Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1265/ehpm.23-00110

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AIMS: Several studies have revealed an association between moderate-to-vigorous physical activity (MVPA) and arterial stiffness, which is a known risk factor for cardiovascular disease. However, a few studies have considered the difference in the longitudinal effect of its intensity in a large general population. Therefore, we examined the effect of MVPA intensity on longitudinal changes in arterial stiffness. METHODS: We conducted a prospective cohort study involving 1,982 Japanese men and women. Arterial stiffness was measured using the cardio-ankle vascular index (CAVI) at baseline and 5-year follow-up. Physical activity was quantified using the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire and categorized into quartiles as MVPA levels. Linear mixed models were used to examine the differences at baseline and the rate of changes in CAVI associated with MVPA levels for over 5 years. RESULTS: The multivariable-adjusted mean differences in CAVI at baseline were significantly lower in the third (β=－0.019 [95% confidence interval {CI}=－0.033 to -0.005]) and fourth (β=－0.018 [95% CI=－0.035 to －0.001]) quartiles of the MVPA group compared with those in the lowest quartile of MVPA, and the significant effect persisted 5 years later. CONCLUSIONS: In summary, this study provides evidence to support the existence of a threshold for beneficial levels of MVPA in the prevention of arterial stiffness. Furthermore, this study suggests that exceeding this threshold may exert similar effects on arterial stiffness. These findings suggest that an optimal level of MVPA exists for preventing arterial stiffness, and exceeding this threshold may not engender additional benefits.

DOI： 10.5551/jat.64173

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OBJECTIVES: Few studies examined the association between deterioration of masticatory ability assessed by objective marker and physical function. Therefore, we examined the association between salivary flow rate which is one of the objective and surrogate marker of masticatory ability and lower Timed Up & Go (TUG) performance which is one of major measurement of physical function among aging Japanese. METHODS: This cross-sectional study enrolled 464 Japanese aged 60-84 years old. Participants chewed tasteless and odorless gum for 5 min, calculated stimulated salivary flow rate (g/min) during all chews. The 3 m TUG was conducted, and 75th percentile value (6.8 s for men and 7.0 s for women) or higher was defined as lower TUG performance. Logistic regression analysis was used to examine the association between stimulated salivary flow rate and lower TUG performance. RESULTS: We found that the stimulated salivary flow rate tended to be negatively associated with the TUG time. We also observed significant negative association between stimulated salivary flow rate and lower TUG performance; the multivariable-adjusted OR (95% confidence interval, CIs) of lower TUG performance for the highest quartile of stimulated salivary flow rate compared with the lowest quartile was 0.34 (0.16-0.69, P for trend = 0.02). Further adjusting for BMI, the association was attenuated but remaind significant; the OR (95% CIs) in highest quartile was 0.37 (0.18-0.76, P for trend = 0.04). CONCLUSIONS: Higher stimulated salivary flow, which means well masticatory ability, was inversely associated with lower TUG performance in the aging Japanese population.

DOI： 10.1016/j.afos.2023.08.001

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Resistin is mainly expressed in human monocytes/macrophages and is associated with insulin resistance, inflammation, and atherosclerosis. Serum resistin is strongly correlated with the G-A haplotype defined by single nucleotide polymorphisms (SNPs) c.-420 C>G (SNP-420) (rs1862513) and c.-358 G>A (SNP-358) (rs3219175) in the promoter region of the human resistin gene (RETN). Smoking is also associated with insulin resistance. We investigated the association between smoking and serum resistin and the effect of the G-A haplotype on this association. Participants were recruited under the Toon Genome Study (an observational epidemiology research in the Japanese population). Of these, 1975 subjects genotyped for both SNP-420 and SNP-358 were analyzed for serum resistin by grouping them based on smoking status and G-A haplotype status. RETN mRNA, isolated from whole blood cells, was evaluated in smokers (n = 7) and age-, sex-, and BMI-matched non-smokers (n = 7) with the G-A haplotype homozygotes. Serum resistin tended to be higher in current smokers who smoked more cigarettes per day (P for trend < 0.0001). The positive association between serum resistin and smoking was strongest in the G-A haplotype homozygotes, followed by heterozygotes and non-carriers (interaction P < 0.0001). This positive association was stronger in the G-A homozygotes than the C-G homozygotes (interaction P < 0.0001). RETN mRNA was 1.40-fold higher in smokers than non-smokers with the G-A homozygotes (P = 0.022). Therefore, the positive association between serum resistin and smoking was strongest in the G-A haplotype homozygotes defined by RETN SNP-420 and SNP-358.

DOI： 10.1038/s10038-023-01176-8

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

AIM/INTRODUCTION: Resistin, which induces insulin resistance, is mainly expressed in monocytes/macrophages in humans. We reported previously that serum resistin was highest in the G-A haplotype defined by resistin single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and - 358 (rs3219175). As sarcopenic obesity is associated with insulin resistance, we aimed to examine whether serum resistin and its haplotypes were associated with sarcopenic obesity at a latent stage. MATERIALS AND METHODS: We cross-sectionally analyzed 567 community-dwelling Japanese participants attending annual medical check-ups in which the sarcopenic obesity index was evaluated. The age- and gender-matched normal glucose tolerance subjects with G-A homozygotes and those with C-G homozygotes were examined via RNA-sequencing and pathway analysis (each n = 3), and RT-PCR (each n = 8). RESULTS: In multivariate logistic regression analyses, the fourth quartile (Q4) of serum resistin and G-A homozygotes were both associated with the latent sarcopenic obesity index defined by a visceral fat area of ≥ 100 cm2 and grip strength Q1 after adjustment for age and gender, with or without other confounding factors. RNA sequencing and pathway analysis showed that tumor necrosis factor (TNF) was involved in the top five pathways in the whole blood cells of G-A homozygotes compared with C-G homozygotes. RT-PCR revealed that TNF mRNA was higher in G-A homozygotes than in C-G homozygotes. CONCLUSIONS: The G-A haplotype was associated with the latent sarcopenic obesity index defined by grip strength in the Japanese cohort, could be mediated by TNF-α.

