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

AIMS: This study aimed to evaluate changes in glycemic control and diabetes treatment by age group in Japanese patients with type 2 diabetes. METHODS: The study included the results of approximately 40,000 patients/year using cross-sectional and retrospective analyses from 2012 to 2019. RESULTS: There was little change in the glycemic control status in all age groups during the study period. However, by age group, patients aged < 45 years continued to have the highest glycated hemoglobinA1c (HbA1c) values during the study period (7.4% ± 1.7% in 2012 and 7.4% ± 1.5% in 2019), especially in insulin-treated patients (8.3% ± 1.9% in 2012 and 8.4% ± 1.8% in 2019). Biguanides and dipeptidyl peptidase-4 inhibitors were widely prescribed. Sulfonylurea and insulin use showed a decreasing trend, but older patients had a higher percentage of prescriptions. Sodium glucose transporter 2 inhibitors were prescribed rapidly, especially in younger patients. CONCLUSIONS: There were no obvious changes in glycemic control over time in the study period. The mean HbA1c level was higher in younger patients, which suggested that improvement is required. In older patients, there was a trend toward greater emphasis on management to avoid hypoglycemia. Different treatment strategies based on age showed different drug choices.

DOI： 10.1016/j.diabres.2023.110599

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

File： 雑誌糖尿病_2023ダイバーシティ.pdf

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

Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional control. Chemical modification of macromolecules, including epigenetics, is expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remains poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O-linked β-N-acetylglucosamine (O-GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O-GlcNAcylation levels causes repression of PGC formation in vivo. Moreover, maternal ketogenic diet intake until mid-gestation affects the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination.

DOI： 10.15252/embr.202356845

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Language：Japanese   Publisher：Academic eXcange for Information Environment and Strategy  

File： 門田_学術情報処理研究_遠隔授業_2022.pdf

DOI： 10.24669/jacn.26.1_79

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

BACKGROUND: An association between a high intake of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) with a lower risk of coronary heart disease was previously reported. However, the association between n-3 PUFAs and cerebrovascular lesions remains unclear. We evaluated this association in a general-population-based sample of Japanese men. METHODS: Participants were community-dwelling men (40-79 years old) living in Kusatsu City, Shiga, Japan. Serum concentrations of n-3 PUFAs, defined as the sum of eicosapentaenoic and docosahexaenoic acids, were measured via gas-liquid chromatography between 2006 and 2008. Magnetic resonance imaging was used to assess cerebrovascular lesions (including intracerebral large-artery stenosis, lacunar infarction, and microbleeds) and white matter lesions between 2012 and 2015. Logistic regression adjusting for conventional cardiovascular risk factors was used to estimate the odds ratio of prevalent cerebrovascular lesions per 1 standard deviation higher serum concentration of n-3 PUFAs. RESULTS: Of a total of 739 men, the numbers (crude prevalence in %) of prevalent cerebral large-artery stenoses, lacunar infarctions, microbleeds, and white matter lesions were 222 (30.0), 162 (21.9), 103 (13.9), and 164 (22.2), respectively. A 1 standard deviation higher concentration of n-3 PUFAs (30.5 μmol/L) was independently associated with lower odds of cerebral large-artery stenosis (multivariable-adjusted odds ratio, 0.80; 95% confidential interval, 0.67-0.97). There were no significant associations of n-3 PUFAs with the other types of lesions. CONCLUSIONS: n-3 PUFAs may have protective effects against large-artery stenosis, but not small vessel lesions, in the brain.

DOI： 10.1159/000524243

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

OBJECTIVE: The intestine is an important organ for nutrient metabolism via absorption and endocrine systems. Nutrients regulate O-GlcNAcylation, a post-translational modification of various proteins by O-GlcNAc transferase (OGT). We have previously shown that general OGT knockout induced severe weight loss and hypoglycaemia in mice. However, little is known about how O-GlcNAcylation in the intestine modulates nutrient metabolism through absorption, especially glucose metabolism. We aimed to reveal the roles of O-GlcNAcylation in glucose absorption by the small intestine and elucidate the mechanism by which O-GlcNAcylation regulates sodium-glucose cotransporter 1 (SGLT1) expression. METHODS: First, we fasted normal mice and examined the changes in glucose transporters and O-GlcNAcylation in the intestine. Then, we generated two lines of small intestine-specific OGT-deficient mice (congenital: Ogt-VKO, tamoxifen-inducible: Ogt-iVKO) and observed the changes in body weight and in glucose and lipid metabolism. Finally, we investigated Sglt1 gene regulation by O-GlcNAcylation using enteroendocrine STC-1 cells. RESULTS: Fasting decreased O-GlcNAcylation in the intestinal epithelium of normal mice. The Ogt-VKO mice showed significantly lower non-fasted blood glucose levels and were underweight compared with litter matched controls. Glycaemic excursion in the Ogt-VKO mice was significantly lower during oral glucose tolerance test, but comparable during intraperitoneal glucose tolerance test. Furthermore, the Ogt-VKO mice exhibited lower Sglt1 expression in the small intestine, compared with the control mice. Interestingly, we obtained similar results using the Ogt-iVKO mice only after tamoxifen administration. Oral D-xylose administration test revealed that the intestinal sugar absorption was diminished in the Ogt-iVKO mice. Additionally, GLP-1 secretion did not sufficiently increase after glucose gavage in the Ogt-iVKO mice. When using STC-1 cells, O-GlcNAcylation increased Sglt1 mRNA via a PKA/CREB-dependent pathway. CONCLUSION: Collectively, loss of O-GlcNAcylation in the intestine reduced glucose absorption via suppression of SGLT1 expression, which may lead to new treatments for malabsorption, obesity and diabetes.

DOI： 10.1016/j.molmet.2022.101458

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

AIM: We aimed to determine whether SGLT2 inhibitor dapagliflozin treatment affects body composition and amino acid (AA) metabolism. METHODS: Fifty-two overweight patients treated by oral antidiabetic agents were randomly assigned to dapagliflozin (Dapa) or a standard treatment (Con) and followed for 24 weeks. The primary outcome was the change in body mass (BM) between baseline and week 24. Body composition, intrahepatic triglyceride (IHTG) content, and plasma AA concentrations were examined as secondary outcomes. RESULTS: The change in BM was significantly larger in the Dapa than in the Con group, with a difference in the mean change of -1.72 kg (95%CI: -2.85, -0.59; P = 0.004) between the groups. Total fat mass was reduced by dapagliflozin treatment, but fat-free mass was maintained. IHTG content was significantly reduced in the Dapa than in the Con (P = 0.033). Changes in AAs showed small differences between the groups, but only serine concentrations were significantly reduced in the Dapa. Intra-group analysis showed that positive associations were observed between changes in branched chain AA concentrations and body composition only in the Dapa. CONCLUSIONS: Dapagliflozin treatment causes a reduction in BM mainly by reducing fat mass. AA metabolism shows subtle changes with dapagliflozin treatment.

DOI： 10.1016/j.diabres.2022.109781

PubMed

Language：English   Publisher：シュプリンガー・ジャパン(株)  

HbA1cおよび空腹時血糖(FPG)と残存歯数の関係を年齢層別に検討した。健康保険組合のレセプト情報と健診結果を統合した2015年度版医療データベースから分析データに欠損のない成人男女233567名(女性52.7%、平均47.7±9.6歳)を抽出し、年代毎にHbA1c(5段階)およびFPG(3段階)で分類して天然歯数を比較した。30代以上の全年代でHbA1cが高いほど歯数が少なく、30代～60代でFPGが高いほど歯数が少なかった(各P<0.001、傾向検定)。40～60代の糖尿病前症(FPG 110～125mg/dL)群は、正常(<110mg/dL)群と比較して、歯数が少なかった(p<0.01)。全年代の非糖尿病者(糖尿病治療なくHbA1c<6.5%かつFPG<126mg/dL)を対象としたサブ解析でもFPGと歯数の間に関連が認められ(調整β=-0.01、p<0.0001)、糖尿病前症群の歯数は正常群に比べ有意に少なかった(推定周辺平均値26.43 vs. 26.67本、p<0.0001)。

Authorship：Last author,　Corresponding author   Language：English  

Atherosclerosis is promoted by systemic factors, such as dyslipidemia, hypertension, diabetes, and smoking, which cause atherosclerosis in blood vessels throughout the body. However, atherosclerotic lesions are characterized by their frequent occurrence in specific vessels and sites. Blood vessels are exposed to various mechanical forces related to blood pressure and flow. Although shear stress promotes the initiation and progression of atherosclerotic lesions, the pathogenesis of site specificity of atherosclerosis is not sufficiently explained by shear stress. We propose the concept of a perivascular mechanical environment (PVME). Compelling evidence suggests that site specificity in atherosclerotic lesions depends on a distinct local PVME. Atheroprone arteries, such as the coronary artery, are markedly affected by externally applied mechanical force (EMF), whereas atheroprotective arteries, such as the internal thoracic artery, are less affected. Recent studies have shown that the coronary artery is affected by cardiac muscle contraction, the carotid artery by the hyoid bone and the thyroid cartilage, and the abdominal aorta and lower extremity arteries by musculoskeletal motion. We speculate that the thoracic cage protects the internal thoracic artery from EMF owing to a favorable PVME. Furthermore, evidence suggests that plaque eccentricity is provided by EMF; plaques are frequently observed on an external force-applied side. In each vascular tree, site-specific characteristics of the PVME differ substantially, inducing individual atherogenicity. From the perspective of the mechanical environment, hemodynamic stress occurs in an inside-out manner, whereas EMF occurs in an outside-in manner. These inward and outward forces apply mechanical load individually, but interact synergistically. The concept of a PVME is a novel pathogenesis of atherosclerosis and also might be a pathogenesis of other arterial diseases.

DOI： 10.3389/fcvm.2022.944356

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tooth loss is associated with nutritional status and significantly affects quality of life, particularly in older individuals. To date, several studies reveal that a high BMI is associated with tooth loss. However, there is a lack of large-scale studies that examined the impact of obesity on residual teeth with respect to age and tooth positions. OBJECTIVE: We assessed the impact of obesity on the number and position of residual teeth by age groups using large scale of Japanese database. METHODS: This was a cross-sectional study of 706150 subjects that were included in the database that combined the data from health insurance claims and health check-up, those lacking information about BMI, HbA1c level, smoking status, and the number of residual teeth were excluded. Thus, a total of 233517 aged 20-74 years were included. Subjects were classified into 4 categories based on BMI, and the number of teeth was compared between age-groups. The percentage of subjects with residual teeth in each position was compared between groups with obesity (BMI ≥25.0 kg/m2) and non-obesity. Logistic regression analysis was performed to clarify whether obesity predicts having <24 teeth. RESULTS: Higher BMI was associated with fewer teeth over 40s (P for trend <0.0001 when <70s). Obesity was associated with the reduction of residual teeth in the maxillary; specifically, the molars were affected over the age 30. Smoking status further affected tooth loss at positions that were not affected by obesity alone. After adjusting for age, sex, smoking status, and HbA1c ≥6.5%, obesity remained an independent predictive factor for having <24 teeth (ORs: 1.35, 95% CIs: 1.30-1.40). CONCLUSIONS: We found that an increase in BMI was associated with a decrease in the number of residual teeth from younger ages independently of smoking status and diabetes in the large scale of Japanese database.

