Publications by authors named "Toyoshi Inoguchi"

95 Publications

Bilirubin is inversely related to diabetic peripheral neuropathy assessed by sural nerve conduction study.

J Diabetes Investig 2021 May 5. Epub 2021 May 5.

Fukuoka City Health Promotion Support Center, Fukuoka, Japan.

Aims/introduction: Diagnosis of diabetic peripheral neuropathy (DPN) depends on subjective findings, certain investigations for DPN risks have not been performed enough. Bilirubin protects against vascular complications by reducing oxidative stress in diabetes, but is not fully tested for DPN. This study aimed to evaluate sural nerve conduction impairments (SNCI) as an objective DPN marker and the contribution of bilirubin to SNCI.

Materials And Methods: Using DPN-Check , SNCI was defined as a decline of amplitude potential or conduction velocity below the normal limit in 150 inpatients with diabetes. The correlations between SNCI and conventional DPN diagnosis criteria, the incidence of diabetic retinopathy/nephropathy, biomarkers for atherosclerosis, cardiac function by ultrasonic cardiogram, and bilirubin were statistically tested, followed by the comparison of logistic regression models for SNCI to find confounders with bilirubin.

Results: The incidence of SNCI was 72.0%. The sensitivity and specificity of SNCI for DPN prediagnosis by simplified criteria were 54.6 and 90.5%, respectively, and similarly corresponded with diabetic retinopathy and nephropathy (sensitivity 57.4 and 50.0%, respectively). SNCI significantly related to diabetes duration, declined estimated glomerular filtration rate, albuminuria and total bilirubin. SNCI incidence was attenuated in the higher bilirubin tertiles (89.8/65.3/54.8%, P < 0.001). Bilirubin was an independent inverse risk factor for SNCI, even after adjustment by known risk factors for DPN and markers for microvascular complications.

Conclusions: SNCI is a comprehensive marker for diabetic complications. We first showed the independent inverse relationship between bilirubin and SNCI through the independent pathway with other complications, provably reducing oxidative stress, as previously reported.
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http://dx.doi.org/10.1111/jdi.13568DOI Listing
May 2021

Relationship between serum bilirubin levels, urinary biopyrrin levels, and retinopathy in patients with diabetes.

PLoS One 2021 11;16(2):e0243407. Epub 2021 Feb 11.

Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka City, Japan.

Objective: Previous reports have indicated that serum bilirubin levels may be associated with diabetic retinopathy. However, the detailed mechanism is not fully understood. In this study, we evaluated the relationship between the severity of diabetic retinopathy and various factors including bilirubin levels and factors influencing bilirubin metabolism.

Methods: The study participants consisted of 94 consecutive patients with diabetes mellitus admitted to Kyushu University Hospital from April 2011 to July 2012. The patients were classified into three groups: no retinopathy (NDR), simple retinopathy (SDR), and pre-proliferative or proliferative retinopathy (PDR). The relationship between the severity of retinopathy and various factors was evaluated using univariate and logistic regression analyses. In addition, multivariate regression analysis was performed to evaluate the significant determinants for bilirubin levels.

Results: In univariate analysis, a significant difference was found among NDR, SDR and PDR in bilirubin levels, duration of diabetes, systolic blood pressure, and macroalbuminuria. Logistic regression analysis showed that PDR was significantly associated with bilirubin levels, duration of diabetes, and systolic blood pressure (OR 0.737, 95% CI 0.570-0.952, P = 0.012; OR 1.085, 95% CI 1.024-1.149, P = 0.006; OR 1.036, 95% CI 1.011-1.062, P = 0.005, respectively). In turn, multivariate regression analysis showed that bilirubin levels were negatively associated with high-sensitivity C-reactive protein levels and PDR, but positively correlated with urinary biopyrrin levels, oxidized metabolites of bilirubin.

Conclusion: PDR was negatively associated with bilirubin levels. This negative association may be due to a decreased production of bilirubin rather than its increased consumption considering the positive association between bilirubin and biopyrrin levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243407PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877782PMC
February 2021

Low dose of sodium-glucose transporter 2 inhibitor ipragliflozin attenuated renal dysfunction and interstitial fibrosis in adenine-induced chronic kidney disease in mice without diabetes.

Metabol Open 2020 Sep 8;7:100049. Epub 2020 Aug 8.

Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitor, a new class of glucose lowering agents, has been shown to be reno-protective in diabetes.

Objective: We aimed to explore whether SGLT2 inhibitor ipragliflozin has a direct reno-protective effect on non-diabetic chronic kidney disease (CKD) in mice.

Methods: CKD mice was induced by feeding of 0.25% w/w adenine containing diet. Low dose ipragliflozin (0.03 or 0.1 mg/kg/day) was orally administered to CKD mice for 4 weeks, concomitantly with adenine containing diet.

Results: CKD mice exhibited increases in kidney weight/body weight ratio, plasma creatinine levels, urinary fatty acid binding protein 1 excretion and plasma interleukin-6 levels, and a decrease in hematocrit, accompanied by morphological changes such as crystal deposits in the tubules, tubular dilatation, interstitial fibrosis, and increased 8-hydroxy-2'-deoxyguanosine staining. Low dose ipragliflozin (0.03 or 0.1 mg/kg/day) did not affect either plasma glucose levels or urinary glucose excretion, while it improved levels in plasma creatinine (P < 0.05 for 0.03 mg/kg/day, P < 0.001 for 0.1 mg/kg/day), interleukin-6 (P < 0.05 for 0.1 mg/kg/day) and hematocrit (P < 0.05 for 0.1 mg/kg/day), and morphological changes dose-dependently except crystal deposit formation in the CKD mice.