DOI： 10.1111/jdi.13998

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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BACKGROUND: Elevated resting heart rate (RHR) is a predictor of incident type 2 diabetes (T2D). Insulin resistance is thought to play a role in this association; however, the extent to which insulin resistance mediates this association is unclear. METHODS: 1309 Japanese individuals without diabetes were recruited during 2009-2012 and followed for 5 years, of whom 78 developed T2D, as diagnosed by the 75 g oral glucose tolerance test. Supine RHR was measured by electrocardiography. Using logistic regression analysis, we examined the association between RHR and incident T2D, and interaction with the homeostasis model assessment of insulin resistance (HOMA-IR) index. Causal mediation analysis was applied to decompose the effect of RHR on the outcome and estimate the proportion mediated by the HOMA-IR index. RESULTS: The sex- and age-adjusted cumulative incidence rate of T2D increased with increasing RHR. After adjustment for sex, age, waist circumference, current smoking status, alcohol use, habitual exercise, and cardiovascular disease medications, individuals with a RHR ≥80 bpm, compared with <60 bpm, showed an increased risk of incident T2D [odds ratio (OR), 2.89; 95 % confidence interval (CI), 1.07 to 7.80]. Multivariate adjusted OR for the total effect per 1 SD increase in RHR on incident T2D was 1.37 (95 % CI, 1.01 to 1.74) in the mediation analysis, and the proportion of the total indirect effect mediated by the HOMA-IR index was 27.5 % (95 % CI, 1.5 to 53.5). CONCLUSIONS: Approximately 30 % of the effect of RHR on incident T2D was explained by the indirect effect of insulin resistance.

DOI： 10.1016/j.jdiacomp.2022.108319

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Fish and omega-3 fatty acid consumption is known to be beneficial for cardiometabolic health. However, the related evidence for individuals with a relatively higher intake of fish or omega-3 unsaturated fatty acids, e.g., Japanese individuals, is scarce. Therefore, this study aimed to examine the association of fish and omega-3 fatty acid intakes with the carotid intima-media thickness (C-IMT) in the Japanese population. In total, 1803 Japanese men and women aged 30-84 years without a history of myocardial infarction or angina pectoris were included in the study. The fish and omega-3 fatty acid intakes were estimated using food frequency questionnaires. The C-IMT was measured using ultrasound imaging, and the participants were classified into three groups: normal, moderate (1.1 to 1.4 mm of maximum C-IMT), and severely increased C-IMT (≥1.5 mm). Multinomial logistic regression models were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI) of the presence of moderately and severely increased C-IMT. The omega-3 fatty acid intake was shown to be associated with lower odds of severely increased C-IMT. The multivariable-adjusted OR (95%CI) was 0.55 (0.31-0.97; p for trend = 0.04). We also found a borderline significant negative association between fish intake and the presence of severely increased C-IMT. In conclusion, omega-3 fatty acid intake might protect against the development of atherosclerosis in the Japanese population.

DOI： 10.3390/nu14173644

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Language：Japanese   Publisher：日本女性栄養・代謝学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：日本体質医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on β-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels. METHODS: Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on β-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose. RESULTS: The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR. CONCLUSIONS: The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00523-4.

DOI： 10.1007/s13340-021-00523-4

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Publishing type：Research paper (scientific journal)   Publisher：SERDI  

DOI： 10.14283/jpad.2022.51

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Language：English   Publishing type：Research paper (scientific journal)  

In the first case, a 60-year-old man who was using continuous subcutaneous insulin infusion (CSII), developed recurrent hypoglycemia due to insulin antibodies. This is the first report of such a case using CSII. In the second case, a 70-year-old man was follow-up case who developed hypoglycemia while using human insulin. In both cases, the hypoglycemia subsided after switching to multiple daily insulin injection and/or insulin preparation. The results of Scatchard analyses of the two cases were similar to those of cases of insulin autoimmune syndrome (IAS) that improved after recovery from hypoglycemia.The clinical characteristics and Scatchard analysis data were essentially the same as those for IAS, except for the presence of insulin administration.

DOI： 10.2169/internalmedicine.7647-21

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Language：Japanese   Publisher：日本体質医学会  

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This study evaluated the Timed Up & Go test (TUG) among healthy Japanese individuals without walking problems to clarify the relationship of TUG performance with physical characteristics and physical activity according to sex and age groups. In total, 797 men and women (30-84 years old) in Toon City, Ehime Prefecture, were assessed from 2016 to 2017. The survey data for physical characteristics, TUG performance, and physical activity measures were used. After adjusting for age according to TUG time and categorization into sex and age groups (30-64 and 65-84 years), the relationship of TUG performance with physical characteristics and physical activities was confirmed using multiple regression analysis. In men, TUG performance was associated with work and household chores in the 30-64-year age group, whereas it was only associated with skeletal muscle mass among those older than 65 years. In women, TUG performance was associated with height and amount of exercise, regardless of age. In conclusion, TUG performance may be maintained by increasing the amount of physical activity for men through work and housework, and increasing the amount of exercise for women, which may prevent the need for long-term care in the future.