DOI： 10.1371/journal.pone.0274465

PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

MYOD-induced microRNA-494-3p expression inhibits fast oxidative myotube formation by downregulating myosin heavy chain 2 (MYH2) in human induced pluripotent stem cells (hiPSCs) during skeletal myogenesis. However, the molecular mechanisms regulating MYH2 expression via miR-494-3p remain unknown. Here, using bioinformatic analyses, we show that miR-494-3p potentially targets the transcript of the E1A-binding protein p300 at its 3′-untranslated region (UTR). Myogenesis in hiPSCs with the Tet/ON-myogenic differentiation 1 (MYOD1) gene (MyoD-hiPSCs) was induced by culturing them in doxycycline-supplemented differentiation medium for 7 days. p300 protein expression decreased after transient induction of miR-494-3p during myogenesis. miR-494-3p mimics decreased the levels of p300 and its downstream targets MYOD and MYH2 and myotube formation efficiency. p300 knockdown decreased myotube formation efficiency, MYH2 expression, and basal oxygen consumption rate. The binding of miR-494-3p to the wild type p300 3′-UTR, but not the mutated site, was confirmed using luciferase assay. Overexpression of p300 rescued the miR-494-3p mimic-induced phenotype in MyoD-hiPSCs. Moreover, miR-494-3p mimic reduced the levels of p300, MYOD, and MYH2 in skeletal muscles in mice. Thus, miR-494-3p might modulate MYH2 expression and fast oxidative myotube formation by directly regulating p300 levels during skeletal myogenesis in MyoD-hiPSCs and murine skeletal muscle tissues.

DOI： 10.1038/s41598-020-80742-y

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Other Link： http://www.nature.com/articles/s41598-020-80742-y

Publishing type：Research paper (scientific journal)  

The clinical implications of alcohol consumption have been extensively examined; however, its effects on brain structures in apparently healthy community-dwellers remain unclear. Therefore, we investigated the relationship between alcohol consumption and brain gray matter volume (GMV) in community-dwelling Japanese men using voxel-based morphometry (VBM). We recruited cognitively intact Japanese men, aged 40–79 years, from a population-based cohort in Shiga, Japan. Brain magnetic resonance imaging was performed, on average, 2 years after demographic and medical information was obtained in 2010–2014. A multivariable linear regression analysis of 639 men was conducted to elucidate the relationship between the amount of alcohol consumed and GMV. VBM statistics were analyzed by threshold-free cluster enhancement with a family-wise error rate of <0.05. The results obtained demonstrated that the amount of alcohol consumed was associated with lower GMV. The VBM analysis showed lower GMV within the parahippocampal, entorhinal, cingulate, insular, temporal, and frontal cortices and cerebellum in very heavy drinkers (≥42 ethanol g/day) than in non-drinkers. Furthermore, alcohol consumption was associated with a higher white matter lesion volume. These results suggest subclinical structural changes similar to alcohol-related neurological diseases.

DOI： 10.1016/j.alcohol.2020.11.006

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Authorship：Corresponding author  

Recent studies using genetically manipulated mouse models have shown the pivotal role of O-linked N-acetylglucosamine modification (O-GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O-GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O-GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O-GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β-cells. Furthermore, we discuss the importance of O-GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications.

DOI： 10.1111/jdi.13359

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

Background: The size of the remnant stomach with respect to weight loss failure after laparoscopic sleeve gastrectomy (LSG) remains controversial. This study aimed to evaluate the impact of the actual size and volume of the remnant stomach, as measured by three-dimensional computed tomography (3D-CT) volumetry, on weight loss after LSG. Methods: The clinical outcomes of 52 patients who underwent LSG between October 2008 and February 2019 were assessed. Weight metrics were recorded at 1, 3, and 6 months and 1 year postoperatively. 3D-CT volumetry was performed 1 year postoperatively, and the total remnant stomach volume (TSV), proximal stomach volume (PSV), antral stomach volume (ASV), and the distance between the pylorus and the distal edge of staple line (DPS) were measured. The relationship between the weight metrics and aforementioned factors was analyzed. Results: Of the 52 patients who underwent LSG, 40 patients participated in this study. The average body mass index preoperatively was 38.3 ± 5.1 kg/m2, and the average percentage of total weight loss (%TWL) 1 year after LSG was 26.6 ± 9.3%. The average TSV, PSV, ASV, and DPS were 123.2 ± 60.3 ml, 73.4 ± 37.2 ml, 49.8 ± 30.3 ml, and 59.9 ± 18.5 mm, respectively. The DPS (r = − 0.394, p = 0.012) and ASV (r = − 0.356, p = 0.024) were correlated with %TWL 1 year postoperatively. Conclusions: The actual DPS and ASV measured by 3D-CT affected weight loss after LSG. 3D-CT may be useful for the immediate identification of factors affecting insufficient weight loss in patients; this may, in turn, aid in the implementation of early intervention treatments.

DOI： 10.1007/s00268-020-05807-5

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

Aim: Diabetes mellitus is a well-known risk factor for onset and progression of periodontal disease. However, the continuous relationship between glycemic control and the number of natural teeth has not been well characterized in large-scale studies. We aimed to determine whether the glycated hemoglobin A1c (HbA1c) level and fasting plasma glucose (FPG) are associated with the number of natural teeth. Methods: A cross-sectional study: A database comprising employment-based health insurance claim and medical check-up data from 706,150 participants between April 2015 and March 2016 in Japan. The exclusion criteria included missing data regarding dental receipts, number of natural teeth, HbA1c, smoking status, and age < 20 years. Ultimately, 233,567 individuals were analyzed. The participants were allocated to five groups according to their HbA1c and three groups according to their FPG, and then the number of natural teeth were compared. Results: Higher HbA1c was associated with fewer teeth in participants ≥ 30 years of age (P for trend < 0.001). Higher FPG was associated with fewer teeth between 30 and 69 years of age (P for trend < 0.001). Participants with impaired fasting glucose was already at risk for fewer teeth between 40 and 69 years of age than those with normal FPG. Conclusions: Glycemic control is strongly associated with the number of natural teeth in the real-world setting. Furthermore, there are continuous relationships of HbA1c and FPG with number of natural teeth including individual with impaired fasting glucose. These data emphasize the importance of glycemic control and appropriate oral care for the protection against tooth loss.

DOI： 10.1007/s13340-021-00533-2

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Authorship：Last author,　Corresponding author  

Purpose of Review: This review aims to summarize the literature on periodontal disease and nutrition, focusing on endothelial dysfunction in diabetic patients, and their impact on oral health. Recent Findings: Environmental factors, including smoking, obesity, and diabetes are well-known risk factors for the onset and progression of the periodontal disease. Indeed, dietary factors show an association with periodontal health through local and systemic environments. In addition, systemic factors, such as insulin resistance and diabetes, may have an important role in the periodontal health. Although molecular mechanisms underlying this are not fully understood, endothelial dysfunction mainly by hyperglycemia and/or chronic inflammation may explain the association between periodontal status and nutrition. In this paper, we reviewed recent progress in this field and propose the potential impact of nutritional intervention in the oral health from the viewpoint of endothelial function. Summary: It is expected to become increasingly important to understand the pathology of diabetes-related periodontal disease and consider nutritional approaches with vascular dysfunction in mind for its prevention and treatment. Further accumulation of evidence is anticipated for the future.

DOI： 10.1007/s40496-021-00297-3

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

Evaluation of total energy expenditure (TEE) and physical activity level (PAL) is important for treatment of patients with type 2 diabetes mellitus (T2DM). However, the validity of accelerometers (ACC) and physical activity questionnaires (PAQ) for estimating TEE and PAL remains unknown in elderly populations with T2DM. We evaluated the accuracy of TEE and PAL results estimated by an ACC (TEEACC and PALACC) and a PAQ (TEEPAQ and PALPAQ) in elderly patients with T2DM. Methods: Fifty-one elderly patients with T2DM (aged 61-79 years) participated in this study. TEEACC was calculated with PALACC using a triaxial ACC (Active style Pro HJA-750c) over 2 weeks and predicted basal metabolic rate (BMR) by Ganpule's equation. TEEPAQ was estimated using predicted BMR and the PALPAQ from the -Japan Public Health Center Study-Long questionnaire. We compared the results to TEEDLW measured with the doubly labeled water (DLW) method and PALDLW calculated with BMR using indirect calorimetry. Results: TEEDLW was 2,165 ± 365 kcal/day, and TEEACC was 2,014 ± 339 kcal/day; TEEACC was strongly correlated with TEEDLW (r = 0.87, p < 0.01) but significantly underestimated (-150 ± 183 kcal/day, p < 0.05). There was no significant difference in TEEPAQ and TEEDLW (-49 ± 284 kcal/day), while the range of difference seemed to be larger than TEEACC. PALDLW, PALACC, and PALPAQ were calculated to be 1.71 ± 0.17, 1.69 ± 0.16, and 1.78 ± 0.24, respectively. -PALACC was strongly correlated with PALDLW (r = 0.71, p < 0.01), and there was no significant difference between the 2 values. PALPAQ was moderately correlated with PALDLW (r = 0.43, p < 0.01) but significantly overestimated. Predicted BMR was significantly lower than the BMR -measured by indirect calorimetry (1,193 ± 186 vs. 1,262 ± 155 kcal/day, p < 0.01). Conclusions: The present ACC and questionnaire showed acceptable correlation of TEE and PAL compared with DLW method in elderly patients with T2DM. Systematic errors in estimating TEE may be improved by the better equation for predicting BMR.

DOI： 10.1159/000506223

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

Aims: Ectopic fat accumulation is related to insulin resistance and diabetes mellitus (DM). However, the effect of fatty liver on DM in non-obese individuals has not been clarified. We investigated whether liver fat accumulation assessed by computed tomography (CT) is associated with the incidence of DM. Methods: In a prospective population-based study, 640 Japanese men were followed up for 5 years. The liver to spleen (L/S) ratio of the CT attenuation value was used as the liver fat accumulation index. We calculated the odds ratio (OR) and 95% confidence interval (CI) for the DM incidence of per 1 standard deviation (SD) lower L/S and those of L/S < 1.0 compared with L/S ≥ 1.0, using logistic regression models. Results: Both per 1 SD lower L/S and L/S < 1.0 were significantly associated with a risk for DM incidence (1 SD lower L/S: OR = 1.57, 95%CI = 1.14–2.16; L/S < 1.0: OR = 2.27, 95%CI = 1.00–5.14). The relationship between L/S and incidence of DM was consistent in the obese and non-obese groups, with thresholds of BMI 25 kg/m2, waist circumference 85 cm, or visceral adipose tissue 100 cm2. Conclusions: Liver fat accumulation assessed by CT was associated with the incidence of DM.

