Publications by authors named "Noriyuki Sonoda"

51 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

Effects of intensive exercise combined with dapagliflozin on body composition in patients with type 2 diabetes: a randomized controlled trial.

Endocr J 2021 Mar 26;68(3):329-343. Epub 2020 Dec 26.

Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

This study was aimed to evaluate the effects of intensive exercise in addition to the administration of sodium-glucose cotransporter 2 inhibitor dapagliflozin (DAPA) on body composition, including fat-free mass, in type 2 diabetes. We randomly assigned 146 patients to 24 weeks of treatment with intensive exercise, including resistance training, plus 5 mg (up to 10 mg) of DAPA daily (IT group) or DAPA alone (CT group). The primary endpoint was the difference in the change in fat-free mass from baseline to 24 weeks between the groups. The skeletal muscle mass index (SMI); metabolic profile, including HbA1c; and regional fat mass were also determined. ANCOVA was used for the group comparison, with least squares mean (LSM) differences and 95% confidence interval (CI). There was no significant difference in the change in fat-free mass (LSM difference -0.1 kg (95% CI: -0.5 to 0.4) and SMI (LSM difference -0.1 kg (95% CI: -0.2 to 0.1) between the groups. In contrast, the reduction of trunk fat mass was significantly higher in the IT group than in the CT group ((LSM difference -0.5 kg [95% CI -0.9 to -0.1]). Higher adherence to the resistance training tended to be associated with changes in HbA1c and high-sensitivity CRP levels. Our study suggests that intensive exercise do not prevent the reduction of fat-free mass after administration of SGLT2 inhibitors but can increase the reduction in abdominal fat, presumably leading to further improvements of hyperglycemia and chronic inflammation than DAPA alone in type 2 diabetes patients.
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http://dx.doi.org/10.1507/endocrj.EJ20-0599DOI Listing
March 2021

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

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

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

[Fulminant type 1 diabetes mellitus following acute pancreatitis and hypoglycemia with sequential imaging of the pancreas using computed tomography: a case report].

Nihon Shokakibyo Gakkai Zasshi 2019;116(2):161-167

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

We herein report a rare case of fulminant type 1 diabetes mellitus (FT1DM) following acute pancreatitis and hypoglycemia, in which the pancreas was evaluated by serial computed tomography (CT). A 30-year-old male presented to a local hospital with a two-day history of abdominal pain and was diagnosed with acute pancreatitis based on elevated serum amylase and peripancreatic fluid collection on CT images. The patient developed sudden hypoglycemia (plasma glucose, 45mg/dL;serum C-peptide, 3.4ng/mL) the next day and hyperglycemia (plasma glucose, 250-480mg/dL) on admission day four. CT revealed a low attenuation area extending from the pancreatic head to the pancreatic tail. On admission day eight, he was referred to our hospital and diagnosed with FT1DM after he developed ketoacidosis immediately after hospitalization, with a plasma glucose level of 442mg/dL, hemoglobin A1c concentration of 5.7% and undetectable urinary C-peptide with a serum C-peptide level of 0.1ng/mL before and after intravenous glucagon loading. CT imaging revealed dramatic improvement at the time, and no pancreatic islets were detected in the pancreatic biopsy specimens.
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http://dx.doi.org/10.11405/nisshoshi.116.161DOI Listing
June 2019

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

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

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

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

Clinical significance of the laparoscopic bariatric surgeries for morbid obesity: initial 30 cases at a single institution in Japan.

Fukuoka Igaku Zasshi 2015 Feb;106(2):33-40

Background: Bariatric surgical procedures are becoming a standard treatment for morbid obesity in many western countries and in some Asian countries.

Aim: The aim of the current study was to evaluate the efficacy and safety of the initial 30 cases of bariatric surgical procedures performed for morbid obesity at a single institution in Japan.

Materials And Methods: From March 2012 until September 2014, 30 bariatric surgical procedures were performed for morbid obesity at a single medical center (Kyushu University Hospital) in Japan.