DOI： 10.3390/healthcare9080933

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本臨床検査医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Autonomic activity is possibly influenced by physical activity (PA). However, it remains unclear whether this association is modified by insulin resistance. METHODS: This population-based study between 2009 and 2012 included 2016 men and women aged 30-79 years. The PA was assessed using a validated questionnaire based on sleep, occupation, transportation, household characteristics, and leisure-time PA. Heart rate (HR) and heart rate variability (HRV) in the sitting position were determined from 5-minute recordings of pulse waves detected by a fingertip sensor. The HRV was calculated as frequency (standard deviation of normal-to-normal [NN] intervals [SDNN]), root mean square of successive differences (RMSSD), and percentage differences between normal NN intervals >50 milliseconds [pNN50]) and time domains. Insulin resistance was evaluated using the homeostasis model assessment index (HOMA-IR). RESULTS: HR, RMSSD, and pNN50 were related to the total and moderate/vigorous PA tertiles in models that included HOMA-IR. The partial regression coefficient of total PA per 1-SD increase was .05 (P = .019) for log-transformed RMSSD and 1.86 (P = .001) for pNN50. No interactive associations were observed between PA and HOMA-IR. CONCLUSIONS: Low total PA was associated with increased HR and low levels of RMSSD and pNN50, reflecting parasympathetic modulation that was not modified by insulin resistance.

DOI： 10.1123/jpah.2020-0110

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

AIMS/INTRODUCTION: Low birthweight is reportedly associated with type 2 diabetes mellitus; however, this association has not been confirmed in the Japanese population, and whether high birthweight is associated with type 2 diabetes mellitus is controversial. We aimed to investigate the association between birthweight and type 2 diabetes mellitus among a general Japanese population. MATERIALS AND METHODS: Overall 1,135 middle- to old-aged Japanese men and women were enrolled in the Toon Health Study. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes mellitus, and a questionnaire survey about birthweight was administered. The association between birthweight and the prevalence of type 2 diabetes mellitus in later life of the participants was examined using multivariable logistic regression analysis. Stratified analysis by current body mass index was also carried out. RESULTS: The mean age was 56.5 ± 12.2 years. Type 2 diabetes mellitus was observed in 9.3% of the participants in this study. Compared with the reference group (2,500-3,999 g), the adjusted odds ratio of the low-birthweight group (<2,500 g) for type 2 diabetes mellitus was 2.46 (95% confidence interval 1.48-4.10). The association between the high-birthweight group (≥4000 g) and type 2 diabetes mellitus was not significant after including family history of diabetes in the multivariable model. The odds ratio of the low-birthweight group for type 2 diabetes mellitus was higher in the overweight/obese group than in the non-overweight group. CONCLUSIONS: Low birthweight was associated with an increased risk of type 2 diabetes mellitus in a Japanese population, especially in overweight/obese individuals.

DOI： 10.1111/jdi.13274

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/jdi.13129

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Language：Japanese   Publishing type：Research paper (scientific journal)  

AIM: The effects of alcohol consumption on Mild Cognitive Impairment (MCI) among the Japanese population had not been fully examined. Therefore, the objective of this study was to examine the association between alcohol consumption and MCI among the Japanese elderly population. METHODS: In total, 421 men and 700 women aged 60-84 years participated in this cross-sectional study. Alcohol consumption was estimated according to frequency and amount of major alcoholic beverages (i.e., beer, Japanese sake, shochu, and wine) consumed by each individual using a self-administered questionnaire. MCI was assessed using the Japanese version of the Montreal Cognitive Assessment. Multivariable odds ratio (OR) and 95% confidence intervals (CIs) of MCI according to alcohol consumption were calculated using logistic models. We further analyzed the associations of the major alcoholic beverages with MCI. RESULTS: The prevalence of MCI was 50.4% among the male participants and 31.4% among the females. A positive association between alcohol consumption and MCI was observed in men, but not in women. The multivariable OR (95% CI) of MCI for ≥ 2 go (46 g ethanol) /day vs. non-drinkers was 1.78 (0.93-3.40, p for trend = 0.045) in men and for ≥ 1 go (23 g ethanol) /day was 0.96 (0.39-2.38, p for trend = 0.92) in women, respectively. We also observed an association between shochu consumption and MCI in men, whereby the multivariable OR (95% CI) of MCI for each 1 go increment was 1.57 (1.18-2.07). CONCLUSION: Our findings suggest that alcohol consumption in moderation may contribute to the prevention of MCI development in men.

DOI： 10.3143/geriatrics.57.300

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Language：English   Publishing type：Research paper (scientific journal)  

AIM/INTRODUCTION: Insulin administration was found to trigger type 1 diabetes in six Japanese type 2 diabetes patients with type 1 diabetes high-risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype. The objective of the present study was to assess the contribution of non-human leukocyte antigen single-nucleotide polymorphisms (SNPs) to the risk of developing insulin-triggered type 1 diabetes. MATERIALS AND METHODS: We genotyped 13 type 1 diabetes susceptible SNPs in six patients and compared them with those in Japanese controls (Hap Map3-JPT). The SNPs that showed statistically significant results were further analyzed using non-diabetic control participants and participants with type 2 diabetes at the Ehime University Hospital. RESULTS: The risk allele frequency of BACH2 rs3757247 in the six patients was significantly more frequent than that in 86 Japanese controls (P = 0.038). No significant difference in the allele frequency was observed in the other SNPs. This result was confirmed by the findings that the risk allele frequency of BACH2 in the six patients was significantly higher than that in the non-diabetic control participants (n = 179) and type 2 diabetes with or without insulin treatment (n = 154 or n = 152; P = 0.035, 0.034 or 0.037, respectively). Despite being statistically not significant, the six patients were all homozygous for the CLEC16A rs12708716 risk allele and five were homozygous for the CLEC16A rs2903692 risk allele. CONCLUSIONS: In addition to type 1 diabetes high-risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype, the possibility that the risk variants of BACH2 and CLEC16A could contribute to the development of insulin-triggered type 1 diabetes cannot be excluded.