DOI： 10.1016/j.diabres.2020.108002

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Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18H04074/

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

File： download.pdf

J-GLOBAL

Language：Japanese   Publisher：THE JAPAN DIABETES SOCIETY  

A 27-year-old woman felt physical fatigue and loss of appetite 7 days after delivering her child. She was emergently hospitalized for disturbance of consciousness due to diabetic ketoacidosis and hyperammonemia 25 days after delivery. Although her metabolic acidosis and hyperglycemia were rapidly corrected with intravenous insulin infusion, the disturbance of consciousness and hyperammonemia did not improve. She had no remarkable medical history or family history of urea cycle disorders (UCDs), but a plasma amino acid analysis showed low serum citrulline levels, indicating UCD. Without additional treatment for hyperammonemia, her consciousness level improved with normalization of her serum ammonia and citrulline levels after oral zinc supplementation for the zinc deficiency (49 μ g/dL). This clinical course strongly suggested that hyperammonemia was caused by the temporary decrease in ornithine transcarbamylase activity due to zinc deficiency. It is necessary to consider the influence of zinc deficiency as a cause of acute hyperammonemia if malnutrition due to a long-term poor appetite is suspected.

DOI： 10.11213/tonyobyo.63.132

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

Background & aims: Although accurate assessment of energy intake (EI) is critical in diabetes care, underreporting of EI on dietary records (DR) is often an issue. However, few studies have examined EI with doubly labeled water (DLW) in patients with diabetes mellitus. We aimed to investigate the impact of sex and obesity on the dissociation of DR from total energy expenditure (TEE) evaluated with DLW in patients with type 2 diabetes. Methods: Fifty-two patients with type 2 diabetes aged 60–79 years were enrolled for the Clinical Evaluation of Energy Requirements in Patients with Diabetes Mellitus (CLEVER-DM) study at a single university hospital. TEE was measured over 14 days by the DLW method as standard. EI was calculated by assessment of 3-day DR by registered dietitians. Results: The mean difference between EI and TEE was 238 ± 412 kcal/day (~10% of TEE). Neither EI nor TEE was significantly different between obese (body mass index (BMI) ≥25 kg/m2) and non-obese (BMI <25 kg/m2) patients. There was a negative correlation between EI/TEE ratio and BMI in women (R = −0.437, P = 0.033) but not in men (R = −0.174, P = 0.377). There was a significant difference in EI/TEE ratio between obese and non-obese patients among women (0.85 ± 0.15 vs. 1.01 ± 0.21, P = 0.045) but not men (0.85 ± 0.20 vs. 0.87 ± 0.17, P = 0.79). Conclusions: EI calculated by 3-day DR may underestimate habitual intake, which is assumed to be equal to TEE measured by the DLW method except in non-obese women with diabetes. Clinical trial registration number: UMIN000023051.

DOI： 10.1016/j.clnesp.2020.07.001

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Aims/Introduction: Sodium–glucose cotransporter 2 inhibitors reduce bodyweight (BW) by creating a negative energy balance. Previous reports have suggested that this BW reduction is mainly loss of body fat and that ~20% of the reduction is lean mass. However, the effects of sodium–glucose cotransporter 2 inhibitors on BW and body composition remain unclear. We examined these effects in Japanese patients with type 2 diabetes mellitus treated with insulin. Materials and Methods: In this open-label, randomized controlled trial, 49 overweight patients (body mass index ≥23 kg/m2) with inadequate glycemic control (hemoglobin A1c >7.0%) receiving insulin treatment were randomly assigned to receive add-on ipragliflozin or no additional treatment (control group). Patients were followed for 24 weeks. The goal for all patients was to achieve glycated hemoglobin <7.0% without hypoglycemia. The primary end-point was a change in BW from baseline to week 24. Body composition was assessed with dual-energy X-ray absorptiometry and bioelectrical impedance analysis. Results: BW change was significantly larger in the ipragliflozin group than in the control group (−2.78 vs −0.22 kg, P < 0.0001). Total fat mass was reduced evenly in the arms, lower limbs and trunk in the ipragliflozin group. Total muscle mass and bone mineral content were maintained, but muscle mass in the arms might have been affected by ipragliflozin treatment. Conclusions: Ipragliflozin treatment for 24 weeks resulted in reduced BW, mainly from fat mass loss. Muscle mass and bone mineral content were maintained. Further study is necessary to elucidate the long-term effects of ipragliflozin.

DOI： 10.1111/jdi.12985

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

Aims/Introduction: Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods: Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross-sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results: The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (<30 mL/min/1.73 m2) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age-dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. Conclusions: During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity- and high age-related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively.

DOI： 10.1111/jdi.12977

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The intestinal microbiome produces short-chain fatty acids (SCFAs) from dietary fiber and has specific effects on other organs. During endurance exercise, fatty acids, glucose, and amino acids are major energy substrates. However, little is known about the role of SCFAs during exercise. To investigate this, mice were administered either multiple antibiotics or a low microbiome-accessible carbohydrate (LMC) diet, before endurance testing on a treadmill. Two-week antibiotic treatment significantly reduced endurance capacity versus the untreated group. In the cecum acetate, propionate, and butyrate became almost undetectable in the antibiotic-treated group, plasma SCFA concentrations were lower, and the microbiome was disrupted. Similarly, 6-wk LMC treatment significantly reduced exercise capacity, and fecal and plasma SCFA concentrations. Continuous acetate but not saline infusion in antibiotic-treated mice restored their exercise capacity (P < 0.05), suggesting that plasma acetate may be an important energy substrate during endurance exercise. In addition, running time was significantly improved in LMC-fed mice by fecal microbiome transplantation from others fed a high microbiome-accessible carbohydrate diet and administered a single portion of fermentable fiber (P < 0.05). In conclusion, the microbiome can contribute to endurance exercise by producing SCFAs. Our findings provide new insight into the effects of the microbiome on systemic metabolism.

DOI： 10.1152/ajpendo.00510.2018

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Objective Assessment of total energy expenditure (TEE) is essential for appropriate recommendations regarding dietary intake and physical activity in patients with and without diabetes mellitus (DM). However, few reports have focused on TEE in patients with DM, particularly in Asian countries. Therefore, we evaluated TEE in Japanese patients with DM using the doubly labeled water (DLW) method and physical activity level (PAL). Research design and methods In this cross-sectional observational study, we evaluated 52 patients with type 2 DM and 15 patients without DM. Free-living TEE was measured over 12-16 days by the DLW method, and PAL was calculated as TEE divided by the basal metabolic rate (BMR) as assessed by indirect calorimetry. The equivalence margin was defined as 5 kcal/kg/day. Results The numbers of patients with DM treated with insulin, oral antidiabetic drugs, and diet were 18 (34.6%), 20 (38.5%), and 14 (26.9%), respectively. The mean±SD level of glycated hemoglobin was 6.9%±0.8% and 5.5%±0.3% in the DM and non-DM group, respectively (p<0.001). The mean body mass index was 23.3±3.0 and 22.7±2.1 kg/m 2 in the DM and non-DM group, respectively. The mean TEE per kilogram body weight adjusted for sex and age was 36.5 kcal/kg/day and 37.5 kcal/kg/day in the DM and non-DM group, respectively, with no significant difference (mean difference,-1.0 kcal/kg/day; 95% CI-4.2 to 2.3 kcal/kg/day). The BMR tended to be higher in the DM than in the non-DM group (mean difference, 33 kcal/day; 95% CI,-15 to 80 kcal/day). The mean PAL adjusted for sex and age was 1.71 and 1.81 in the DM and non-DM group, respectively, without a significant difference (mean difference,-0.10; 95% CI-0.21 to 0.01). Conclusion TEE was comparable between Japanese patients with and without DM. Trial registration number UMIN000023051.

DOI： 10.1136/bmjdrc-2019-000648

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Aims/Introduction: Preprandial metformin administration significantly reduces postprandial plasma triglyceride levels in animal studies by reducing intestinal absorption through delayed gastric emptying. However, this effect has not been shown in a clinical study. Therefore, we planned to investigate the efficacy of preprandial metformin administration on postprandial hypertriglyceridemia and the related gastrointestinal effects in patients with type 2 diabetes mellitus. Materials and Methods: A total of 11 patients taking single-dose metformin at 500–1,000 mg, with non-fasting plasma triglyceride levels of 150–1,000 mg/dL, were recruited at a single university hospital. The difference between preprandial and postprandial metformin administration on postprandial hypertriglyceridemia was examined by a meal test. The gastrointestinal effects of metformin, including stomach heaviness, heartburn and satiety, were also assessed using a visual analog scale. Results: The mean bodyweight of patients was 80.6 kg (body mass index 27.9 kg/m2), and the mean non-fasting plasma triglyceride level was 275.9 ± 57.0 mg/dL. The area under the curve of triglyceride during the meal test was significantly lower in the preprandial protocol than in the postprandial protocol (P < 0.05). Compared with postprandial administration, preprandial administration of metformin increased satiety (P = 0.036) without stomach heaviness or heartburn. Conclusions: Preprandial metformin administration significantly reduced plasma triglyceride level during meal testing without marked exacerbation of gastrointestinal adverse effects. The present results suggest that a simple change in the timing of metformin administration represents a novel approach for enhancing triglyceride-lowering strategies in patients with type 2 diabetes mellitus and postprandial hypertriglyceridemia.

DOI： 10.1111/jdi.13016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Endocrine Society  

Laparoscopic sleeve gastrectomy has been proven effective in treating obesity-associated type 2 diabetes mellitus (T2DM). However, reports of the effect of laparoscopic sleeve gastrectomy on glucose metabolism in Japanese obese patients with T2DM are rare. The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy on glucose tolerance in Japanese obese patients with T2DM, and to analyze factors influencing diabetes remission after surgery. This was a retrospective analysis of data for 24 consecutive patients with T2DM who underwent laparoscopic sleeve gastrectomy. We investigated weight loss and its impact on T2DM 1 year postoperatively. We also compared baseline characteristics and postoperative factors between patients who achieved diabetes remission and patients without remission. Mean body weight loss and percent total weight loss were 23.9 kg and 23.3%, respectively. Mean hemoglobin A1c levels dropped from 7.3 ± 0.3% to 6.1 ± 0.2%, and 18 patients (75%) achieved diabetes remission 1 year postoperatively. Patients achieving remission had significantly lower hemoglobin A1c levels (p = 0.026), higher fasting C-peptide values (p < 0.001), shorter diabetes duration (p < 0.001), lower insulin requirement (p = 0.002), and higher area under the insulin response curve (p < 0.001) and insulinogenic index (p < 0.001) during oral glucose tolerance testing. In conclusion, laparoscopic sleeve gastrectomy is an effective treatment for Japanese obese patients with T2DM. Preserving insulin secretion is the major determinant of diabetes remission.

DOI： 10.1507/endocrj.EJ19-0054

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Authorship：Corresponding author   Language：English   Publisher：AMER DIABETES ASSOC  

Mitochondria are critical in heat generation in brown and beige adipocytes. Mitochondrial number and function are regulated in response to external stimuli, such as cold exposure and β3 adrenergic receptor agonist. However, the molecular mechanisms regulating mitochondrial biogenesis during browning, especially by microRNAs, remain unknown. We investigated the role of miR-494-3p in mitochondrial biogenesis during adipogenesis and browning. Intermittent mild cold exposure of mice induced PPARγ coactivator1-α (PGC1-α) and mitochondrial TFAM, PDH, and ANT1/2 expression along with uncoupling protein-1 (Ucp1) in inguinal white adipose tissue (iWAT). miR-494-3p levels were significantly downregulated in iWAT upon cold exposure (p < 0.05). miR-494-3p overexpression substantially reduced PGC1-α expression and its downstream targets TFAM, PDH and MTCO1 in 3T3-L1 white and beige adipocytes (p < 0.05). miR-494-3p inhibition in 3T3-L1 white adipocytes resulted in increased PDH (p < 0.05). PGC1-α, TFAM and Ucp1 mRNA levels were robustly downregulated by miR-494-3p overexpression in 3T3-L1 beige adipocytes, along with strongly decreased oxygen consumption rate. PGC1-α and Ucp1 proteins were downregulated by miR-494-3p in primary beige cells (p < 0.05). Luciferase assays confirmed PGC1-α as a direct gene target of miR-494-3p. Our findings demonstrate that decreased miR-494-3p expression during browning regulates mitochondrial biogenesis and thermogenesis through PGC1-α.