Conclusions: Low-dose ipragliflozin has a reno-protective effect in non-diabetic adenine-induced CKD mice, independently of plasma glucose levels and urinary glucose excretion. Low dose SGLT2 inhibitor may be a useful therapeutic option for non-diabetic CKD with the advantage of fewer adverse effects.
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http://dx.doi.org/10.1016/j.metop.2020.100049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520892PMC
September 2020

Aberrant activation of bone marrow Ly6C high monocytes in diabetic mice contributes to impaired glucose tolerance.

PLoS One 2020 25;15(2):e0229401. Epub 2020 Feb 25.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Accumulating evidence indicates that diabetes and obesity are associated with chronic low-grade inflammation and multiple organ failure. Tissue-infiltrated inflammatory M1 macrophages are aberrantly activated in these conditions and contribute to hyperglycemia and insulin resistance. However, it is unclear at which stage these cells become aberrantly activated: as precursor monocytes in the bone marrow or as differentiated macrophages in tissues. We examined the abundance, activation state, and function of bone marrow-derived Ly6Chigh monocytes in mice with diabetes and/or obesity. Ly6Chigh monocytes were FACS-purified from six groups of male mice consisting of type 2 diabetes model db/db mice, streptozotocin (STZ) induced insulin depletion mice, high fat diet (HFD) induced obesity mice and each control mice. Ly6Chigh monocytes were then analyzed for the expression of inflammation markers by qRT-PCR. In addition, bone marrow-derived Ly6Chigh monocytes from db/+ and db/db mice were fluorescently labeled and injected into groups of db/db recipient mice. Cell trafficking to tissues and levels of markers were examined in the recipient mice. The expression of many inflammation-related genes was significantly increased in Ly6Chigh monocytes from db/db mice, compared with the control. Bone marrow-derived Ly6Chigh monocytes isolated from db/db mice, but not from db/+ mice, displayed prominent infiltration into peripheral tissues at 1 week after transfer into db/db mice. The recipients of db/db Ly6Chigh monocytes also exhibited significantly increased serum glucose levels and worsening tolerance compared with mice receiving db/+ Ly6Chigh monocytes. These novel observations suggest that activated Ly6Chigh monocytes may contribute to the glucose intolerance observed in diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229401PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041861PMC
May 2020

The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation.

PLoS One 2020 7;15(2):e0228750. Epub 2020 Feb 7.

Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.

Objective: Accumulating epidemiological studies have demonstrated that diabetes is an important risk factor for dementia. However, the underlying pathological and molecular mechanisms, and effective treatment, have not been fully elucidated. Herein, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, on diabetes-related cognitive impairment.

Method: Streptozotocin (STZ)-induced diabetic mice were treated with linagliptin (3 mg/kg/24 h) for 17 weeks. The radial arm water maze test was performed, followed by evaluation of oxidative stress using DNP-MRI and the expression of NAD(P)H oxidase components and proinflammatory cytokines and of microglial activity.

Results: Administration of linagliptin did not affect the plasma glucose and body weight of diabetic mice; however, it improved cognitive impairment. Additionally, linagliptin reduced oxidative stress and the mRNA expression of NAD(P)H oxidase component and TNF-α, and the number and body area of microglia, all of which were significantly increased in diabetic mice.

Conclusions: Linagliptin may have a beneficial effect on diabetes-related dementia by inhibiting oxidative stress and microglial activation, independently of glucose-lowering.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006898PMC
May 2020

Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for diabetic complications and disability in activities of daily living in elderly patients with diabetes.

Metabolism 2020 02 29;103:153995. Epub 2019 Oct 29.

Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan. Electronic address:

Background: Oxidative stress may play an important role in the development of diabetic complications. The ratio of human nonmercaptalbumin (HNA; oxidized form) to human mercaptalbumin (HMA; reduced form) has attracted attention as an indicator for systemic redox states. In this study, we measured the ratio in elderly patients with diabetes and evaluated its association with diabetic complications and disability in activities of daily living (ADL disability).

Methods: One hundred twenty-six elderly patients with diabetes, aged 70 years and older, under medical care at Yukuhashi Central Hospital from April 2018 to June 2018, were continuously recruited. HNA%, defined as HNA / (HNA + HMA) × 100, was measured by a high-performance liquid chromatography method. First, multivariate regression analysis was performed to evaluate which variables were significant determinants for HNA%. Next, to evaluate the association of HNA% with ADL disability, logistic regression analysis in various models was performed. Then we plotted the receiver operating characteristic (ROC) curve and calculated the under area the curve (AUC), sensitivity, and specificity in each model.

Results: In elderly patients with diabetes, multiple regression analysis showed that serum bilirubin levels and albumin levels, both of which are major endogenous anti-oxidants, and chronic renal failure (or proliferative nephropathy) were significantly associated with HNA%, suggesting that HNA% may be a good biomarker for oxidative stress in those patients. We then evaluated the association of HNA% with ADL disability in various logistic regression models. Model using only HNA% showed that it was a significant determinant for ADL disability (OR 1.158, 95% CI 1.077-1.244, P < 0.001). Model using HNA% and age showed that both variables were significant determinants for ADL disability (OR 1.160, 95% CI 1.069-1.258, P < 0.001; OR 1.258, 95% CI 1.110-1.427, P < 0.001, respectively). ROC analysis showed that the AUC of HNA% alone was 0.765. The AUC of model using HNA% and age was further increased to 0.866.