DOI： 10.1111/jdi.13057

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.diabres.2019.04.029

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.2169/internalmedicine.1360-18

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Objective: Resistin is secreted by monocytes/macrophages and is associated with insulin resistance, inflammation and cardiovascular diseases. In the Japanese cohort, serum resistin is tightly associated with a single-nucleotide polymorphism (SNP) at -420 (rs1862513) in the promoter region of the human resistin gene. However, interactions between SNP-420 and environmental factors remain to be elucidated. The aim of this study was to investigate the association between serum resistin levels and nutrient intake, and the effect of SNP-420 on this association. Design, Participants and Measurements: The Toon Genome Study is a cohort study of Japanese community-dwelling subjects. A total of 1981 participants were cross-sectionally analysed. Each nutrient intake was assessed using the semiquantitative food frequency questionnaire and categorized into the quartiles (Q1-Q4). Serum resistin was measured by ELISA. Results: Serum resistin tended to be inversely associated with fish intake and positively associated with meat intake after adjustment for age, sex, BMI and energy intake. Serum resistin was inversely associated with n-3 polyunsaturated fatty acids (PUFA) intake after adjustment for age, sex, BMI and energy intake (Q1 12.5, Q2 12.5, Q3 12.2, Q4 11.5 ng/mL
P for trend =.007). This inverse association was strongest in the G/G genotype of SNP-420, followed by C/G and C/C (G/G, Q1 18.9, Q2 19.5, Q3 18.4, Q4 14.5 ng/mL, P =.001
C/G, 14.4, 13.3, 13.1, 12.9, P =.015
C/C, 9.5, 9.5, 9.2, 8.8, P =.020
P for interaction =.004). Conclusions: The inverse association between serum resistin and n-3 PUFA intake was strongest in SNP-420 G/G genotype in the Japanese cohort.

DOI： 10.1111/cen.13500

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: Insulin resistance is strongly associated with metabolic syndrome (MetS), but it is not known how this association is influenced by the autonomic nervous system, which controls insulin secretion.
Methods and Results: The subjects were 2,016 individuals aged 30-79 years enrolled between 2009 and 2012. MetS was determined using the harmonized MetS definition, which includes waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2 h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. The 5-min heart rate variability (HRV) was evaluated using time-domain indices of standard deviations of NN intervals (SDNN) and root mean square of successive differences (RMSSD). Power spectral analysis yielded frequency-domain measures for HRV: high-frequency (HF) power, low-frequency (LF) power and LF/HF. Multivariable adjusted logistic models showed that the highest quartiles for SDNN, RMSSD, LF, and HF vs. the lowest quartiles had a significant association with MetS. RMSSD, HF, and LF/HF remained significantly associated with MetS after adjustment for HOMA-IR (or ISI). Additive interactions between the levels of high LF/HF and high HOMA-IR (or low ISI) were significantly positive.
Conclusions: Sympathovagal imbalance as evidenced by low HF and high LF/HF modified the association of insulin resistance or low insulin sensitivity with MetS.

DOI： 10.1253/circj.CJ-17-0192

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Language：Japanese  

症例は81歳、女性。平成14年(69歳)より高血圧症にて当院通院中、平成26年9月器質化肺炎で入院、ミノマイシンなどで効果なく、ステロイドパルス療法を施行。経過順調で外来にてステロイドを継続投。同年12月下旬血糖100mg/dL、HbA1c6.3%であったが平成27年1月中旬高血糖症状が急激に出現し1月末血糖432mg/dL、HbA1c8.9%、糖尿病ケトーシスで再入院した。入院時各種血清膵酵素軽度上昇、GAD抗体、IA2抗体、ZincT-8抗体、インスリン抗体は陰性。朝食前/食後2時間血中CPR0.25/0.56ng/mLとインスリン分泌の低下が見られ1型糖尿病と診断した。HLAはDRB1*04:05-DQB1*04:01。入院後ただちにインスリン強化療法を開始し血糖コントロール改善。退院後もステロイド及びインスリン強化療法を継続し同年10月、翌年9月のインスリン分泌低下は変わらず。結論:ステロイド使用時にまれではあるが1型糖尿病を発症する可能性もあり注意が必要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

Context: We previously reported that single nucleotide polymorphism (SNP)-420 C&gt;G (rs1862513) in the promoter region of RETN was associated with type 2 diabetes. Plasma resistin was tightly correlated with SNP-420 genotypes. SNP-420 is a CpG-SNP affecting the sequence of cytosine-phosphate-guanine dinucleotides.
Objective: To examine whether methylation at SNP-420 affects plasma resistin, we analyzed plasma resistin and methylation at RETN SNP-420.
Design and Methods: Genomic DNA was extracted from peripheral white blood cells in 2078 Japanese subjects. Quantification of the methylation was performed by pyrosequencing after DNA bisulfite conversion.
Results: Methylation at SNP-420 was highest in the C/C genotype (36.9 +/- 5.7%), followed by C/G (21.4 +/- 3.5%) and G/G (2.9 +/- 1.4%; P, 0.001). When assessed in each genotype, methylation at SNP-420was inverselyassociatedwithplasmaresistin in the C/C (beta = -0.134, P, 0.001) or C/G(beta = -0.227, P&lt;0.001) genotype. In THP-1 humanmonocytes intrinsically having the C/C genotype, a demethylating reagent, 5-aza-dC, decreased the methylation at SNP-420 and increased RETN messenger RNA. SNP+ 1263 (rs3745369), located in the 3' untranslated region of RETN, was also associated with methylation at SNP-420. In addition, highly sensitive C-reactive protein was inversely associated with methylation at SNP-420 in the C/C genotype, whereas body mass index was positively associated.
Conclusions: Plasma resistin was inversely associated with the extent of methylation at SNP-420 mainly dependent on the SNP-420 genotype. The association can also be explained partially independent of SNP-420 genotypes. SNP-420 could have dual, genetic and epigenetic effects on plasma resistin.