DOI： 10.1038/s41598-018-33438-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background Teff is a staple food in Ethiopia that is rich in dietary fiber. Although gaining popularity in Western countries because it is gluten-free, the effects of teff on glucose metabolism remain unknown. Aim To evaluate the effects of teff on body weight and glucose metabolism compared with an isocaloric diet containing wheat. Results Mice fed teff weighed approximately 13% less than mice fed wheat (p < 0.05). The teff-based diet improved glucose tolerance compared with the wheat group with normal chow but not with a high-fat diet. Reduced adipose inflammation characterized by lower expression of TNFα, Mcp1, and CD11c, together with higher levels of cecal short chain fatty acids such as acetate, compared with the control diet containing wheat after 14 weeks of dietary treatment. In addition, beige adipocyte formation, characterized by increased expression of Ucp-1 (~7-fold) and Cidea (~3-fold), was observed in the teff groups compared with the wheat group. Moreover, a body-weight matched experiment revealed that teff improved glucose tolerance in a manner independent of body weight reduction after 6 weeks of dietary treatment. Enhanced beige adipocyte formation without improved adipose inflammation in a body-weight matched experiment suggests that the improved glucose metabolism was a consequence of beige adipocyte formation, but not solely through adipose inflammation. However, these differences between teff- and wheat-containing diets were not observed in the high-fat diet group. Conclusions Teff improved glucose tolerance likely by promoting beige adipocyte formation and improved adipose inflammation.

DOI： 10.1371/journal.pone.0201661

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

Aims/Introduction: Diabetes and obesity are important health and economic concerns. We investigated the influence of obesity on diabetes control, the annual medical expenditures and medications in Japanese patients with type 2 diabetes who were relatively lean in comparison with those in Western countries. Materials and Methods: A total of 402 Japanese patients with type 2 diabetes were enrolled and their annual medical expenditures investigated. Obesity was defined as body mass index ≥25 kg/m2, according to the obesity classifications from the Japan Society for the Study of Obesity. Results: A total of 165 patients (41.0%) were classified as obese. The obese group was younger, had poor glycemic control and higher frequency of hypertension than the non-obese group. The median total annual medical expenditures for all participants was \269,333 (interquartile range \169,664–437,437), which was equivalent to approximately $US2,450. The annual medical expenditure was significantly higher in patients with obesity than in non-obese patients (P < 0.001). This difference was mainly attributed to the annual expenditures for medication and hospitalization. In particular, the medication expenditures and the average number of drug classes for hyperglycemia and hypertension were significantly higher in the obese group. Conclusions: Japanese patients with type 2 diabetes and obesity had higher annual medical expenditures and a larger number of medications, but their diabetes control care was insufficient in comparison with those without obesity. Further studies are required to assess the effect of reducing bodyweight on diabetes control and costs.

DOI： 10.1111/jdi.12766

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine (GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated. In this study, we created skeletal muscle-specific Ogt knockout (Ogt-MKO) mice and analyzed their glucose metabolism. During an intraperitoneal glucose tolerance test, blood glucose was slightly lower in Ogt-MKO mice than in control Ogt-flox mice. High fat diet-induced obesity and insulin resistance were reversed in Ogt-MKO mice. In addition, 12-month-old Ogt-MKO mice had lower adipose and body mass. A single bout of exercise significantly reduced blood glucose in Ogt-MKO mice, probably because of higher AMP-activated protein kinase α (AMPKα) protein expression. Furthermore, intraperitoneal injection of 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, resulted in a more marked decrease in blood glucose levels in Ogt-MKO mice than in controls. Finally, Ogt knockdown by siRNA in C2C12 myotubes significantly increased protein expression of AMPKα glucose uptake and oxidation. In conclusion, loss of O-GlcNAcylation facilitates glucose utilization in skeletal muscle, potentially through AMPK activation. The inhibition of O-GlcNAcylation in skeletal muscle may have an anti-diabetic effect, through an enhancement of glucose utilization during exercise.

DOI： 10.1016/j.bbrc.2017.12.081

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

© 2017, Springer-Verlag Berlin Heidelberg. Aims/hypothesis: O-GlcNAcylation is characterised by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (OGT) and serves in sensing intracellular nutrients by modulating various cellular processes. Although it has been speculated that O-GlcNAcylation is associated with glucose metabolism, its exact role in whole body glucose metabolism has not been fully elucidated. Here, we investigated whether loss of O-GlcNAcylation globally and in specific organs affected glucose metabolism in mammals under physiological conditions. Methods: Tamoxifen-inducible global Ogt-knockout (Ogt-KO) mice were generated by crossbreeding Ogt-flox mice with R26-Cre-ERT2 mice. Liver, skeletal muscle, adipose tissue and pancreatic beta cell-specific Ogt-KO mice were generated by crossbreeding Ogt-flox mice with Alb-Cre, Mlc1f-Cre, Adipoq-Cre and Pdx1PB-CreER™ mice, respectively. Glucose metabolism was evaluated by i.p. glucose and insulin tolerance tests. Results: Tamoxifen-inducible global Ogt-KO mice exhibited a lethal phenotype from 4 weeks post injection, suggesting that O-GlcNAcylation is essential for survival in adult mice. Tissue-specific Ogt deletion from insulin-sensitive organs, including liver, skeletal muscle and adipose tissue, had little impact on glucose metabolism under physiological conditions. However, pancreatic beta cell-specific Ogt-KO mice displayed transient hypoglycaemia (Ogt-flox 5.46 ± 0.41 vs Ogt-βKO 3.88 ± 0.26 mmol/l) associated with about twofold higher insulin secretion and accelerated adiposity, followed by subsequent hyperglycaemia (Ogt-flox 6.34 ± 0.32 vs Ogt-βKO 26.4 ± 2.37 mmol/l) with insulin depletion accompanied by beta cell apoptosis. Conclusions/interpretation: These findings suggest that O-GlcNAcylation has little effect on glucose metabolism in insulin-sensitive tissues but plays a crucial role in pancreatic beta cell function and survival under physiological conditions. Our results provide novel insight into O-GlcNAc biology and physiology in glucose metabolism.

DOI： 10.1007/s00125-017-4327-y

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：American Diabetes Association  

Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. O-linked N-acetylglucosamine (O-GlcNAc) modification is characterized by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of O-GlcNAc modification in adipose tissues. Here, we report the critical role of O-GlcNAc modification in cold-induced thermogenesis. Deletion of Ogt in WAT and BAT using adiponectin promoter-driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, Ogt deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator-activated receptor g coactivator 1-a protein expression. This phenotype was further confirmed by deletion of Ogt in BAT using Ucp1 promoter-driven Cre recombinase, suggesting that O-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid-rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, O-GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses.

DOI： 10.2337/db16-1427

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect.

DOI： 10.3390/nu9070654

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride-lowering effect of metformin. Here, we examined the effects of metformin on lipid metabolism after olive oil-loading in 129S mice fed a high fat diet for three weeks. Metformin administration (250 mg/kg) for one week decreased postprandial plasma triglycerides. Pre-administration (250 mg/kg) of metformin resulted in a stronger triglyceride-lowering effect (approximately 45% lower area under the curve) than post-administration. A single administration (250 mg/kg) of metformin lowered plasma postprandial triglycerides comparably to administration for one week, suggesting an acute effect of metformin on postprandial hypertriglyceridemia. To explore whole body lipid metabolism after fat-loading, stomach size, fat absorption in the intestine, and fat oxidation (13C/12C ratio in expired CO2after administration of glyceryl-1-13C tripalmitate) were measured with and without metformin (250 mg/kg) pre-treatment. In metformin-treated mice, larger stomach size, lower fat oxidation, and no change in lipid absorption were observed. In conclusion, metformin administration before fat loading reduced postprandial hypertriglyceridemia, most likely by delaying gastric emptying.

DOI： 10.3390/ijms18061282

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

© 2017 Kondo et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background & Aims A fiber-rich diet has a cardioprotective effect, but the mechanism for this remains unclear. We hypothesized that a fiber-rich diet with brown rice improves endothelial function in patients with type 2 diabetes mellitus. Methods Twenty-eight patients with type 2 diabetes mellitus at a single general hospital in Japan were randomly assigned to a brown rice (n = 14) or white rice (n = 14) diet and were followed for 8 weeks. The primary outcome was changes in endothelial function determined from flow debt repayment by reactive hyperemia using strain-gauge plethysmography in the fasting state. Secondary outcomes were changes in HbA1c, postprandial glucose excursions, and markers of oxidative stress and inflammation. The area under the curve for glucose after ingesting 250 kcal of assigned rice was compared between baseline (T0) and at the end of the intervention (T1) to estimate glucose excursions in each group. Results Improvement in endothelial function, assessed by fasting flow debt repayment (20.4% vs. -5.8%, p = 0.004), was significantly greater in the brown rice diet group than the white rice diet group, although the between-group difference in change of fiber intake was small (5.6 g/day vs. -1.2 g/day, p<0.0001). Changes in total, HDL-, and LDL-cholesterol, and urine 8-isoprostane levels did not differ between the two groups. The high-sensitivity C-reactive protein level tended to improve in the brown rice diet group compared with the white rice diet group (0.01 μg/L vs. -0.04 μg/L, p = 0.063). The area under the curve for glucose was subtly but consistently lower in the brown rice diet group (T0: 21.4 mmol/L∗h vs. 24.0 mmol/L∗h, p = 0.043, T1: 20.4 mmol/L∗h vs. 23.3 mmol/L∗h, p = 0.046) without changes in HbA1c. Conclusions Intervention with a fiber-rich diet with brown rice effectively improved endothelial function, without changes in HbA1c levels, possibly through reducing glucose excursions.

DOI： 10.1371/journal.pone.0179869

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Publishing type：Research paper (scientific journal)  

© 2016, The Japan Diabetes Society. We herein report a case involving a woman with type 1 diabetes and a history of metal allergy who developed a local delayed-type (type IV) allergy to zinc-containing insulin. She had been treated by continuous subcutaneous insulin infusion, but her glycemic control was poor, and she developed diabetic ketoacidosis. Her plasma insulin concentration was unexpectedly low during use of insulin lispro, but it was recovered by changing from the zinc-containing insulin lispro to the zinc-free insulin glulisine. Intradermal tests showed no reactions to various insulins except for zinc chloride. A skin biopsy at the injection site of insulin lispro showed invasion of lymphocytes, neutrophils, and eosinophils, but a skin biopsy at the injection site of insulin glulisine showed invasion of only lymphocytes. A drug lymphocyte stimulation test against polaprezinc, an antiulcer drug containing zinc, was positive. Therefore, we diagnosed the patient with local delayed allergy to zinc-containing insulin. Insulin allergy should be considered as a possible cause of poor glycemic control and diabetic ketoacidosis in patients with type 1 diabetes.