Conclusions: HNA% was significantly associated with diabetic complications and ADL disability, thereby may be clinically useful as an oxidative stress marker in elderly patients with diabetes.
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http://dx.doi.org/10.1016/j.metabol.2019.153995DOI Listing
February 2020

Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines.

PLoS One 2019 2;14(10):e0223302. Epub 2019 Oct 2.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model.

Method: Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues.

Results: In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice.

Conclusions: Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774504PMC
March 2020

Dynamic nuclear polarization magnetic resonance imaging and the oxygen-sensitive paramagnetic agent OX63 provide a noninvasive quantitative evaluation of kidney hypoxia in diabetic mice.

Kidney Int 2019 09 24;96(3):787-792. Epub 2019 May 24.

Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan; Fukuoka City Health Promotion Support Center, Fukuoka City, Japan. Electronic address:

Renal hypoxia may play an important role in the progression of diabetic nephropathy. However, tools that noninvasively and quantitatively measure oxygen tension in the kidney are lacking. Here, we evaluated the feasibility of a noninvasive and quantitative imaging technique using dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) in combination with the oxygen-sensitive paramagnetic agent OX63 for measuring oxygen tension in the kidney. Our results demonstrate that the DNP-MRI technique can yield quantitative maps of oxygen tension in the mouse renal cortex. Using this procedure, we also showed that oxygen tension was less elevated in the renal cortex of both streptozotocin-induced type 1 diabetic mice and db/db mice, a model of type 2 diabetes, than in the renal cortex of age-matched control mice of each respective model. Oxygen tension in streptozotocin-exposed mice was significantly improved by insulin treatment. Thus, the noninvasive and quantitative DNP-MRI technique appears to be useful for studying the pathophysiological role of hypoxia.
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http://dx.doi.org/10.1016/j.kint.2019.04.034DOI Listing
September 2019

Poorly controlled diabetes during pregnancy and lactation activates the Foxo1 pathway and causes glucose intolerance in adult offspring.

Sci Rep 2019 07 15;9(1):10181. Epub 2019 Jul 15.

Division of Epigenomics and Development, Department of Molecular and Structural Biology Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

Exposure to maternal diabetes during pregnancy results in diabetes in offspring, but its underlying mechanisms are unclear. Here, we investigated the phenotype and molecular defects of the offspring of poorly controlled diabetic female mice generated by streptozotocin (STZ) administration. Offspring was exposed to maternal diabetes during pregnancy and lactation. The body weight of STZ offspring was lower than that of control offspring at birth and in adulthood, and glucose tolerance was impaired in adult STZ offspring. Interestingly, the phenotype was more pronounced in male offspring. We next investigated the morphology of islets and expression of β cell-related genes, but no significant changes were observed. However, transcriptome analysis of the liver revealed activation of the fork head box protein O1 (Foxo1) pathway in STZ male offspring. Notably, two key gluconeogenesis enzyme genes, glucose 6 phosphatase catalytic subunit (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1), were upregulated. Consistent with this finding, phosphorylation of Foxo1 was decreased in the liver of STZ male offspring. These changes were not obvious in female offspring. The activation of Foxo1 and gluconeogenesis in the liver may have contributed to the impaired glucose tolerance of STZ male offspring.
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http://dx.doi.org/10.1038/s41598-019-46638-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629688PMC
July 2019

Serum bilirubin level is a strong predictor for disability in activities in daily living (ADL) in Japanese elderly patients with diabetes.

Sci Rep 2019 05 8;9(1):7069. Epub 2019 May 8.

Yukuhashi Central Hospital, Yukuhashi, Japan.

Elderly patients with diabetes are at increased risk of frailty and disability in activities of daily living (ADL). Recent evidence has shown that oxidative stress is associated with these conditions. In this cross-sectional study, we aimed to assess whether serum level of bilirubin, a strong endogenous antioxidant, can predict ADL disability in elderly patients with diabetes. Forty elderly patients aged 70 years and older with diabetes and ADL disability and 158 elderly patients with diabetes and without ADL disability were continuously recruited. Multivariate logistic regression models showed that serum bilirubin level was a significant predictor for ADL disability. Receiver operating characteristic analysis showed that the area under the curve (AUC) of serum bilirubin level alone for ADL disability was 0.887 (95% CI 0.837-0.936, P < 0.001) and the cut-off value was 0.4 mg/dL (sensitivity = 88.0% and specificity = 65.0%). The predictive ability was further increased by the addition of age (AUC = 0.921) or addition of age, body mass index, red blood cell count, cerebrovascular disease and chronic renal failure (AUC = 0.953). In conclusion, low serum bilirubin level is a strong predictive biomarker for ADL disability in elderly patients with diabetes, and its clinical utility is suggested.
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http://dx.doi.org/10.1038/s41598-019-43543-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506601PMC
May 2019

Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells.

Sci Rep 2019 03 18;9(1):4703. Epub 2019 Mar 18.

Fukuoka City Health Promotion Support Center, Fukuoka, Japan.

Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.
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http://dx.doi.org/10.1038/s41598-019-41253-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423112PMC
March 2019

Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52-week data from the PROVIDE study.

Diabetes Obes Metab 2019 07 1;21(7):1737-1744. Epub 2019 Apr 1.

Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan.

The aim of this study was to evaluate the efficacy and safety of pemafibrate in people with type 2 diabetes and hypertriglyceridaemia over a 52-week period. Participants were randomly assigned to receive treatment with placebo or pemafibrate at a dose of 0.2 or 0.4 mg/d for 24 weeks (treatment period 1). The main results from treatment period 1 have been reported previously. The assigned treatment was continued up to week 52, except that the placebo was changed to pemafibrate 0.2 mg/d after week 24 (treatment period 2). The percentage changes in fasting serum triglyceride (TG) levels at week 52 (last observation carried forward) were -48.2%, -42.3%, and -46.4% in the placebo/pemafibrate 0.2 mg/d (n = 57), pemafibrate 0.2 mg/d (n = 54), and pemafibrate 0.4 mg/d (n = 55) groups, respectively. Levels of TG, non-HDL cholesterol and total cholesterol stably decreased, whereas levels of HDL cholesterol increased with pemafibrate treatments over 52 weeks. Pemafibrate was well tolerated throughout the study period. The present study is the first to show that pemafibrate treatment substantially ameliorated lipid abnormalities and was well tolerated for 52 weeks in people with type 2 diabetes and hypertriglyceridaemia.
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http://dx.doi.org/10.1111/dom.13686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617746PMC
July 2019

Ankle-brachial index measured by oscillometry is predictive for cardiovascular disease and premature death in the Japanese population: An individual participant data meta-analysis.

Atherosclerosis 2018 08 31;275:141-148. Epub 2018 May 31.

Department of Cardiology, Tokyo Medical University, Tokyo, Japan.

Background And Aims: The ankle-brachial index (ABI) is a predictor of cardiovascular disease (CVD) and premature death. However, few studies on this marker are available in the general Asian populations. This study aimed to investigate the association between ABI measured with oscillometry and the risk of these outcomes.

Methods: We conducted an individual participant data meta-analysis in 10,679 community-dwelling Japanese individuals without a history of CVD. The primary outcome was a composite of CVD events and all-cause mortality.

Results: During an average of 7.8 years of follow-up, 720 participants experienced the primary outcome. The multivariable-adjusted hazard ratios (HRs) of the primary outcome significantly increased with a lower ABI. The HRs were 1.07 (95% confidence interval [CI] 0.91-1.27) for ABI of 1.00-1.09, HR 1.37 (95% CI 1.04-1.81) for ABI of 0.91-0.99, and HR 1.60 (95% CI 1.06-2.41) for ABI of ≤0.90, compared with ABI of 1.10-1.19. Furthermore, a high ABI (≥1.30) was associated with a greater risk of outcome (HR 2.42 [95% CI 1.14-5.13]). Similar tendencies were observed for CVD events alone and all-cause mortality alone. Addition of ABI to a model with the Framingham risk score marginally improved the c-statistics (p = 0.08) and integrated discrimination improvement (p < 0.05) for the primary outcome.

Conclusions: The present study suggests that lower and higher ABI are significantly associated with an increased risk of CVD and all-cause mortality in the Japanese population. The ABI, which is easily measured by oscillometry, may be incorporated into daily clinical practice to identify high-risk populations.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.05.048DOI Listing
August 2018

Simultaneously Measured Interarm Blood Pressure Difference and Stroke: An Individual Participants Data Meta-Analysis.

Hypertension 2018 06 9;71(6):1030-1038. Epub 2018 Apr 9.

From the Department of Cardiology and Division of Preemptive Medicine for Vascular Damage, Tokyo Medical University, Japan (H.T., C.M., A.Y.).

We conducted individual participant data meta-analysis to examine the validity of interarm blood pressure difference in simultaneous measurement as a marker to identify subjects with ankle-brachial pressure index <0.90 and to predict future cardiovascular events. We collected individual participant data on 13 317 Japanese subjects from 10 cohorts (general population-based cohorts, cohorts of patients with past history of cardiovascular events, and those with cardiovascular risk factors). Binary logistic regression analysis with adjustments identified interarm blood pressure difference >5 mm Hg as being associated with a significant odds ratio for the presence of ankle-brachial pressure index <0.90 (odds ratio, 2.19; 95% confidence interval, 1.60-3.03; <0.01). Among 11 726 subjects without a past history of cardiovascular disease, 249 developed stroke during the average follow-up period of 7.4 years. Interarm blood pressure difference >15 mm Hg was associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke (hazard ratio, 2.42; 95% confidence interval, 1.27-4.60; <0.01). Therefore, interarm blood pressure differences, measured simultaneously in both arms, may be associated with vascular damage in the systemic arterial tree. These differences may be useful for identifying subjects with an ankle-brachial pressure index of <0.90 in the overall study population, and also a reliable predictor of future stroke in subjects without a past history of cardiovascular disease. These findings support the recommendation to measure blood pressure in both arms at the first visit.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.10923DOI Listing
June 2018

p66Shc Signaling Mediates Diabetes-Related Cognitive Decline.

Sci Rep 2018 02 16;8(1):3213. Epub 2018 Feb 16.

Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Accumlating evidence have suggested that diabetes mellitus links dementia, notably of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. Several studies have shown oxidative stress (OS) to be one of the major factors in the pathogenesis of diabetic complications. Here we show OS involvement in brain damage in a diabetic animal model that is at least partially mediated through an AD-pathology-independent mechanism apart from amyloid-β accumulation. We investigated the contribution of the p66Shc signaling pathway to diabetes-related cognitive decline using p66Shc knockout (-/-) mice. p66Shc (-/-) mice have less OS in the brain and are resistant to diabetes-induced brain damage. Moreover, p66Shc (-/-) diabetic mice show significantly less cognitive dysfunction and decreased levels of OS and the numbers of microglia. This study postulates a p66Shc-mediated inflammatory cascade leading to OS as a causative pathogenic mechanism in diabetes-associated cognitive impairment that is at least partially mediated through an AD-pathology-independent mechanism.
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http://dx.doi.org/10.1038/s41598-018-21426-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816624PMC
February 2018

DNA methylation of the Klf14 gene region in whole blood cells provides prediction for the chronic inflammation in the adipose tissue.

Biochem Biophys Res Commun 2018 03 6;497(3):908-915. Epub 2018 Feb 6.

FUKUOKA Health Promotion Support Center, Japan. Electronic address:

Krüppel-Like Factor 14 (KLF14) gene, which appears to be a master regulator of gene expression in the adipose tissue and have previously been associated with BMI and Type 2 diabetes (T2D) by large genome-wide association studies. In order to find predictive biomarkers for the development of T2D, it is necessary to take epigenomic changes affected by environmental factors into account. This study focuses on ageing and obesity, which are T2D risk factors, and examines epigenetic changes and inflammatory changes. We investigated DNA methylation changes in the Klf14 promoter region in different organs of mice for comparing aging and weight. We found that methylation levels of these sites were increased with aging and weight in the spleen, the adipose tissue, the kidney, the lung, the colon and the whole blood cells. In addition, in the spleen, the adipose tissue and the whole blood, these epigenetic changes were also significantly associated with inflammatory levels. Moreover, not only Klf14, but also expression levels of some downstream genes were decreased with methylation in the spleen, the adipose tissue and the whole blood cells. Taken together, our results suggest that methylation changes of Klf14 in those tissues may be associated with changes in gene expression and inflammation on the adipose tissue of obesity and T2D. In addition, the methylation changes in the whole blood cells may serve as a predictive epigenetic biomarker for the development of T2D.
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http://dx.doi.org/10.1016/j.bbrc.2017.12.104DOI Listing
March 2018

Serum Bilirubin Concentration is Associated with Left Ventricular Remodeling in Patients with Type 2 Diabetes Mellitus: A Cohort Study.

Diabetes Ther 2018 Feb 15;9(1):331-338. Epub 2018 Jan 15.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Introduction: Previous studies have shown that serum bilirubin concentration is inversely associated with the risk of cardiovascular disease. The relationship between serum bilirubin concentration and left ventricular geometry, however, has not been investigated in patients with diabetes mellitus.

Methods: In this cohort study, 158 asymptomatic patients with type 2 diabetes mellitus without overt heart disease were enrolled. Left ventricular structure and function were assessed using echocardiography. Serum bilirubin concentration, glycemic control, lipid profile, and other clinical characteristics were evaluated, and their association with left ventricular geometry was determined. Patients with New York Heart Association Functional Classification greater than I, left ventricular ejection fraction less than 50%, history of coronary artery disease, severe valvulopathy, chronic atrial fibrillation, or creatinine clearance less than 30 ml/min, and those receiving insulin treatment, were excluded.

Results: Univariate analyses showed that relative wall thickness (RWT) was significantly correlated with diastolic blood pressure (P = 0.003), HbA1c (P = 0.024), total cholesterol (P = 0.043), urinary albumin (P = 0.023), and serum bilirubin concentration (P = 0.009). There was no association between left ventricular mass index and serum bilirubin concentration. Multivariate linear regression analysis showed that log RWT was positively correlated with diastolic blood pressure (P = 0.010) and that log RWT was inversely correlated with log bilirubin (P = 0.003). In addition, the patients with bilirubin less than 0.8 mg/dl had a higher prevalence of concentric left ventricular remodeling compared with those with bilirubin 0.8 mg/dl or more.

Conclusion: Our study shows that the serum bilirubin concentration may be associated with the progression of concentric left ventricular remodeling in patients with type 2 diabetes mellitus.
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http://dx.doi.org/10.1007/s13300-018-0368-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801254PMC
February 2018

Effects of Pemafibrate, a Novel Selective PPARα Modulator, on Lipid and Glucose Metabolism in Patients With Type 2 Diabetes and Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial.

Diabetes Care 2018 03 3;41(3):538-546. Epub 2018 Jan 3.

Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan.

Objective: Type 2 diabetes is frequently complicated with atherogenic dyslipidemia. This study aimed to evaluate the efficacy and safety of pemafibrate (K-877) in patients with type 2 diabetes comorbid with hypertriglyceridemia.

Research Design And Methods: Patients were randomly assigned to three groups and received placebo ( = 57), 0.2 mg/day pemafibrate ( = 54), or 0.4 mg/day pemafibrate ( = 55) for 24 weeks (treatment period 1). Subsequently, the patients received follow-up treatment for another 28 weeks (treatment period 2), in which the placebo was switched to 0.2 mg/day pemafibrate. This article presents the results of treatment period 1, which were the primary objectives.