DOI： 10.1210/jc.2016-2417

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

We herein report the case of an 81-year-old woman who developed type 1 diabetes after the administration of glucocorticoid. In September 2015, she was admitted to our hospital due to organizing pneumonia. The patient was treated with steroid pulse therapy followed by the oral administration of glucocorticoid. After the improvement of the patient's pneumonia, she was treated with oral glucocorticoid in an outpatient clinic. While her blood glucose level remained within the normal range in December, she suddenly complained of hyperglycemic symptoms in the middle of January 2016. Then, at the end of January, she was readmitted to the hospital due to diabetic ketosis. Her blood glucose and HbA1c levels were 432 mg/dL, and 8.9 %, respectively. Her serum pancreatic enzyme levels were slightly elevated, and she was negative for both GAD and IA-2 antibodies. The multiple daily injection of insulin (MDI) improved her hyperglycemia, but her serum C- peptide levels before and after meals were low at 0.25, and 0.56 ng/mL, respectively. She was found to have a high-risk HLA haplotype of type 1 diabetes, DRB1∗04: 05-DQB1∗04: 01. After discharge from our hospital, she was treated with MDI and glucocorticoid. Her serum C-peptide levels remained low during 2015 and 2016. The above findings suggest that the administration of glucocorticoid may have triggered type 1 diabetes in this patient.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene (RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP -358 G&gt;A, followed by rs1423096 C&gt;T, SNP -420 C&gt;G, and rs10401670 C&gt;T (P = 5.39 x 10(-47), 1.81 x 10(-22), 2.09 x 10(-16), and 9.25 x 10(-15), respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.

DOI： 10.1152/physiolgenomics.00040.2016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aims/Introduction: Resistin, secreted from adipocytes, causes insulin resistance in mice. In humans, the resistin gene is mainly expressed in monocytes and macrophages. Tunicamycin is known to induce endoplasmic reticulum (ER) stress, and reduce resistin gene expression in 3T3-L1 mouse adipocytes. The aim of the present study was to examine whether ER stress affects resistin gene expression in human monocytes.
Materials and Methods: The relationship between resistin messenger ribonucleic acid (mRNA) and ER stress markers mRNA was analyzed by reverse transcription polymerase chain reaction in isolated monocytes of 30 healthy volunteers. The effect of endotoxin/lipopolysaccharides or tunicamycin on resistin gene expression was analyzed in THP-1 human monocytes. Signaling pathways leading to resistin mRNA were assessed by the knockdown using small interfering RNA or overexpression of key molecules involved in unfolded protein response.
Results: Resistin mRNA was positively associated with immunoglobulin heavy chain-binding protein (BiP) or CAAT/enhancer binding protein-alpha homologous protein (CHOP) mRNA in human isolated monocytes. In THP-1 cells, lipopolysaccharides increased mRNA of BiP, pancreatic endoplasmic reticulum eukaryotic initiation factor 2 alpha kinase (PERK) and CHOP, as well as resistin. Tunicamycin also increased resistin mRNA. This induction appeared to be dose-and time-dependent. Tunicamycin-induced resistin mRNA was inhibited by chemical chaperone, 4-phenylbutyric acid. The knockdown of either PERK, activating transcription factor 4 (ATF4) or CHOP reduced tunicamycin-induced resistin mRNA. Conversely, overexpression of ATF4 or CHOP increased resistin mRNA.
Conclusions: Endoplasmic reticulum stress induced by tunicamycin increased resistin mRNA through the PERK-ATF4-CHOP pathway in THP-1 human monocytes. ER stress could lead to insulin resistance through enhanced resistin gene expression in human monocytes.

DOI： 10.1111/jdi.12434

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Objective: Lower heart rate variability (HRV) is associated with the inflammation that is linked with the progression of atherosclerosis. We examined this association, taking insulin sensitivity into consideration, as it is related to both HRV and inflammation.
Methods: Subjects were 1728 individuals ages 30-79 years who did not smoke between 2009 and 2012. C-reactive protein (CRP) concentrations and white blood cell (WBC) counts were assessed as markers of inflammation. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. Pulse was recorded for 5 min, and time-domain HRV indices of standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) were calculated. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power and LF/HF.
Results: Sex and age-adjusted logistic models presented quartiles of SDNN, RMSSD, LF, and HF significantly associated with the highest quartile of CRP or WBC. After adjustment for body mass index and ISI, the associations were attenuated for WBC; however, even after further adjustment for several variables, SDNN, RMSSD, LF, and HF remained significantly associated with elevated CRP concentrations. When results were stratified by weight, the associations appeared more evident among non-overweight individuals.
Conclusion: Lowered HRV, primarily due to parasympathetic dysfunction, was associated with elevated inflammation, independent of weight, insulin sensitivity, and other related factors. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2015.10.112

