPG levels were significantly associated with increased risk of developing diabetes (p<0.01 for trend): the multivariable-adjusted HR was 8.41 (95% CI 4.97 to 14.24) for the highest versus the lowest quartile, and 2.26 (2.04 to 2.52) per 1 SD increase. This association was attenuated but remained significant after further adjustment for fasting and 2-hour postload plasma glucose levels. Incorporation of 30 mPG into the model including traditional risk factors with fasting and 2-hour postload plasma glucose levels for diabetes improved the predictive ability of type 2 diabetes (improvement in Harrell's C-statistics values: from 0.828 to 0.839, p<0.01; IDI: 0.016, p<0.01; cNRI: 0.103, p=0.37). CONCLUSIONS: Elevated 30 mPG levels were associated with increased risk of diabetes, and inclusion of 30 mPG levels significantly improved the predictive ability for future diabetes, suggesting that 30 mPG may be useful for identifying high-risk populations for type 2 diabetes.

Ratios of serum eicosapentaenoic acid to arachidonic acid and docosahexaenoic acid to arachidonic acid were inversely associated with serum resistin levels: The Hisayama Study.

AIMS/INTRODUCTION: Resistin is an adipocyte-derived polypeptide that leads to the progression of insulin resistance and subsequent atherosclerosis. Some studies have reported an association between self-reported intake of n-3 polyunsaturated fatty acids (PUFAs) and serum resistin levels. However, no studies have investigated the association between the ratio of serum levels of n-3 to serum n-6 PUFAs and the serum resistin concentration in the general population. MATERIALS AND METHODS: We carried out a cross-sectional study of 3,200 community-dwelling Japanese individuals aged ≥40 years in 2002-2003. The ratios of serum eicosapentaenoic acid or docosahexaenoic acid to arachidonic acid (AA) were categorized into quartiles. The associations of serum eicosapentaenoic acid/AA and docosahexaenoic acid/AA with the serum resistin concentration were assessed using linear regression models with adjustment for potential confounding factors. RESULTS: The geometric mean of serum resistin was 10.3 ng/mL. The age- and sex-adjusted geometric mean of serum resistin decreased significantly with increased levels of serum eicosapentaenoic acid/AA (quartile 1: 11.3 ng/mL; quartile 2: 10.6 ng/mL; quartile 3: 10.3 ng/mL; quartile 4: 9.3 ng/mL; P for trend <0.001). A similar association was observed for serum docosahexaenoic acid/AA (quartile 1: 11.1 ng/mL; quartile 2: 10.6 ng/mL; quartile 3: 10.1 ng/mL; quartile 4: 9.7 ng/mL; P for trend <0.001). An adjustment for potential confounding factors did not change these associations. CONCLUSIONS: Higher ratios of serum n-3 to n-6 PUFAs were associated with lower serum resistin levels. Consumption of a large amount of n-3 PUFAs might have desirable effects on resistin-mediated diseases.

Small Dense Low-Density Lipoprotein Cholesterol and the Risk of Coronary Heart Disease in a Japanese Community.

AIMS: This study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in a Japanese community. METHODS: A total of 3,080 participants without prior cardiovascular disease, aged 40 years or older, were followed up for 8 years. The participants were divided into the quartiles of serum sdLDL cholesterol levels. The risk estimates were computed using a Cox proportional hazards model. RESULTS: During the follow-up period, 79 subjects developed CHD. Subjects in the highest quartile had a 5.41- fold (95% confidence interval, 2.12-13.82) higher risk of CHD than those in the lowest quartile after controlling for confounders. In the analysis classifying the participants into four groups according to the levels of serum sdLDL cholesterol and serum low-density lipoprotein (LDL) cholesterol levels, the risk of CHD almost doubled in subjects with sdLDL cholesterol of ≥ 32.9 mg/dL (median), regardless of serum LDL cholesterol levels, as compared with subjects with serum sdLDL cholesterol of ＜32.9 mg/dL and serum LDL cholesterol of ＜120.1 mg/dL (median). When serum sdLDL cholesterol levels were incorporated into a model with known cardiovascular risk factors, c-statistics was significantly increased (from 0.77 to 0.79; p=0.02), and the net reclassification improvement was also significant (0.40; p＜0.001). CONCLUSIONS: The present findings suggest that the serum sdLDL cholesterol level is a relevant biomarker for the future development of CHD that offers benefit beyond the serum LDL cholesterol level and a possible therapeutic target to reduce the burden of CHD in a Japanese community.

Serum Ethylamine Levels as an Indicator of l-Theanine Consumption and the Risk of Type 2 Diabetes in a General Japanese Population: The Hisayama Study.