Results: All of the operations procedures were planned laparoscopic procedures, and none required conversion to laparotomy. There were no perioperative or postoperative mortalities. Postoperative complications occurred in 3 patients: 1 patient developed an intra-abdominal abscess, 1 patient experienced temporary food intolerance, and 1 patient developed small bowel obstruction. The excessive body weight reduction rates after surgery at 1 month, 3 months, 6 months, and 1 year post-surgery were 26.1%, 39.2%, 41.7%, and 51.2%, respectively. The mean body mass index (BMI) at the same time points were 38.3%, 36.4%, 35.5%, and 31.4%, respectively. Eighteen patients had type II diabetes mellitus (T2DM). The mean preoperative fasting blood glucose levels were 169 ± 37 mg/dL. Following surgery, the blood glucose levels at 3, 6 and 12 months were 113 ± 12, 115 ± 22, and 110 ± 19, mg/dL, respectively. The preoperative HbA1c percentage was 7.9 ± 0.5. Following surgery, the HbA1c percentages at 3, 6, and 12 months were 6.9 ± 0.5, 6.2 ± 0.9, and 5.9 ± 0.6, respectively.

Conclusions: Bariatric surgical procedures are effective and safe for the treatment of morbid obesity. Our results indicate that the mechanism of improvement of diabetes and related diseases following bariatric surgical procedures is not simply as a result of calorie restriction and weight reduction.
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February 2015

GLP-1 analog liraglutide protects against cardiac steatosis, oxidative stress and apoptosis in streptozotocin-induced diabetic rats.

Atherosclerosis 2015 May 18;240(1):250-9. Epub 2015 Mar 18.

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

Objective: Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits cardiac steatosis, oxidative stress and apoptosis in streptozotocin (STZ)-induced type 1 diabetic rats, via activation of AMPK-Sirt1 pathway.

Methods: Diabetic rats were treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Myocardial steatosis (detected by oil red O staining and myocardial triglyceride and diacylglycerol (DAG) contents assay), expression of protein kinase C (PKC), heart NAD(P)H oxidase activity, oxidative stress markers (8-hydroxy-2'-deoxyguanosine staining), apoptosis (TUNEL analysis) and genes that affect apoptosis and lipid metabolism were evaluated.

Results: Administration of liraglutide did not affect plasma glucose and insulin levels or body weights in STZ-induced diabetic rats, but normalized myocardial steatosis, expression of PKC, NAD(P)H oxidase activity, oxidative stress markers and apoptosis, all of which were significantly increased in diabetic hearts. Additionally, expression of genes mediating lipid uptake, synthesis and oxidation were increased in the diabetic hearts, and these increases were all reduced by liraglutide. In addition, liraglutide increased expression of Sirt1 and phosphorylated AMPK in the diabetic hearts.

Conclusions: Liraglutide may have a beneficial effect on cardiac steatosis, DAG-PKC-NAD(P)H pathway, oxidative stress and apoptosis via activation of AMPK-Sirt1 pathway, independently of a glucose-lowering effect.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.026DOI Listing
May 2015

Brachial-ankle pulse wave velocity predicts all-cause mortality and cardiovascular events in patients with diabetes: the Kyushu Prevention Study of Atherosclerosis.

Diabetes Care 2014 Aug 4;37(8):2383-90. Epub 2014 Jun 4.

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

Objective: Whether brachial-ankle pulse wave velocity (baPWV), a noninvasive marker for arterial stiffness, is a useful predictive maker for cardiovascular events in subjects with diabetes is not established. In the present cohort study, we evaluated the benefit of baPWV for the prediction of cardiovascular morbidity and mortality in subjects with diabetes.

Research Design And Methods: A total of 4,272 outpatients with diabetes were enrolled in the Kyushu Prevention Study of Atherosclerosis. Of these, 3,628 subjects, excluding those with an ankle-brachial index of <0.9, were prospectively followed for 3.2 ± 2.2 years. The baPWV at baseline was classified by recursive partitioning (RP) for each end point. We plotted the Kaplan-Meier curves for high- and low-baPWV groups, which were designated based on the cutoff points, and calculated Cox proportional hazards models.

Results: The elevation of baPWV quartiles was significantly correlated to the incidence of coronary artery events, cerebrovascular events, and all-cause mortality. RP revealed baPWVs of 14 and 24 m/s as statistically adequate cutoff points for cardiovascular events and mortality, respectively. High-baPWV classes showed significantly low event-free ratios in Kaplan-Meier curves for all end points and remained independent risks for all-cause mortality and cerebrovascular events, but not for coronary artery events after adjustments for age, sex, BMI, hypertension, hyperlipidemia, smoking, and hemoglobin A1c by Cox proportional hazards models.