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

Hypoglycemia can cause arrhythmia or cardiovascular diseases through the autonomic nervous system. We analyzed the alterations in ECG and autonomic nerve activities during nocturnal hypoglycemia in an insulin- dependent type 1 diabetic patient using Holter electrocardiography with continuous glucose monitoring (CGM). The patient was a 77-year-old man with slowly progressive type 1 diabetes for 30 years. The CGM analyses showed that nocturnal hypoglycemia continued for 4 hours without clinical symptoms. During this period, Holter electrocardiography showed a decrease in a parasympathetic nerve activity parameter (high frequency: HF), and an increase in a sympathetic nerve activity parameter (low frequency/high frequency: LF/HF) compared to the non-hypoglycemic period based on heart rate variability analyses using the Maximum Entropy Method. An increase in the number of ventricular premature beats and the prolongation of the corrected QT interval (QTc) were also detected. We successfully assessed the effect of nocturnal hypoglycemia on autonomic nerve activities using concomitant Holter electrocardiography and CGM in an insulin- Treated patient.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN EPIDEMIOLOGICAL ASSOC  

Background: Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited.
Methods: Between 2009-2012, the Toon Health Study recruited 1899 individuals aged 30-79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF: HF ratio.
Results: Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF: HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF: HF ratio with decreased ISI was also apparent in nonoverweight individuals. The interaction between LF: HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF: HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41-3.10).
Conclusions: Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals.

DOI： 10.2188/jea.JE20140254

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Language：English   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Context: Insulin administration causes various types of immune responses to insulin. We previously reported three cases of type 1 diabetes mellitus (T1DM) triggered by insulin administration in Japanese type 2 diabetes mellitus patients.
Objective: The objective of this study was to collect information and characterize insulin-triggered T1DM immunologically and genetically.
Methods: Data for six patients ( four men and two women) with insulin-triggered T1DM aged 59.5 +/- 12.8 years were collected. Serum or urinary C-peptides, islet-related autoantibodies, insulin antibody, human leukocyte antigen, or the insulin gene variable number of tandem repeat genotype were analyzed. Th1- or Th2-associated responses were evaluated using an Enzyme-Linked ImmunoSpot assay.
Results: None of the subjects had received insulin therapy or had an autoantibody to the 65-kDa isoform of glutamic acid decarboxylase before insulin administration. After insulin administration blood glucose control deteriorated acutely without any apparent cause, whereas C-peptide levels rapidly decreased to insulin-deficient levels. The mean duration of insulin administration to the development of T1DM was 7.7 +/- 6.1 months. Islet-related autoantibodies became positive, whereas insulin allergy or a high titer of insulin antibody was observed in several cases. All had T1DM high-risk human leukocyte antigen class II (IDDM1) and the insulin gene variable number of tandem repeats genotype (IDDM2). GAD-reactive and insulin peptide-reactive Th1 cells, but not Th2 cells, were identified in two of four cases.
Conclusions: The findings suggest that insulin administration may have triggered TIDM in patients with type 2 diabetes mellitus. IDDM1 and IDDM 2 as well as autoreactive T cells may contribute to the development of T1DM. Developing insulin-triggered T1DM if a patient's blood glucose control acutely deteriorates after insulin administration should be carefully considered.

DOI： 10.1210/jc.2014-1759

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Resistin is an adipokine secreted from adipocytes in mice. We previously reported that a single nucleotide polymorphism (SNP) -420 (rs1862513) in the human resistin gene (RETN), is correlated with plasma resistin. Decorin is a multifunctional proteoglycan, and its isoform, lacking 14 amino acids from the N terminal region of mature core decorin, recently was identified as a resistin receptor in mice. To examine whether SNPs in the vicinity of the human decorin gene (DCN) are associated with plasma resistin, we cross-sectionally analyzed six tag SNPs selected around DCN in the same linkage disequilibrium block in 2,078 communitydwelling Japanese subjects. Plasma resistin was associated with the rs7139228, rs7956537, rs516115, and rs3138167 genotypes in DCN. A multiple regression analysis revealed that the genotype of rs7308752 (G/G) or rs516115 (C/C) was associated with decreased plasma resistin after adjusted for age, sex, BMI, and the RETN SNP rs1862513. The effect of rs7139228 and rs1862513 seemed to be additive without synergistic interaction. Therefore, plasma resistin was associated with some tag SNPs around DCN in the general Japanese population. The possibility that human decorin is a human resistin receptor should be pursued. © 2013 by the American Diabetes Association.

DOI： 10.2337/db12-0058

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOS PRESS  

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population.
METHODS: This study included 1,978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging.
RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2 +/- 0.7, Q2: 2.0 +/- 0.7, Q3: 1.9 +/- 0.7, Q4: 1.8 +/- 0.6, p &lt; 0.001) and insulin resistance (1.0 +/- 0.6, 1.2 +/- 0.7, 1.3 +/- 0.8, 1.5 +/- 1.0, p &lt; 0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (beta = -0.074, p = 0.019) and insulin resistance (beta = 0.115, p &lt; 0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p = 0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r = -0.250, p &lt; 0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80-0.95), p = 0.001).
CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance.

DOI： 10.3233/CH-2012-1634

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

Aims: We investigated the effects of carbohydrate counting (CC) on glycemic control and the quality of life in Japanese patients with adult-onset type 1 diabetes as a pilot study.
Patients and methods: Seven patients with type 1 diabetes (3 males and 4 females) aged 62.0 ± 11.9 years were instructed in CC with subsequent insulin dose adjustments. We measured the HbA1c, glycated albumin, body mass index (BMI) and lipid profile, recorded daily energy intake and insulin dose, and administered the Diabetes Satisfaction Questionnaire (DTSQ) and the shortened version of the Diabetes Diet-Related Quality-of-Life (sDDRQOL) scale questionnaire at baseline, 3 or 6 months, and 12 months.
Results: Glycated albumin but not HbA1c was significantly reduced at 6 months (P = 0.021), and both HbA1c and glycated albumin were significantly reduced at 12 months (P = 0.004 and P = 0.003, respectively) compared with those at baseline. The total satisfaction score of the DTSQ and burden of diet therapy score of the sDDRQOL scale were significantly improved at 3 and 12 months compared with those at baseline (P = 0.047 and P = 0.034 in the former and P = 0.049 and P = 0.044 in the latter). BMI, lipid profile, daily energy intake and insulin dose at 12 months were not different compared with those at baseline.
Conclusions: This study suggests that CC may improve glycemic control as well as the quality of life without worsening lipid profiles or increasing the BMI in patients with type 1 diabetes.