DOI： 10.1007/s13340-016-0264-0

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© 2016, The Japan Diabetes Society. Aims: We assessed the association between smoking status and mild cognitive impairment (MCI) in Japanese diabetic patients. Methods: This cross-sectional study included 323 diabetic patients, aged 40–79 years, who were referred to an outpatient diabetic clinic between January and July 2013 at Shiga University of Medical Science Hospital (Otsu, Japan). Cognitive function was assessed using the mini-mental state examination (MMSE), and patients were classified into two categories: normal cognitive function (MMSE score ≥27) and MCI (MMSE score 22–26). Logistic regression analysis was used to estimate the multivariable-adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for MCI in current smokers and ex-smokers compared with never-smokers. Results: Of the 323 patients, 55 (17.0 %), 134 (41.5 %), and 134 (41.5 %) were current smokers, ex-smokers, and never-smokers, respectively. Of these, 68 (21.0 %) patients had MCI. After adjusting for age, sex, systolic blood pressure, body mass index, high-density lipoprotein cholesterol, estimated glomerular filtration rate, hemoglobin A1c, insulin therapy, sulfonylurea, history of coronary heart disease, exercise habit, drinking status, and education, the OR for MCI was 3.62 (95 % CI 1.26–10.40) in current smokers compared with never-smokers. In addition, the multivariable-adjusted ORs for MCI were 3.02 (95 % CI 0.64–14.32) in current smokers <30.0 pack-years and 4.90 (95 % CI 1.32–18.16) in current smokers ≥30.0 pack-years, compared with never-smokers (p for trend = 0.017). Conclusions: Current smoking, especially current smoking for which cumulative lifetime exposure was high, was associated with MCI, as assessed using the MMSE in Japanese diabetic patients.

DOI： 10.1007/s13340-016-0256-0

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Mitochondrial ferritin (FtMt) is believed to play an antioxidant role via iron regulation, and FtMt gene mutation has been reported in age-related macular degeneration (AMD). However, little is known about FtMt's functions in the retina and any links to AMD. In this study, we observed age-related increase in FtMt and hypoxia-inducible factor-1α (HIF-1α) in murine retinal pigment epithelium (RPE). FtMt overexpression in ARPE-19 cells stabilized HIF-1α, and increased the secretion of vascular endothelial growth factor. Conversely, HIF-1α stabilization reduced the protein level of the mature, functional form of FtMt. FtMt-overexpressing ARPE-19 cells exhibited less oxidative phosphorylation but unchanged production of adenosine triphosphate, enhanced mitochondrial fission, and triggered mitophagy in a HIF-1α-dependent manner. These findings suggest that increased FtMt in RPE may be protective via triggering mitophagy but cause wet AMD by inducing neovascularization due to increased vascular endothelial growth factor secretion. However, reduced level of functional FtMt in RPE under hypoxia may allow dry AMD through susceptibility to age-related stress.

DOI： 10.1016/j.neurobiolaging.2016.07.025

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BACKGROUND: Management of postprandial hyperglycemia is a key aspect in diabetes treatment. We developed a novel system to measure glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET) for simple monitoring of postprandial glucose excursions. In this study, we evaluated the relationship between our system and continuous glucose monitoring (CGM) by comparing glucose AUC obtained using MIET with that obtained using CGM for a long duration. METHODS: Twenty diabetic inpatients wearing a CGM system were enrolled. For MIET measurement, a plastic microneedle array was applied to the skin as pretreatment, and hydrogels were placed on the pretreated area to collect interstitial fluid. Hydrogels were replaced every 2 or 4 hours and AUC was predicted on the basis of glucose and sodium ion levels. RESULTS: AUC predicted by MIET correlated well with that measured by CGM (r=0.93). Good performances of both consecutive 2- and 4-hour measurements were observed (measurement error: 11.7%±10.2% for 2 hours and 11.1%±7.9% for 4 hours), indicating the possibility of repetitive measurements up to 8 hours. The influence of neither glucose fluctuation nor average glucose level over the measurement accuracy was observed through 8 hours. CONCLUSION: Our system showed good relationship with AUC values from CGM up to 8 hours, indicating that single pretreatment can cover a large portion of glucose excursion in a day. These results indicated possibility of our system to contribute to convenient monitoring of glucose excursions for a long duration.

DOI： 10.4093/dmj.2016.40.4.326

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Publishing type：Research paper (scientific journal)  

© 2016 The Authors. Renal sinus fat is partially characteristic of peri-vascular adipose tissue, however, RSF volume (RSFV) is associated with visceral adipose tissue (VATV). Therefore, the ratio of RSFV to VATV (RSFV/VATV ratio) can distinguish the importance of RSF as an extension of VAT versus its perivascular effects. We assessed the association of RSFV/VATV ratio with coronary artery calcification score (CACS) in 189 patients with suspected coronary artery disease. RSFV of the right kidney and VATV were quantified by using image data of unenhanced abdominal CT. CACS were measured on unenhanced ECG-gated CT images. This article contains data on explanatory scheme of how to measure RSFV on unenhanced abdominal CT, CT indication and exclusion criteria of study population, sex-adjusted association between RSFV with risk factors of coronary vascular diseases and metabolic indices, multivariate linear regression analysis with CACS as the dependent variable in the total study population. The data are supplemental to our original research article describing detailed association between RSFV/VATV ratio and CACS including sub-groups analyses classified by the age of 70 "Renal sinus fat volume on computed tomography in middle-aged patients at risk for cardiovascular disease and its association with coronary artery calcification" Murakami et al. [1].

DOI： 10.1016/j.dib.2016.04.027

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

Aims: This study assessed the association between attentional function and postural instability in older Japanese patients with diabetes. Methods: This cross-sectional study included 168 older patients with diabetes who were referred to an outpatient diabetic clinic between June and July 2013. The Trail Making Test-A (TMT-A) was used to evaluate attentional function. Posturography was used to evaluate postural sway. Indices of postural sway were the total length and the enveloped area. Analysis of covariance was used to estimate the multivariable-adjusted means of indices of postural sway according to tertile of TMT-A. Results: After adjustment for age, sex, regular exercise, diabetic retinopathy, bilateral numbness and/or paresthesia in the feet, hemoglobin A1c level, quadriceps strength, and Mini-Mental State Examination score, patients with lower attentional function had higher postural sway length (tertile 3 vs. tertile 1, p = 0.010) and enveloped area (tertile 3 vs. tertile 1, p = 0.030) levels than those with higher attentional function. Conclusions: Among older patients with diabetes who did not have dementia, patients with lower attentional function may have more postural instability than those with higher attentional function.

DOI： 10.1007/s13340-015-0231-1

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

Aim: This study assessed the association between symptoms of bilateral numbness and/or paresthesia in the feet and postural instability in Japanese patients with diabetes. Methods: This cross-sectional study included 303 patients with diabetes, aged 40–88 years, who were referred to an outpatient diabetic clinic between January and July 2013 at Shiga University of Medical Science Hospital. A posturography test was used to evaluate postural sway in patients. Indices of postural sway were the total length and the enveloped area. Analysis of covariance was used to estimate the multivariable-adjusted means of indices of postural sway according to the presence or absence of symptoms of bilateral numbness and/or paresthesia in the feet. Results: Of 303 patients, 35 (11.6 %) had symptoms of bilateral numbness and/or paresthesia in the feet. After adjustment for age, sex, diabetic retinopathy, regular exercise, body mass index, hemoglobin A1c level, and quadriceps’ strength, patients with symptoms had higher levels of postural sway length and an enveloped area in the posturography test than those without symptoms. In addition, we observed similar results when we analyzed 234 patients aged ≥60 years. Conclusions: Our findings suggest that patients who had symptoms of bilateral numbness and/or paresthesia in the feet may have more postural instability than those without symptoms.

DOI： 10.1007/s13340-015-0214-2

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

Objective: Renal sinus fat (RSF) behaves as one of the perivascular fats, however RSF volume (RSFV) is considerably affected by visceral adipose tissue volume (VTAV). The ratio of RSFV to VATV (RSFV/VATV ratio) can be an index of regional perivascular fat accumulation corrected for the influence of VATV. The aim of this study was to investigate the relation between RSFV/VATV ratio and coronary artery calcium (CAC) in patients with suspected coronary artery disease.
Methods: One hundred and eighty-nine patients (mean age 66.7 +/- 10.2; 72% men) underwent ECG-gated cardiac computed tomography (CT) and unenhanced abdominal CT. CAC score (CACS) was assessed using axial CT images. RSFV was measured by partially manipulated segmentation of the right kidney. VATV was automatically quantified in the upper abdomen. Logistic and correlation analyses were performed to examine the correlations between CAC, RSFV/VATV ratio, and risk factors of cardiovascular diseases in total and subgroups classified by the patients' age.
Results: Log-transformed RSFV/VATV ratio was associated with CAC presence in 112 middle-aged patients less than 69 years of age as well as total. This association remained significant after multivariate adjustment only in the middle-aged patients (OR 15.9, 95% CI 1.15-218.8). In total, RSFV/VATV ratio (r = 0.228, p = 0.002) and age (r = 0.316, p &lt; 0.001) correlated with CACS on univariate analyses, but only age correlated on multivariate analyses. RSFV/VATV ratio correlated with CACS in the middle-aged patients (r = 0.418, p &lt; 0.001), as well as on multivariate analyses.
Conclusions: We demonstrated that RSFV/VATV could be an independent risk indicator of CAC in the middle-aged patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2015.12.014

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

Amla is one of the most important plants in Indian traditional medicine and has been shown to improve various age-related disorders while decreasing oxidative stress. Mitochondrial dysfunction is a proposed cause of aging through elevated oxidative stress. In this study, we investigated the effects of Amla on mitochondrial function in C2C12 myotubes, a murine skeletal muscle cell model with abundant mitochondria. Based on cell flux analysis, treatment with an extract of Amla fruit enhanced mitochondrial spare respiratory capacity, which enables cells to overcome various stresses. To further explore the mechanisms underlying these effects on mitochondrial function, we analyzed mitochondrial biogenesis and antioxidant systems, both proposed regulators of mitochondrial spare respiratory capacity. We found that Amla treatment stimulated both systems accompanied by AMPK and Nrf2 activation. Furthermore, we found that Amla treatment exhibited cytoprotective effects and lowered reactive oxygen species (ROS) levels in cells subjected to t-BHP-induced oxidative stress. These effects were accompanied by increased oxygen consumption, suggesting that Amla protected cells against oxidative stress by using enhanced spare respiratory capacity to produce more energy. Thus we identified protective effects of Amla, involving activation of mitochondrial function, which potentially explain its various effects on age-related disorders.