Conclusions: This large-scale cohort study provided evidence that high baPWV is a useful independent predictor of mortality and cardiovascular morbidity in subjects with diabetes.
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http://dx.doi.org/10.2337/dc13-1886DOI Listing
August 2014

Association of borderline ankle-brachial index with mortality and the incidence of peripheral artery disease in diabetic patients.

Atherosclerosis 2014 Jun 27;234(2):360-5. Epub 2014 Mar 27.

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

Objective: Peripheral artery disease (PAD) and diabetes mellitus are significant risk factors for all-cause death or cardiovascular death. PAD occurs more frequently in diabetic than in non-diabetic patients. However, the association of ankle-brachial index (ABI), especially borderline ABI, with clinical outcomes has not been fully elucidated in diabetic patients. This study aimed to investigate the association of ABI with mortality and the incidence of PAD in Japanese diabetic patients.

Methods: This observational study included 3981 diabetic patients (61.0 ± 11.8 years of age, 59.4% men), registered in the Kyushu Prevention Study for Atherosclerosis. Patients were divided into 3 groups according to the value of ABI at baseline: ABI ≤0.90 (abnormal ABI:354 patients), 0.91 ≤ ABI ≤ 0.99 (borderline ABI:333 patients), and 1.00 ≤ ABI ≤ 1.40 (normal ABI:3294 patients).

Results: Cumulative incidence of all-cause death was significantly higher in patients with abnormal and borderline ABI than in those with normal ABI (34.4% vs. 13.5%, P < 0.0001 and 26.1% vs. 13.5%, P < 0.0001, respectively). In multivariate analysis, the risks for all-cause death in patients with abnormal ABI (HR:2.16; 95%CI:1.46-3.14; P = 0.0002) and borderline ABI (HR:1.78; 95%CI:1.14-2.70; P = 0.01) were significantly higher than in those with normal ABI. The incidence of PAD was remarkably higher in patients with borderline ABI than in those with normal ABI (32.2% vs.9.6%, P < 0.0001). After adjustment, the risk for PAD was significantly higher in patients with borderline ABI than in those with normal ABI (HR:3.10; 95%CI:1.90-4.95; P < 0.0001).

Conclusions: Borderline ABI in diabetic patients was associated with significantly higher risks for mortality and PAD compared with normal ABI.
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http://dx.doi.org/10.1016/j.atherosclerosis.2014.03.018DOI Listing
June 2014

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice.

Am J Physiol Endocrinol Metab 2014 May 1;306(10):E1163-75. Epub 2014 Apr 1.

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

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic β-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic β-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.
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http://dx.doi.org/10.1152/ajpendo.00688.2013DOI Listing
May 2014

Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells.

Atherosclerosis 2014 Jan 5;232(1):156-64. Epub 2013 Nov 5.

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

Objective: Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress.

Methods: Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P)H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P)H oxidase pathway was assessed by translocation of GFP-fused PKCβ2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P)H oxidase, in addition to endogenous PKC phosphorylation and NAD(P)H oxidase activity.

Results: High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKCβ2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P)H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects.

Conclusions: Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC-NAD(P)H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.10.025DOI Listing
January 2014

Targeting obesity, insulin resistance and Type 2 diabetes with immunotherapy: the challenges ahead.

Immunotherapy 2014 ;6(1):5-7

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

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http://dx.doi.org/10.2217/imt.13.142DOI Listing
August 2014

Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice.

Biochem Biophys Res Commun 2013 Aug 22;438(1):224-9. Epub 2013 Jul 22.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.
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http://dx.doi.org/10.1016/j.bbrc.2013.07.063DOI Listing
August 2013

CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues.

Biochem Biophys Res Commun 2013 Aug 18;438(1):103-9. Epub 2013 Jul 18.

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

It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophage polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein α, peroxisome proliferator-activated receptor γ, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.
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http://dx.doi.org/10.1016/j.bbrc.2013.07.034DOI Listing
August 2013

[Role of oxidative stress in pathogenesis of diabetic complications].

Nihon Rinsho 2012 Jul;70 Suppl 5:231-5

Innovation Center for Medical Redox Navigation, Kyushu University.

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July 2012