DOI： 10.1007/s13340-013-0153-8

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Aims: Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of a single-nucleotide polymorphism (SNP)-420 (rs1862513) in the human resistin gene (RETN) resulted in an increase in circulating resistin and susceptibility to type 2 diabetes (T2D). Whereas PPARG Pro12Ala Pro/Pro and RETN SNP-420 G/G genotypes were synergistically associated with plasma resistin, no other trans-acting SNPs associated with circulating resistin have been reported. Methods: We cross-sectionally analyzed the association between plasma resistin and SNPs recently reported to be associated with T2D in 2,038 community-dwelling Japanese individuals. These SNPs are located around the TCF7L2, KCNJ11, IGF2BP2, CDKN2A/B, SLC30A8, CDKAL1, GCKR, HHEX, KCNQ1, WFS1, TCF2, TSPAN8, CDC123, ADAMTS9, THADA, JAZF1, PANK1, IRS1, HK1, and MTNR1B genes. The SNPs were analyzed by TaqMan assays, and plasma resistin was determined by ensyme-linked immunosorbent assay (ELISA). Results: Plasma resistin was significantly associated with rs7578597 in THADA [C/C 6. 81, C/T 8. 64 ± 5. 26, T/T 11. 54 ± 6. 54 ng/ml
P = 0. 0159, analysis of variance (ANOVA)]. Plasma resistin appeared to be higher in individuals with the THADA T/T and RETN SNP-420 G/G genotypes. A multiple regression analysis revealed that plasma resistin was also associated with THADA after adjustment for age, gender, body mass index, and SNP-420 (β = 1. 89, P = 0. 036). A nominal association between plasma resistin and rs4607103 in ADAMTS9 disappeared after multivariate adjustment. Conclusions: Circulating resistin was associated with rs7578597 in THADA in the general Japanese population. In addition to the cis-acting effect of SNP-420 in the RETN promoter, circulating resistin could be affected by other trans-acting SNPs. © 2011 The Japan Diabetes Society.

DOI： 10.1007/s13340-011-0039-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective Central aortic blood pressure (BP) has been postulated to correlate more closely with cardiovascular disease risk than brachial cuff BP. However, the effect of insulin sensitivity and resistance on central BP is not fully understood. Here, we evaluated the associations between insulin sensitivity/resistance and central BP using the oral glucose tolerance test.
Methods A total of 1034 Japanese participants were enrolled in this study. The absolute pressure of the late systolic peak (SBP2) of the brachial BP obtained by the radial waveform was considered to be the central systolic BP. Oral glucose tolerance test was performed by administering 75 g of glucose, and blood samples were obtained at 0, 60, 120 min after glucose loading.
Results Mean SBP2 was found to be lower than mean brachial systolic BP (SBP) (119 +/- 20, 126 +/- 19 mmHg, P &lt; 0.001), and differences between SBP and SBP2 were significantly larger in patients with reduced insulin sensitivity (-8.2 +/- 5.2, -7.2 +/- 5.3, -7.1 +/- 5.1, and -6.5 +/- 4.9 mmHg, in the first, second, third and fourth quartiles, respectively; P = 0.002) and increased insulin resistance (-6.6 +/- 5.1, -6.6 +/- 4.8, -7.3 +/- 4.8, -8.5 +/- 5.6 mmHg, P &lt; 0.001). Multiple linear regression analysis identified reduced insulin sensitivity (beta = 0.067, P = 0.033) and increased insulin resistance (beta = -0.081, P = 0.009) as independent determinants of the difference between SBP and SBP2.
Conclusion Given that both insulin sensitivity and insulin resistance were found to be significant determinants of the difference between SBP and SBP2 in a healthy general population, we suggest measuring the SBP2 in individuals with impaired insulin action in order to accurately assess their risk of developing cardiovascular disease. J Hypertens 29:1948-1954 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/HJH.0b013e32834abd06

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Methods. A total of 3192 community-dwelling subjects (1377 men, 1815 women), aged &gt;= 40 years and without renal failure, were divided into four groups according to quartiles of serum resistin concentrations: &lt; 7.1, 7.2-9.9, 10.0-14.7 and &gt;= 14.8 ng/mL. The associations of resistin levels with renal function status were examined cross-sectionally. The estimated glomerular filtration rate (eGFR) was calculated using the equation from the Modification of Diet in Renal Disease Study, and CKD was defined as an eGFR of &lt; 60 mL/min/1.73 m(2).
Results. The age- and sex-adjusted mean values of eGFR decreased significantly with elevating quartiles of resistin (P for trend &lt; 0.001). The age- and sex-adjusted odds ratios (ORs) for the presence of CKD increased progressively with higher quartiles of resistin. This trend remained robust even after controlling for age, sex, body mass index, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein (hs-CRP), triglycerides, high-density lipoprotein and total cholesterol, hypertension, current smoking, current drinking, and regular exercise [second quartile: OR 1.44, 95% confidence interval (CI) 1.05-1.99; third quartile: OR 2.15, 95% CI 1.58-2.92; fourth quartile: OR 2.32, 95% CI 1.71-3.16; P for trend &lt; 0.001]. In stratified analyses, high resistin level (&gt;= 7.2 ng/mL) was a significant relevant factor in CKD, independent of HOMA-IR or hs-CRP level.
Conclusion. Our findings suggest that elevated resistin level is significantly associated with the likelihood of CKD in the general Japanese population.