Results: The pemafibrate groups showed significantly reduced fasting serum triglyceride levels by ∼45% compared with the placebo group ( < 0.001). Additionally, the pemafibrate groups displayed significant decreases in non-HDL and remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, ApoB48, and ApoCIII levels and significant increases in HDL cholesterol and ApoA-I levels. LDL cholesterol levels were not considerably altered in the pemafibrate groups. Furthermore, the 0.2 mg/day pemafibrate group showed a significantly reduced HOMA-insulin resistance score compared with the placebo group; however, no significant changes compared with placebo were found in fasting plasma glucose, fasting insulin, glycoalbumin, or HbA levels. The pemafibrate groups also showed significantly increased fibroblast growth factor 21 levels compared with the placebo group. All groups displayed comparable rates of adverse events and drug reactions.

Conclusions: Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in patients with type 2 diabetes comorbid with hypertriglyceridemia.
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http://dx.doi.org/10.2337/dc17-1589DOI Listing
March 2018

Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension.

Circ J 2017 Sep 24;81(10):1540-1542. Epub 2017 Aug 24.

Department of Cardiology, Tokyo Medical University.

Background: The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD.

Conclusions: The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s.
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http://dx.doi.org/10.1253/circj.CJ-17-0636DOI Listing
September 2017

Renoprotective effect of a novel selective PPARα modulator K-877 in db/db mice: A role of diacylglycerol-protein kinase C-NAD(P)H oxidase pathway.

Metabolism 2017 06 3;71:33-45. Epub 2017 Mar 3.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. Electronic address:

Objective: Several clinical studies have shown the beneficial effects of peroxisome proliferator-activated receptor α (PPARα) agonists on diabetic nephropathy. However, the molecular mechanism is not fully understood. Here we show that K-877, a novel selective PPARα modulator, ameliorates nephropathy in db/db mice via inhibition of renal lipid content and oxidative stress.

Methods And Results: K-877 (0.5mg/kg/day) was administered to db/db mice for 2 or 12weeks. Short-term treatment did not affect body weight or plasma glucose levels in db/db mice, but attenuated albuminuria, along with improvement of plasma lipid profiles, lipid content including total diacylglycerol (DAG) levels, protein kinase C (PKC) activity, NAD(P)H oxidase-4 expression, and oxidative stress markers, all of which were significantly increased in diabetic kidneys. It increased phosphorylation of 5'-AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and expression of several genes mediating fatty acid β-oxidation. In addition, long-term treatment ameliorated renal mesangial expansion in db/db mice and improved glycemic control.

Conclusions: K-877 administration ameliorates diabetic nephropathy, at least in part, via inhibition of renal lipid content and oxidative stress. The underlying mechanism may be mediated by modulating the renal AMPK-ACC pathway, subsequent acceleration of fatty acid β-oxidation and inhibition of fatty acid synthesis, and thus inhibition of the DAG-PKC-NAD(P)H oxidase pathway, in addition to its systemic effect including improvement of the plasma lipid profile and glycemic control.
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http://dx.doi.org/10.1016/j.metabol.2017.02.013DOI Listing
June 2017

Brachial-Ankle Pulse Wave Velocity and the Risk Prediction of Cardiovascular Disease: An Individual Participant Data Meta-Analysis.

Hypertension 2017 06 24;69(6):1045-1052. Epub 2017 Apr 24.

From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences (T. Ohkuma), Department of Epidemiology and Public Health, Graduate School of Medical Sciences (T.N.), Innovation Center for Medical Redox Navigation (T.I.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (Y.M.), Kyushu University, Fukuoka, Japan; Department of Cardiology, Tokyo Medical University, Japan (H.T., A.Y.); Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan (K. Kario, S.H.); Faculty of Nursing Science, Tsuruga Nursing University, Japan (Y.K.); Department of Regional Resource Management, Faculty of Collaborative Regional Innovation, Ehime University, Japan (K. Kohara); Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Japan (Y.T.); Department of Internal Medicine, Iwate Medical University, Japan (Motoyuki Nakamura); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (T. Ohkubo); Departments of Metabolism and Endocrinology, Juntendo University, Graduate School of Medicine, Tokyo, Japan (H.W.); Research Center for Lifestyle-Related Disease, Tohoku Rosai Hospital, Sendai, Japan (M.M.); Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan (M.O.); Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Japan (N.I.); Department of Cardiovascular Medicine, Cardiovascular Institute, Japan (Michinari Nakamura); Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Japan (T.S.); and Hypertension and Cardiometabolic Unit, (1st) Department of Cardiology, Athens Medical School, Hippokration Hospital, Greece (C.V.).