DOI： 10.1155/2016/1735841

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PubMed

Language：English  

DOI： 10.1155/2016/5831538

PubMed

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

Mitochondrial oxidative capacity in skeletal muscle is known to decrease in diabetic patients, and sarcopenia is a risk factor for diabetes, particularly in elderly people. We previously revealed that microRNA (miR)-494 inhibits mitochondrial biogenesis during myogenic differentiation in murine C2C12 cells and others reported that exercise regulates miR-494 levels in obese sedentary individuals with increased risk of type 2 diabetes. In this study, to investigate the therapeutic potential of miR-494, we first investigated the role of miR-494 during human skeletal myogenesis. Using human induced pluripotent stem (hiPS) cells stably transfected with the Tet/ON-myogenic differentiation 1(MYOD1) gene (MyoD-hiPS cells), we found that miR-494 expression transiently increased and was downregulated after myogenic induction. In miR-494 transfected MyoD-hiPS cells, the level of high oxidative fiber (type IIa) marker proteins specifically decreased, while no change in the total number of cells was observed. In contrast, the expression of both type I and type Ilx markers was unaffected by miR-494 overexpression. Furthermore, miR-494 overexpression suppressed basal oxygen consumption rate concomitant with the inhibition of myotube formation and without significant effects on the mitochondrial content. These results suggest that miR-494 plays a novel role in the fiber type-specific skeletal myogenesis in MyoD-hiPS cells, distinct from murine C2C12 myogenesis. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.10.128

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI  

N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have protective effects against atherosclerosis. Monocyte chemotactic protein (MCP)-1 is a major inflammatory mediator in the progression of atherosclerosis. However, little is known about the regulation of Mcp-1 by DHA and EPA in vessels and vascular smooth muscle cells (VSMCs). In this study, we compared the effect of DHA and EPA on the expression of Mcp-1 in rat arterial strips and rat VSMCs. DHA, but not EPA, suppressed Mcp-1 expression in arterial strips. Furthermore, DHA generated 4-hydroxy hexenal (4-HHE), an end product of n-3 polyunsaturated fatty acids (PUFAs), in arterial strips as measured by liquid chromatography-tandem mass spectrometry. In addition, 4-HHE treatment suppressed Mcp-1 expression in arterial strips, suggesting 4-HHE derived from DHA may be involved in the mechanism of this phenomenon. In contrast, Mcp-1 expression was stimulated by DHA, EPA and 4-HHE through p38 kinase and the Keap1-Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway in VSMCs. In conclusion, there is a dual effect of n-3 PUFAs on the regulation of Mcp-1 expression. Further study is necessary to elucidate the pathological role of this phenomenon.

DOI： 10.3390/nu7095381

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Previous studies have implicated age-associated reductions in mitochondrial oxidative phosphorylation activity in skeletal muscle as a predisposing factor for intramyocellular lipid (IMCL) accumulation and muscle insulin resistance (IR) in the elderly. To further investigate potential alterations in muscle mitochondrial function associated with aging, we assessed basal and insulin-stimulated rates of muscle pyruvate dehydrogenase (V-PDH) flux relative to citrate synthase flux (V-CS) in healthy lean, elderly subjects and healthy young body mass index-and activity-matched subjects. V-PDH/V-CS flux was assessed from the C-13 incorporation from of infused [1-C-13] glucose into glutamate [4-C-13] relative to alanine [3-C-13] assessed by LC-tandem MS in muscle biopsies. Insulin-stimulated rates of muscle glucose uptake were reduced by 25% (P &lt; 0.01) in the elderly subjects and were associated with similar to 70% (P &lt; 0.04) increase in IMCL, assessed by H-1 magnetic resonance spectroscopy. Basal V-PDH/V-CS fluxes were similar between the groups (young: 0.20 +/- 0.03; elderly: 0.14 +/- 0.03) and increased approximately threefold in the young subjects following insulin stimulation. However, this increase was severely blunted in the elderly subjects (young: 0.55 +/- 0.04; elderly: 0.18 +/- 0.02, P = 0.0002) and was associated with an similar to 40% (P = 0.004) reduction in insulin activation of Akt. These results provide new insights into acquired mitochondrial abnormalities associated with aging and demonstrate that age-associated reductions in muscle mitochondrial function and increased IMCL are associated with a marked inability of mitochondria to switch from lipid to glucose oxidation during insulin stimulation.

DOI： 10.1073/pnas.1514844112

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PubMed

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

The objective of this study was to explore predictors, including social factors, lifestyle factors, and factors relevant to glycemic control and treatment, for mild and severe hypoglycemia in insulin-treated Japanese diabetic patients. This study included 123 insulin-treated diabetic patients who were referred to the diabetes clinic between January and July 2013 at Shiga University of Medical Science Hospital. After a survey examining the various factors, patients were followed for 6 months. During the follow-up period, blood glucose was self-monitored. Mild hypoglycemia was defined as blood glucose level 50-69 mg/dl, and severe hypoglycemia was defined as blood glucose level &lt;= 49 mg/dl. Multinomial logistic regression was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) of each factor for mild and severe hypoglycemia. During the 6-month follow-up period, 41 (33.3%) patients experienced mild hypoglycemia, and 20 (16.3%) experienced severe hypoglycemia. In multivariable-adjusted analyses, assistance from family members at the time of the insulin injection [presence/absence, OR (95% CI): 0.39 (0.16-0.97)] and drinking [current drinker/non- and ex-drinker, OR (95% CI): 4.89 (1.68-14.25)] affected mild hypoglycemia. Assistance from family members at the time of insulin injection [presence/absence, OR (95% CI): 0.19 (0.05-0.75)] and intensive insulin therapy [yes/no, OR (95% CI): 3.61 (1.06-12.26)] affected severe hypoglycemia. In conclusion, our findings suggest that not only a factor relevant to glycemic control and treatment (intensive insulin therapy) but also a social factor (assistance from family members) and a lifestyle factor (current drinking) were predictors for mild or severe hypoglycemia in Japanese insulin-treated diabetic patients.

DOI： 10.1371/journal.pone.0130584

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PubMed

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

To quantitatively evaluate the efficacy of methylprednisolone pulse therapy for extraocular muscle inflammation in thyroid-associated ophthalmopathy (TAO) using the short-tau inversion-recovery (STIR) technique of magnetic resonance imaging (MRI).
The signal intensities of the superior rectus (SR), inferior rectus (IR), lateral rectus (LR), medial rectus (MR), and superior oblique (SO) muscles were measured using the STIR images from 34 eyes of 17 patients with TAO before and after methylprednisolone pulse therapy and 19 eyes of 19 controls. The signal intensity ratio (SIR) of the signal intensity in muscles to that in brain white matter was calculated.
The mean SIRs of the controls were 1.08 +/- A 0.26 in the SR, 1.32 +/- A 0.29 in the IR, 1.34 +/- A 0.19 in the LR, 1.47 +/- A 0.25 in the MR, and 1.28 +/- A 0.22 in the SO muscles. SIRs exceeding 2.0 were out of the normal range. The SIRs of the patients with TAO before treatment were 2.19 +/- A 0.64, 2.44 +/- A 0.58, 1.96 +/- A 0.43, 2.24 +/- A 0.47, and 1.91 +/- A 0.42, respectively, which was significantly (P &lt; 0.001) higher than those of the controls; after treatment, the mean SIRs were 1.82 +/- A 0.57, 1.81 +/- A 0.49, 1.64 +/- A 0.35, 1.88 +/- A 0.43, and 1.54 +/- A 0.33, respectively, significantly (P &lt; 0.001) lower in all muscles than those before treatment. However, the SIRs of some muscles remained over 2.0. Moreover, all cases that had deterioration of TAO had one or more muscles with a SIR exceeding 2.5 after treatment.
Extraocular muscle inflammation in TAO improved with treatment. However, inflammation in some muscles persisted after treatment, and a high SIR in the muscle after treatment suggested the risk of deterioration of TAO.

DOI： 10.1007/s10384-014-0365-x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Objective. The beneficial effects of fish and n-3 polyunsaturated fatty acids (PUFAs) consumption on atherosclerosis have been reported in numerous epidemiological studies. However, to the best of our knowledge, the effects of a fish-based diet intervention on endothelial function have not been investigated. Therefore, we studied these effects in postmenopausal women with type 2 diabetes mellitus (T2DM).
Materials/Methods. Twenty-three postmenopausal women with T2DM were assigned to two four-week periods of either a fish-based diet (n-3 PUFAs &gt;= 3.0 g/day) or a control diet in a randomized crossover design. Endothelial function was measured with reactive hyperemia using strain-gauge plethysmography and compared with the serum levels offatty acids and their metabolites. Endothelial function was determined with peak forearm blood flow (Peak), duration of reactive hyperemia (Duration) and flow debt repayment (FDR).
Results. A fish-based dietary intervention improved Peak by 63.7%, Duration by 27.9% and FDR by 70.7%, compared to the control diet. Serum n-3 PUPA levels increased after the fishbased diet period and decreased after the control diet, compared with the baseline (1.49 vs. 0.97 vs. 1.19 mmol/l, p &lt;0.0001). There was no correlation between serum n-3 PUPA levels and endothelial function. An increased ratio of epoxyeicosatrienoic acid/dihydroxyeicosatrienoic acid was observed after a fish-based diet intervention, possibly due to the inhibition of the activity of soluble epoxide hydrolase.
Conclusions. A fish-based dietary intervention improves endothelial function in postmenopausal women with T2DM. Dissociation between the serum n-3 PUPA concentration and endothelial function suggests that the other factors may contribute to this phenomenon. (c) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2014.04.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Periodontal disease is related to aging, smoking habits, diabetes mellitus, and systemic inflammation. However, there remains limited evidence about causality from intervention studies. An effective diet for prevention of periodontal disease has not been well established. The current study was an intervention study examining the effects of a high-fiber, low-fat diet on periodontal disease markers in high-risk subjects. Forty-seven volunteers were interviewed for recruitment into the study. Twenty-one volunteers with a body mass index of at least 25.0 kg/m(2) or with impaired glucose tolerance were enrolled in the study. After a 2- to 3-week run-in period, subjects were provided with a test meal consisting of high fiber and low fat (30 kcal/kg of ideal body weight) 3 times a day for 8 weeks and followed by a regular diet for 24 weeks. Four hundred twenty-five teeth from 17 subjects were analyzed. Periodontal disease markers assessed as probing depth (2.28 vs 2.21 vs 2.13 mm; P &lt; .0001), clinical attachment loss (6.11 vs 6.06 vs 5.98 mm; P &lt; .0001), and bleeding on probing (16.2 vs 13.2 vs 14.6%; P = .005) showed significant reductions after the test-meal period, and these improvements persisted until the follow-up period. Body weight (P &lt; .0001), HbA1c (P &lt; .0001), and high-sensitivity C-reactive protein (P = .038) levels showed improvement after the test-meal period; they returned to baseline levels after the follow-up period. In conclusion, treatment with a high-fiber, low-fat diet for 8 weeks effectively improved periodontal disease markers as well as metabolic profiles, at least in part, by effects other than the reduction of total energy intake. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.nutres.2014.06.001

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Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)   Publisher：滋賀医科大学雑誌刊行会  

Excess bodyweight is a major public health concern. Obesity, as measured by body-mass index (BMI), has increased inrecent decades in many populations in the world. Obesity is an important risk factor for mortality and morbidity from cardiovascular diseases,diabetes, cancers, and musculoskeletal disorders, causing deaths worldwide. The bariatric surgery is the most efficacious therapy for morbidobesity today. The global total number of bariatric operations performed in 2011 was more than three hundred thousand. In our country, thenumber of bariatric operations performed in 2011 was more than 150 and it is increasing. Obese patient often has psychological and/or socialproblems, which induce a condition that is difficult to treat. Therefore multidisciplinary team approach is needed as American Society forMetabolic & Bariatric Surgery (ASMBS), International Federation for the Surgery of Obesity & Metabolic Disorders (IFSO) and JapaneseSociety for the Surgery of Obesity and Metabolic Disorders（JSSO）mentioned in their guidelines. We have performed bariatric surgery andhave taken a multidisciplinary team approach since 2008. Our team consists of doctors, nurses, dieticians, clinical psychotherapists, socialworkers and Nutrition Support Team (NST). In this paper, we describe our multidisciplinary team approach for surgical treatment for morbidobesity.