OBJECTIVE: This study investigated the association between serum ethylamine levels as an indicator of l-theanine consumption and the development of type 2 diabetes in a Japanese community. RESEARCH DESIGN AND METHODS: A total of 2,253 community-dwelling Japanese individuals aged 40-79 years without diabetes were monitored for 7 years. Serum ethylamine levels were divided into quartiles: ≤0.86, 0.87-2.10, 2.11-5.28, and ≥5.29 ng/mL. Kinetic analysis of serum ethylamine concentrations was performed after ingestion of l-theanine-rich green tea products containing 8 mg of l-theanine by 12 healthy volunteers. RESULTS: During follow-up, 282 subjects developed type 2 diabetes. The age- and sex-adjusted cumulative incidence of type 2 diabetes decreased significantly with elevating levels of serum ethylamine (P for trend = 0.04). This association remained unchanged after adjusting for potential confounding factors. The multivariable-adjusted hazard ratio (HR) for type 2 diabetes was significantly lower in the fourth quartile of serum ethylamine than in the first quartile (HR 0.69, 95% CI 0.49-0.98). This trend of decrease in diabetic risk across serum ethylamine levels was more prominent in middle-aged subjects and in subjects with prediabetes, obesity, or insulin resistance. Kinetic analysis estimated that the minimum concentration at the steady state was >5.90 ng/mL in the case of twice-daily ingestion with an interval of 12 h. CONCLUSIONS: Higher serum ethylamine was significantly associated with lower risk of the development of type 2 diabetes in a general Japanese population. The measurement of serum ethylamine concentration would be a useful biomarker for the objective estimation of l-theanine consumption.

Association Between Genetic Risk and Development of Type 2 Diabetes in a General Japanese Population: The Hisayama Study.

CONTEXT: Although recent genetic studies have identified many susceptibility loci associated with type 2 diabetes (T2D), the usefulness of such loci for precision medicine remains uncertain. OBJECTIVE: This study investigated the impact of genetic risk score (GRS) on the development of T2D in a general Japanese population. PARTICIPANTS: The current study consists of 1465 subjects aged 40 to 79 years without diabetes who underwent a health examination in 2002. DESIGN: The GRS was generated using the literature-based effect size for T2D of 84 susceptibility loci for the Japanese population, and the risk estimates of GRS on the incidence of T2D were computed by using a Cox proportional hazard model in a 10-year follow-up study. The influence of GRS on the predictive ability was estimated with Harrell C statistics, integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI). RESULTS: During the 10-year follow-up, 199 subjects experienced T2D. The risk of developing T2D increased significantly with elevating quintiles of GRS (multivariable-adjusted hazard ratio for the fifth vs first quintile, 2.85; 95% CI, 1.83 to 4.44). When incorporating GRS into the multivariable model comprising environmental risk factors, the Harrell C statistics (95% CI) increased from 0.681 (0.645 to 0.717) to 0.707 (0.672 to 0.742) and the predictive ability of T2D was significantly improved (IDI, 0.0376; 95% CI, 0.0284 to 0.0494; cNRI, 0.3565; 95% CI, 0.1278 to 0.5829). GRS was also associated with the risk of T2D independently of environmental risk factors. CONCLUSIONS: These findings suggest the usefulness of GRS for identifying a high-risk population together with environmental risk factors in the Japanese population.

Seasonal Variation in Severe Glucose-lowering Drug-induced Hypoglycemia in Patients with Type 2 Diabetes.

Objective Glucose-lowering drug-induced hypoglycemia is a serious complication and there have been a few reports of seasonal variations in hypoglycemia in patients with type 2 diabetes. The aim of the present study was to examine the association between severe drug-induced hypoglycemia and seasonal variations, and to elucidate the contributing factors. Methods This retrospective, single center clinical study, analyzed the cases of 125 patients who required emergency hospitalization for severe drug-induced hypoglycemia between January 1, 2001 and December 31, 2014. The period from November to April was defined as the cold season. Results Severe hypoglycemia occurred more often in the cold season than in the warm season. In the cold season, 62 of 9,981 (0.6%) emergency department visits involved patients who required hospitalization for drug-induced hypoglycemia. In contrast, in the warm season, 27 of 8,649 (0.3%) visits involved patients who required hospitalization for drug-induced hypoglycemia (p=0.002). The proportion of patients treated with sulfonylurea (SU) in the cold season was higher than that in the warm season. Even the use of low-dose SU caused hypoglycemia in the cold season. In the SU-treated group, the proportion of patients with white blood cell and/or C-reactive protein elevation was higher in the cold season than in the warm season (p=0.04). Conclusion Severe glucose-lowering drug-induced hypoglycemia occured more frequently in the cold season than in the warm season, and was associated with an inflammatory state in patients treated with SU.