An individual participant data meta-analysis was conducted in the data of 14 673 Japanese participants without a history of cardiovascular disease (CVD) to examine the association of the brachial-ankle pulse wave velocity (baPWV) with the risk of development of CVD. During the average 6.4-year follow-up period, 687 participants died and 735 developed cardiovascular events. A higher baPWV was significantly associated with a higher risk of CVD, even after adjustments for conventional risk factors ( for trend <0.001). When the baPWV values were classified into quintiles, the multivariable-adjusted hazard ratio for CVD increased significantly as the baPWV quintile increased. The hazard ratio in the subjects with baPWV values in quintile 5 versus that in those with the values in quintile 1 was 3.50 (2.14-5.74; <0.001). Every 1 SD increase of the baPWV was associated with a 1.19-fold (1.10-1.29; <0.001) increase in the risk of CVD. Moreover, addition of baPWV to a model incorporating the Framingham risk score significantly increased the C statistics from 0.8026 to 0.8131 (<0.001) and also improved the category-free net reclassification (0.247; <0.001). The present meta-analysis clearly established baPWV as an independent predictor of the risk of development of CVD in Japanese subjects without preexisting CVD. Thus, measurement of the baPWV could enhance the efficacy of prediction of the risk of development of CVD over that of the Framingham risk score, which is based on the traditional cardiovascular risk factors.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09097DOI Listing
June 2017

Arterial pressure lability is improved by sodium-glucose cotransporter 2 inhibitor in streptozotocin-induced diabetic rats.

Hypertens Res 2017 Jul 16;40(7):646-651. Epub 2017 Feb 16.

Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Center for Disruptive Cardiovascular Medicine, Fukuoka, Japan.

To prevent cardiovascular events in patients with diabetes mellitus (DM), it is essential to reduce arterial pressure (AP). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) prevents cardiovascular events via the depressor response in patients with DM. In the present study, we examined whether SGLT2i ameliorates AP lability in DM rats. Ten-week-old male Sprague-Dawley rats were administered a single intravenous injection of streptozotocin (50 mg kg) and were divided into three groups treated with low-dose SGLT2i, vehicle (VEH) or subcutaneously implanted insulin pellets (SGLT2i, VEH and Insulin group, respectively) for 14 days. SGLT2i reduced blood glucose, but its effect was lower than that of insulin. The telemetered mean AP at the end of the experiment did not differ among the SGLT2i, Insulin and VEH groups (83±7 vs. 98±9 vs. 90±8 mm Hg, respectively, n=5 for each). The standard deviation of AP as the index of lability was significantly smaller during the active period in the SGLT2i group than in the VEH group (5.6±0.5 vs. 7.0±0.7 mm Hg, n=5 for each, P<0.05). Sympathetic nerve activity during the active period was significantly lower in the SGLT2i group than in the VEH group. Baroreflex sensitivity (BRS) was significantly higher in the SGLT2i group than in the VEH group. The standard deviation of AP and sympathoexcitation did not differ between the Insulin and VEH groups. In conclusion, SGLT2i at a non-depressor dose ameliorated the AP lability associated with sympathoinhibition during the active period and improved the BRS in streptozotocin-induced DM rats.
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http://dx.doi.org/10.1038/hr.2017.14DOI Listing
July 2017

Hyperinsulinemia and sulfonylurea use are independently associated with left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus with suboptimal blood glucose control.

BMJ Open Diabetes Res Care 2016 18;4(1):e000223. Epub 2016 Aug 18.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.

Objective: Although diabetes mellitus is associated with an increased risk of heart failure with preserved ejection fraction, the underlying mechanisms leading to left ventricular diastolic dysfunction (LVDD) remain poorly understood. The study was designed to assess the risk factors for LVDD in patients with type 2 diabetes mellitus.

Research Design And Methods: The study cohort included 101 asymptomatic patients with type 2 diabetes mellitus without overt heart disease. Left ventricular diastolic function was estimated as the ratio of early diastolic velocity (E) from transmitral inflow to early diastolic velocity (e') of tissue Doppler at mitral annulus (E/e'). Parameters of glycemic control, plasma insulin concentration, treatment with antidiabetic drugs, lipid profile, and other clinical characteristics were evaluated, and their association with E/e' determined. Patients with New York Heart Association class >1, ejection fraction <50%, history of coronary artery disease, severe valvulopathy, chronic atrial fibrillation, or creatinine clearance <30 mL/min, as well as those receiving insulin treatment, were excluded.

Results: Univariate analysis showed that E/e' was significantly correlated with age (p<0.001), sex (p<0.001), duration of diabetes (p=0.002), systolic blood pressure (p=0.017), pulse pressure (p=0.010), fasting insulin concentration (p=0.025), and sulfonylurea use (p<0.001). Multivariate linear regression analysis showed that log E/e' was significantly and positively correlated with log age (p=0.034), female sex (p=0.019), log fasting insulin concentration (p=0.010), and sulfonylurea use (p=0.027).

Conclusions: Hyperinsulinemia and sulfonylurea use may be important in the development of LVDD in patients with type 2 diabetes mellitus.
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http://dx.doi.org/10.1136/bmjdrc-2016-000223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013397PMC
September 2016

Bilirubin as an important physiological modulator of oxidative stress and chronic inflammation in metabolic syndrome and diabetes: a new aspect on old molecule.

Diabetol Int 2016 Dec 21;7(4):338-341. Epub 2016 Sep 21.

2Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582 Japan.

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http://dx.doi.org/10.1007/s13340-016-0288-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224966PMC
December 2016

Evaluation of Brain Redox Status and Its Association with Cognitive Dysfunction in Diabetic Animal Models by Redox Molecular Imaging (ReMI).

Yakugaku Zasshi 2016 ;136(8):1081-6

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University.

Oxidative stress contributes to the development of diabetic complications. Increasing epidemiologic evidence suggests that diabetes mellitus is associated with dementia and cognitive decline. However, the underlying mechanisms are not fully understood. We have evaluated brain redox status and its association of cognitive dysfunction in diabetic animal models by dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) and other oxidative stress markers. In this review, we discuss the role of oxidative stress in the development of diabetes-related dementia and clinical regulation of the redox state in new approaches to augmenting diabetes-related dementia.
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http://dx.doi.org/10.1248/yakushi.15-00234-2DOI Listing
May 2017

[Oxidative stress and chronic inflammation].