Language：Japanese   Publisher：滋賀医科大学  

本研究では、外来通院中の糖尿病患者を対象に軽症及び重症を含めた低血糖症状ありの割合、低血糖症状出現頻度、自覚症状、対処法を明らかにすることで、外来通院中の糖尿病患者の低血糖の実態を把握することを目的とした。2013年1月から9月までの期間に滋賀医科大学医学部附属病院糖尿病内分泌内科外来に通院した40歳から79歳の糖尿病患者374名(平均年齢65.3±9.8歳、男性63.1%)において、過去3ヵ月間に1度でも低血糖症状があった者は91名(24.3%)であった。性別では、男性に比べて女性で低血糖症状があった者が有意に多く(p<0.001)、一方年代による有意差は見られなかった(p=0.140)。低血糖症状ありの者の半数以上が1ヵ月あたり複数回の低血糖症状を自覚しており、自覚症状は、"冷や汗"が72名(79.1%)と最も多く、次いで"手指の震え"42名(46.2%)であった。対処法は、"血糖を測る"が58名(63.7%)と最も多く、次いで"ブドウ糖を摂取する"が50名(54.9%)、"砂糖を摂取する"が44名(48.4%)であり、対処をしなかった者はいなかった。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J04402&link_issn=&doc_id=20140319260010&doc_link_id=1403008&url=https%3A%2F%2Fkango-sakuin.nurse.or.jp%2Fnid%2F1403008&type=%8D%C5%90V%8A%C5%8C%EC%8D%F5%88%F8Web&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00014_1.gif

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

It has recently been reported that expression of heme oxygenase-1 (HO-1) plays a protective role against many diseases. Furthermore, n-3 polyunsaturated fatty acids (PUFAs) were shown to induce HO-1 expression in several cells in vitro, and in a few cases also in vivo. However, very few reports have demonstrated that n-3 PUFAs induce HO-1 in vivo.
In this study, we examined the effect of fish-oil dietary supplementation on the distribution of fatty acids and their peroxidative metabolites and on the expression of HO-1 in multiple tissues (liver, kidney, heart, lung, spleen, intestine, skeletal muscle, white adipose, brown adipose, brain, aorta, and plasma) of C57BL/6 mice. Mice were divided into 4 groups, and fed a control, safflower-oil, and fish-oil diet for 3 weeks. One group was fed a fish-oil diet for just 1 week. The concentration of fatty acids, 4-hydroxy hexenal (4-HHE), and 4-hydroxy nonenal (4-HNE), and the expression of HO-1 mRNA were measured in the same tissues.
We found that the concentration of 4-HHE (a product of n-3 PUFAs peroxidation) and expression of HO-1 mRNA were significantly increased after fish-oil treatment in most tissues. In addition, these increases were paralleled by an increase in the level of docosahexaenoic acid (DHA) but not eicosapentaenoic acid (EPA) in each tissue. These results are consistent with our previous results showing that DHA induces HO-1 expression through 4-HHE in vascular endothelial cells. In conclusion, we hypothesize that the HO-1-mediated protective effect of the fish oil diet may be through production of 4-HHE from DHA but not EPA in various tissues. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.12.085

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

Objective The aim of this study was to search for novel markers of visceral adiposity. Methods Visceral (omental) and subcutaneous adipose tissues were obtained from 43 Japanese men. Microarray analysis using total RNA from visceral and subcutaneous adipose tissues obtained from five men with abdominal obesity and five nonobese men was first conducted. Then the expression pattern of candidate genes identified in the human study in mouse models of adiposity was examined. Results Among 30,500 genes evaluated, the mRNA expression of CCDC3 (encoding coiled-coil domain-containing protein 3) was upregulated in omental adipose tissues from abdominally obese subjects (3.07-fold) but not in subcutaneous adipose tissues (0.89-fold). Similar expression patterns were found in two distinct mouse models of obesity. In the analysis of all 43 men, CCDC3 mRNA levels in omental, but not in subcutaneous adipose tissue, were positively correlated with waist circumference and body mass index. CCDC3 was predicted to be a secretory protein, which was confirmed by western blotting, as overexpressed CCDC3 was secreted into the culture media. Conclusions The expression of CCDC3 is specifically increased in visceral adipose tissues in abdominally obese subjects. These results suggest that CCDC3 is a potential biomarker for estimating visceral adiposity. Copyright © 2013 The Obesity Society.

DOI： 10.1002/oby.20645

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PubMed

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

Nonalcoholic fatty liver disease is the most frequent liver disease. Ezetimibe, an inhibitor of intestinal cholesterol absorption, has been reported to ameliorate hepatic steatosis in human and animal models. To explore how ezetimibe reduces hepatic steatosis, we investigated the effects of ezetimibe on the expression of lipogenic enzymes and intestinal lipid metabolism in mice fed a high-fat or a high-fructose diet. CBA/JN mice were fed a high-fat diet or a high-fructose diet for 8 wk with or without ezetimibe. High-fat diet induced hepatic steatosis accompanied by hyperinsulinemia. Treatment with ezetimibe reduced hepatic steatosis, insulin levels, and glucose production from pyruvate in mice fed the high-fat diet, suggesting a reduction of insulin resistance in the liver. In the intestinal analysis, ezetimibe reduced the expression of fatty acid transfer protein-4 and apoB-48 in mice fed the high-fat diet. However, treatment with ezetimibe did not prevent hepatic steatosis, hyperinsulinemia, and intestinal apoB-48 expression in mice fed the high-fructose diet. Ezetimibe decreased liver X receptor-≥ binding to the sterol regulatory elementbinding protein-1c promoter but not expression of carbohydrate response element-binding protein and fatty acid synthase in mice fed the highfructose diet, suggesting that ezetimibe did not reduce hepatic lipogenesis induced by the high-fructose diet. Elevation of hepatic and intestinal lipogenesis in mice fed a high-fructose diet may partly explain the differences in the effect of ezetimibe. © 2013 the American Physiological Society.

DOI： 10.1152/ajpendo.00442.2012

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PubMed

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

Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra-aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra-vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA.

DOI： 10.1371/journal.pone.0069415

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

Background: Enhanced secretion of glucagon-like peptide-1 (GLP-1) has been suggested as a possible mechanism underlying the improvement in type 2 diabetes mellitus (T2DM) after laparoscopic sleeve gastrectomy (LSG). However, the reason for enhanced GLP-1 secretion during glucose challenge after LSG remains unclear because LSG does not include intestinal bypass. In this study, we focused on the effects of LSG on GLP-1 secretion and intestinal motility during the oral glucose tolerance test (OGTT) using cine magnetic resonance imaging (MRI) before and 3 months after LSG.
Methods: LSG was performed in 12 obese patients with a body mass index &gt;35 kg/m(2). Six patients had T2DM. OGTT was performed before and 3 months after the surgery. Body weight, hemoglobin A1c (HbA1c), and GLP-1 levels during OGTT were examined, and intestinal motility during OGTT was assessed using cine MRI.
Results: Body weight was significantly decreased after surgery in all the cases. HbA1c was markedly decreased in all the diabetic subjects. In all cases, GLP-1 secretion during OGTT was enhanced and cine MRI showed markedly increased intestinal motility at 15 and 30 min during OGTT after LSG.
Conclusions: LSG leads to accelerated intestinal motility and reduced intestinal transit time, which may be involved in the mechanism underlying enhanced GLP-1 secretion during OGTT after LSG.

DOI： 10.1371/journal.pone.0065739

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

Dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery. In this case, the patient was a 47-year-old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer. She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between one and two hours after a meal. Because a 75g oral glucose tolerance test (75g-OGTT) induced both acute postprandial tachycardia (within 1 hour) and postprandial hypoglycemia, we diagnosed this patient with early and late dumping syndrome. Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as postprandial tachycardia, weakness, headache, palpitation, and dizziness. We therefore used the somatostatin analogue octreotide, which has been reported as an effective therapy for early dumping syndrome. Octreotide prevented the symptoms of early dumping syndrome, especially postprandial tachycardia, but caused postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75g-OGTT following subcutaneous injection of octreotide. No change was observed in vasoactive intestinal polypeptide (VIP), which is the gastrointestinal peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient. © The Japan Endocrine Society.

DOI： 10.1507/endocrj.EJ12-0288

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PubMed

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

DOI： 10.1016/j.bbrc.2012.10.115

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

DOI： 10.1016/j.bbrc.2011.11.114

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

DOI： 10.1073/pnas.1205675109

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

DOI： 10.2337/db11-1391

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1152/ajpendo.00097.2012

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

Abnormal secretion of adipocytokines promotes atherosclerosis, diabetes and insulin resistance, and is mainly induced by adipocyte hypertrophy. Recently, the circulating adipocytokine concentrations were reported to change in the postprandial period, as the levels of TNFα, IL-6 IL-8 and MCP-1 increased after a meal, whereas that of adiponectin decreased. These data suggest that prandial modulation of cytokines may be involved in the pathogenesis of atherosclerosis in type 2 diabetes. However, the regulatory mechanism of such change is still unclear. In the present study, we identified this mechanism with a special focus on the functions of protein kinase C (PKC) and of the transcription factor AP-2β, both of which are associated with the pathophysiology of adipocytokine regulation. PKCμ was highly phosphorylated in the re-feeding condition compared to the fasting condition in mouse adipose tissue, while other PKC isoforms remained unchanged. Furthermore, overexpression of PKCμ in 3T3-L1 adipocytes, but not other PKC isoforms, positively regulated the mRNA expression and promoter activity of MCP-1 and IL-6, and negatively regulated those of adiponectin. AP-2β had similar effects on the expression and promoter activity of these adipocytokines. Interestingly, overexpression of PKCμ enhanced the stimulatory and inhibitory effects of AP-2β on the expression of these adipocytokines. Finally, PKCμ could not activate a mutant MCP-1 promoter lacking the AP-2β binding domain. Our results suggest that postprandial activation of PKCμ plays a role in disordered postprandial adipocytokine expression through AP-2β.