DOI： 10.1093/ndt/gfq155

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

It was recently reported that GCKR rs780094 was associated with fasting plasma glucose (FPG) and triglyceride (TG) levels in various ethnic populations (A allele for low FPG and high TG). An association between GCKR rs780094 and type 2 diabetes mellitus (T2DM) (A allele for low risk) has also been reported. We examined the association between GCKR rs780094 and T2DM in Japanese subjects by analyzing 488 cases and 398 controls. A meta-analysis was performed involving two previous association studies. We also analyzed the association between the single-nucleotide polymorphism and clinical parameters in the general Japanese population (n=1854). In the case-control study, the A allele of GCKR rs780094 was associated with a reduced risk of T2DM (odds ratio=0.711 (95% confidence interval=0.589-0.859), P=4.2 x 10(-4)). A meta-analysis confirmed the association of GCKR rs780094 with T2DM susceptibility. In the general Japanese population, subjects with the A/A genotype had lower levels of FPG, fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the G/G genotype. Conversely, subjects with the A/A genotype had higher levels of TG than those with the G/G genotype. We replicated GCKR rs780094 as a marker of T2DM susceptibility in Japanese subjects. This suggests that GCKR rs780094 is a common variant for T2DM susceptibility in various ethnic groups. Journal of Human Genetics (2010) 55, 600-604; doi:10.1038/jhg.2010.75; published online 24 June 2010

DOI： 10.1038/jhg.2010.75

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

DOI： 10.1007/s00125-010-1665-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at 2420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P, 10(-13) in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r(2) = 0.98), and were tightly correlated with SNP-420 (r(2) = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r(2) = 0.5224, P = 4.94610 2324; G at SNP-420, r(2) = 0.2616, P = 1.71610(-133)). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at 2358, generally had G at -420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P &lt; 0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at 2420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at 2358 may not exist, suggesting that SNP-358 could explain this ethnic difference.

DOI： 10.1371/journal.pone.0009718

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOC  

The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P=0.012). When studies I and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.51 1, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Resistin, secreted from adipocytes, causes insulin resistance in mice. The relationship between resistin and coronary artery disease is highly controversial, and the information regarding resistin and ischemic stroke is limited. In the present study, the association between serum resistin concentration and cardiovascular disease (CVD) was investigated in a general Japanese population.
Methods: A total of 3,201 community-dwelling individuals aged 40 years or older (1,382 men and 1,819 women) were divided into quintiles of serum resistin, and the association between resistin and CVD was examined cross-sectionally. The combined effect of either diabetes or hypertension and high serum resistin was also assessed. Serum resistin was measured using ELISA.
Results: Compared to those without CVD, age-and sex-adjusted mean serum resistin concentrations were greater in subjects with CVD (p = 0.002) or ischemic stroke (p &lt; 0.001), especially in those with lacunar and atherothrombotic infarction, but not elevated in subjects with hemorrhagic stroke or coronary heart disease. When analyzed by quintile of serum resistin concentration, the age-and sex-adjusted odds ratio (OR) for having CVD and ischemic stroke increased with quintile of serum resistin (p for trends, 0.02 for CVD, &lt; 0.001 for ischemic stroke), while such associations were not observed for hemorrhagic stroke or coronary heart disease. Compared to the first quintile, the age-and sex-adjusted OR of ischemic stroke was greater in the third (OR = 3.54; 95% confidence interval [CI], 1.17-10.67; p = 0.02), fourth (OR = 4.48; 95% CI, 1.53-13.09; p = 0.006), and fifth quintiles (OR = 4.70; 95% CI, 1.62-13.61; p = 0.004). These associations remained substantially unchanged even after adjustment for other confounding factors including high-sensitivity C-reactive protein. In the stratified analysis, the combination of high serum resistin and either diabetes or hypertension markedly increased the risk of ischemic stroke.
Conclusion: Elevated serum resistin concentration appears to be an independent risk factor for ischemic stroke, especially lacunar and atherothrombotic infarction in the general Japanese population. The combination of high resistin and the presence of either diabetes or hypertension increased the risk of ischemic stroke.

DOI： 10.1186/1475-2840-8-60

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Resistin, secreted from adipocytes, causes insulin resistance and diabetes in rodents. To determine the relation between serum resistin and diabetic microangiopathies in humans, we analyzed 238 Japanese T2DM subjects. Mean serum resistin was higher in subjects with either advanced retinopathy (preproliferative or proliferative) (P = 0.0130), advanced nephropathy (stage III or IV) (P = 0.0151), or neuropathy (P = 0.0013). Simple regression analysis showed that serum resistin was positively correlated with retinopathy stage (P = 0.0212), nephropathy stage (P = 0.0052), and neuropathy (P = 0.0013). Multiple regression analysis adjusted for age, gender, and BMI, revealed that serum resistin was correlated with retinopathy stage (P = 0.0144), nephropathy stage (P = 0.0111), and neuropathy (P = 0.0053). Serum resistin was positively correlated with the number of advanced microangiopathies, independent of age, gender, BMI, and either the duration of T2DM (P = 0.0318) or serum creatinine (P = 0.0092). Therefore, serum resistin was positively correlated with the severity of microangiopathies in T2DM. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.01.144

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

DOI： 10.2337/db18-1720-P

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DOI： 10.11213/tonyobyo.60.507

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Language：Japanese   Publisher：日本体質医学会  

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DOI： 10.11213/tonyobyo.59.475

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Other Link： http://search.jamas.or.jp/link/ui/2008273555

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