Nihon Rinsho 2016 Apr;74 Suppl 2:73-6

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April 2016

Silent myocardial ischemia in asymptomatic patients with type 2 diabetes mellitus without previous histories of cardiovascular disease.

Int J Cardiol 2016 Aug 11;216:151-5. Epub 2016 Apr 11.

Cardiovascular Center, Munakata Suikokai General Hospital, Fukutsu, Japan.

Background: The number of patients with type 2 diabetes mellitus (T2DM) continues to increase all over the world. Cardiovascular disease (CVD), especially coronary artery disease (CAD), is a major cause of the morbidity and mortality in patients with T2DM. The prognosis of patients with silent myocardial ischemia (SMI) is worse than that in those without.

Methods And Results: Thus, to assess how many patients with SMI existed among those patients, CVD screening tests were performed in 128 asymptomatic patients with T2DM without previous histories of CVD. SMI could be detected in 24 patients (19%) by exercise stress tests and/or the coronary fractional flow reserve. Their 12-lead electrocardiogram and cardiac ultrasonography were both normal. Compared to those without SMI, those with had a statistically significant longer history of T2DM (17±1 versus 11±1years, p=0.006), and the co-existence of a family history of CVD (42% versus 21%, p=0.037). Furthermore, these factors were demonstrated as independent risk factors of SMI by a multivariate analysis (Odds ratio 1.060 and 4.000, respectively), and in accordance with the disease duration of T2DM, the prevalence of patients with SMI has been increasing (p=0.019).

Conclusions: Physicians should be aware of these conditions when examining patients with T2DM, especially with a family history of CVD and/or long disease duration (>11years) of T2DM, even though they have no symptoms, previous histories of CVDs, and/or abnormal findings on the 12-lead electrocardiogram and cardiac ultrasonography. This may be an effective, safe, and attractive diagnostic strategy for those asymptomatic patients with T2DM.
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http://dx.doi.org/10.1016/j.ijcard.2016.04.008DOI Listing
August 2016

A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats.

Metabolism 2016 Mar 2;65(3):138-45. Epub 2015 Nov 2.

The Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aims: Recently various dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged because of their high effectiveness and safety. In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, has a scavenging activity on hydroxyl radical (·OH).

Methods: ·OH and superoxide (O2(-)) were detected by electron spin resonance (ESR) spectroscopy. ·OH and O2(-) were generated in vitro by the Fenton reaction and a hypoxanthine-xanthine oxidase system, respectively. The level of free radicals was estimated from the ESR signal intensity. The product via teneligliptin and ·OH reaction was identified by thin layer chromatography and mass spectrometry analysis. In vivo effect was also evaluated using DPP-4 deficient rats with streptozotocin-induced diabetes.

Results: ESR spectroscopy analysis showed that teneligliptin did not scavenge O2(-), but scavenged ·OH in a dose dependent manner. Its activity was greater than that of glutathione. The reaction product appeared to have an oxygen-atom added structure to that of teneligliptin, which was identical to the most abundant metabolite of teneligliptin in human plasma. Furthermore, using DPP-4 deficient rat, teneligliptin did not affect plasma glucose levels or body weight, but normalized increased levels of 8-hydroxy-2'-deoxyguanosine in urine, kidney and aorta of diabetic rats, supporting that teneligliptin may have a ·OH scavenging activity in vivo independently of DPP-4 inhibition.

Conclusions: Teneligliptin is not only effective as DPP-4 inhibitor, but may also be beneficial as ·OH scavenger, which may be useful in the prevention of diabetic complications.
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http://dx.doi.org/10.1016/j.metabol.2015.10.030DOI Listing
March 2016

Clinical significance of barriers to blood glucose control in type 2 diabetes patients with insufficient glycemic control.

Patient Prefer Adherence 2015 25;9:837-45. Epub 2015 Jun 25.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The purpose of this study was to assess actual barriers to blood glucose control in patients with type 2 diabetes mellitus and to investigate barrier-related factors in an exploratory manner.

Methods: This cross-sectional study assessed patients with type 2 diabetes mellitus treated as outpatients at medical institutions within Fukuoka Prefecture, Japan. Barriers to blood glucose control were examined in patients with glycated hemoglobin ≥6.9% using a nine-item questionnaire. Answers were also obtained from physicians in charge of the patients for seven of nine questions.

Results: Seven hundred and thirteen patients answered the questionnaire. Many physicians and patients described barriers that involved difficulty in complying with diet therapy. For six of the seven barriers, patient awareness was lower than physician awareness. Patient-reported lack of concern for diabetes mellitus was more prevalent among patients with macrovascular complications. Patients who reported difficulty in compliance with exercise therapy and fear of hypoglycemia were more likely to suffer from microvascular complications.

Conclusion: For many of the barriers to blood glucose control, patients were less aware than physicians, suggesting that we need to take action to raise patient awareness. Of interest are the observations that the relevant barriers differed for macrovascular and microvascular complications and that the relationship between presence of macrovascular complications and lack of concern about diabetes mellitus.
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http://dx.doi.org/10.2147/PPA.S84268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485849PMC
July 2015