DOI： 10.3892/ijmm.2011.651

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PubMed

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

Aim: The aim of our study was to investigate whether serum levels of soluble tumor necrosis factor α receptor (sTNFR) 1 and 2 are markers for renal dysfunction in type 2 diabetic patients without overt proteinuria. Methods: Japanese type 2 diabetic patients without overt proteinuria (n = 168) enrolled in the prospective observational follow-up study in 2001 were retrospectively analyzed. At baseline, the serum levels of sTNFR1 and sTNFR2 were measured by sandwich ELISA. The associations between these markers and change in estimated glomerular filtration rate (eGFR) after 5 years were evaluated. Results: The levels of sTNFR1 and sTNFR2 closely correlated. At baseline, sTNFR1 and sTNFR2 associated inversely with eGFR. After 5 years, patients with high level of both sTNFR1 and sTNFR2 showed a greater decline in eGFR (-13.8 ± 15.5% versus -8.5 ± 11.8%, P = 0.027) and a 4-fold higher risk for a GFR decline of ≥25% than those with high level of only one receptor or low level of both receptors. These associations were enhanced in diabetic women. Conclusions: The higher levels of sTNFR1 and sTNFR2 were associated with a greater decline in eGFR in type 2 diabetic patients without proteinuria, especially in diabetic women. © 2011 Elsevier Ireland Ltd.

DOI： 10.1016/j.diabres.2011.01.008

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PubMed

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.5551/jat.3657

Scopus

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

DOI： 10.1016/j.bbrc.2010.01.056

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

DOI： 10.1038/ijo.2009.295

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

DOI： 10.1016/j.bbrc.2010.09.124

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

We previously reported an association between the activating protein (AP)-2 beta transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2 beta showed stronger AP-2 beta expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2 beta leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study, we found that overexpression of AP-2 beta in 3T3-L1 adipocytes accelerated the promoter activity of monocyte chemoattractant protein-1 (MCP-1) and subsequently increased both mRNA and protein expression and protein secretion. Furthermore, knockdown of endogenous AP-2 beta by RNA interference reduced the mRNA and the protein expression of MCP-1. EMSAs and chromatin immunoprecipitation assays revealed specific binding of AP-2 beta to MCP-1 promoter regions, in vitro and in vivo. Additionally, site-directed mutagenesis of the AP-2 binding site located at-137 to-129 relative to the transcription start site markedly diminished MCP-1 promoter activity, whereas other putative AP-2 binding sites did not. Our results clearly show that AP-2 beta directly enhanced MCP-1 secretion by binding to its promoter. Thus, we propose that AP-2 beta positively regulates MCP-1 expression; subsequently contributes to the infiltration of macrophages to adipose tissue; and leads to insulin resistance, type 2 diabetes, and cardiovascular diseases. (Endocrinology 150: 1654-1661, 2009)

DOI： 10.1210/en.2008-1361

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

Scopus

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

DOI： 10.1016/j.atherosclerosis.2009.01.010

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

OBJECTIVE-Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo.
RESEARCH DESIGN AND METHODS-To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser(302), Sera(307), and Ser(612) mutated to alanine (Tg IRS-1 Ser -&gt; Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo.
RESULTS-Tg IRS-1 Ser -&gt; Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser -&gt; Ala mice displayed a significant increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates.
CONCLUSIONS-These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.

DOI： 10.2337/db06-0454

Web of Science

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

Individuals born with a low birth weight (LBW) have an increased prevalence of type 2 diabetes, but the mechanisms responsible for this association are unknown. Given the important role of insulin resistance in the pathogenesis of type 2 diabetes, we examined insulin sensitivity in a rat model of LBW due to intrauterine fetal stress. During the last 7 days of gestation, rat dams were treated with dexamethasone and insulin sensitivity was assessed in the LBW offspring by a hyperinsulinemic euglycemic clamp. The LBW group had liver-specific insulin resistance associated with increased levels of PEPCK expression. These changes were associated with pituitary hyperplasia of the ACTH-secreting cells, increased morning plasma ACTH concentrations, elevated corticosterone secretion during restraint stress, and an similar to 70% increase in 24-h urine corticosterone excretion. These data support the hypothesis that prenatal stress can result in chronic hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in increased plasma corticosterone concentrations, upregulation of hepatic gluconeogenesis, and hepatic insulin resistance.

DOI： 10.1152/ajpendo.00356.2007

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two iso-forms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGAT1 and DGAT2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because we have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase C-is an element of activation, we next sought to understand the paradoxical reduction in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were associated with reduced expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic genes ( CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase C-is an element of activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation.

DOI： 10.1074/jbc.M704213200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P &lt; 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P &lt; 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-a null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPA-R-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P &lt; 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha- and diacylglycerol-dependent manner.

DOI： 10.2337/db06-1206

Web of Science

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

Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-alpha 2 activity by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with D-guanidinopropionic acid (beta-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging.

DOI： 10.1016/j.cmet.2007.01.008

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

Recent studies using magnetic resonance spectroscopy have shown that decreased insulin-stimulated muscle glycogen synthesis due to a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of type 2 diabetes. The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-epsilon, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. More recently, magnetic resonance spectroscopy studies in healthy lean elderly subjects and healthy lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial function may predispose these individuals to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can be mostly attributed to reductions in mitochondrial density. By elucidating the cellular and molecular mechanisms responsible for insulin resistance, these studies provide potential new targets for the treatment and prevention of type 2 diabetes.

DOI： 10.2337/db06-S002

Web of Science

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

The transcription factor farnesoid X receptor (FXR) has recently been implicated in the control of hepatic triglyceride production. Activation of FXR may ameliorate hypertriglyceridemia, a cardinal feature of the metabolic syndrome. Because hamsters share many characteristic features of human lipid metabolism, we used a high-fructose-fed hamster model to study the impact of FXR activation with chenodeoxycholic acid (CDCA) on plasma lipoprotein metabolism. Male Syrian hamsters fed a diet containing 60% kcal from fructose for 2 wk developed hypertriglyceridemia and hypercholesterolemia ( + 120 and + 60%, P = 0.005 and 0.0004 vs. controls) due to increased hepatic lipoprotein production. This could be largely attributed to enhanced hepatic de novo lipogenesis, as indicated by increased expression of sterol regulatory element-binding protein-1, fatty acid synthase, and steaoryl-CoA desaturase-1. Lipoprotein analysis demonstrated that the increase in plasma triglycerides occurred in the VLDL density range, whereas increases in VLDL, IDL/LDL, and HDL cholesterol accounted for the elevated plasma cholesterol concentrations. Addition of 0.1% CDCA to the high-fructose diet decreased hepatic de novo lipogenesis and consequently triglyceride production and prevented the increases in plasma triglycerides and cholesterol ( - 40 and - 18%, P = 0.03 and 0.03 vs. high fructose-fed animals). CDCA-treated animals had lower VLDL triglycerides and decreased VLDL and IDL/LDL cholesterol plasma concentrations. These data demonstrate that activation of FXR with CDCA effectively lowers plasma triglyceride and cholesterol concentrations, mainly by decreasing de novo lipogenesis and hepatic secretion of triglyceride-rich lipoproteins. Our studies identify activators of FXR as promising new tools in the therapy of hypertriglyceridemic states, including the insulin resistance syndrome and type 2 diabetes.

DOI： 10.1152/ajpendo.00355.2005

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations two-to threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 It, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)gamma inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPAR alpha-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPAR-gamma-dependent and PPAR alpha-independent manner in epididymal fat.

DOI： 10.2337/diabetes.55.04.06.db05-0985

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

To further explore the nature of the mitochondrial dysfunction and insulin resistance that occur in the muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured mitochondrial. content by electron microscopy and insulin signaling in muscle biopsy samples obtained from these individuals before and during a hyperinsulinemic-euglycemic clamp. The rate of insulin-stimulated muscle glucose uptake was approximately 60% lower in the IR offspring than the control subjects and was associated with an approximately 60% increase in the intramyocellular lipid content as assessed by H-1 magnetic resonance spectroscopy. Muscle mitochondrial density was 38% lower in the IR offspring. These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. These data provide new insights into the earliest defects that may be responsible for the development of type 2 diabetes and support the hypothesis that reductions in mitochondrial content result in decreased mitochondrial function, which predisposes IR offspring to intramyocellular lipid accumulation, which in turn activates a serine kinase cascade that leads to defects in insulin signaling and action in muscle.

DOI： 10.1172/JC125151

Web of Science

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

In order to investigate the role of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) in the pathogenesis of hepatic steatosis and hepatic insulin resistance, we examined whole-body insulin action in awake mtGPAT1 knockout (mtGPAT1(-/-)) and wild-type (wt) mice after regular control diet or three weeks of high-fat feeding. In contrast to high-fat-fed wt mice, mtGPAT1(-/-) mice displayed markedly lower hepatic triacylglycerol and diacylglycerol concentrations and were protected from hepatic insulin resistance possibly due to a lower diacylglycerol-mediated PKC is an element of activation. Hepatic acyl-CoA has previously been implicated in the pathogenesis of insulin resistance. Surprisingly, compared to wt mice, mtGPAT1(-/-) mice exhibited increased hepatic insulin sensitivity despite an almost 2-fold elevation in hepatic acyl-CoA content. These data suggest that mtGPAT1 might serve as a novel target for treatment of hepatic steatosis and hepatic insulin resistance and that long chain acyl-CoA's do not mediate fat-induced hepatic insulin resistance in this model.

DOI： 10.1016/j.cmet.2005.06.006

Web of Science

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

For measuring glutamine:fructose-6-phospbate amidotransferase (GFAT) activity in cultured cells, an enzyme method-GDH method was set up with high-efficiency, high-sensitivity and simple operation by determining the formed glutamate. During the process of making samples, reduced glutathione (GSH, 5 mM) and glucose-6-phophate Na-2 (5 mM) were added to the buffer for scraping the cells. The range of protein content in the samples was 80-150 mug. In the GFAT activity assay, the end product reduced acetylpyridine adenine dinucleotide (APADH) was determined at 370 nm directly. The suitable concentrations of the reactants fructose-6-phosphate (F-6-P), glutamine, acetylpyridine adenine dinucleotide (APAD) and glutamate dehydrogenase (GDH) were 0.8, 6 and 0.3 mM and 6 U, respectively. However, the excess of APAD may interfere with the APADH measurement. The reaction time course was 90 min. The GFAT activity in 3T3-LI, L6, HepG2 and HIRc cells were 1.84-8.51 nmol glutamate/mg protein . min. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jbbm.2003.02.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3(N-/-)). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3(N-/-) mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db/db and ob/ob obese models and distinguishes them from other genetic models of obesity. Thus, STAB in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.

DOI： 10.1073/pnas.0303992101

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

It is reported that 3-phosphoinositide-dependent protein kinase-1 (PDK-1) is activated in a phosphatidylinositol 3,4,5-trisphosphate-dependent manner and phosphorylates Akt, p70S6 kinase, and atypical protein kinase C (PKC), but its function on insulin signaling is still unclear. We cloned a full-length pdk-1 cDNA from a human brain cDNA library, and the adenovirus to overexpress wild type PDK-1 (PDK-1WT) or membrane-targeted PDK-1 (PDK-1CAAX) was constructed. Overexpressed PDK-1WT existed mainly at cytosol, and PDK-1CAAX was located at the plasma membrane. In 3T3-L1 adipocytes, insulin induced mobility shift of PDk-1 protein, but overexpressed PDK-1WT and CAAX were shifted at the basal state. Insulin stimulated tyrosine phosphorylation of PDK-1WT, but PDK-1CAAX was already tyrosine-phosphorylated at the basal state. Overexpression of PDK-1WT led to a full activation of PKCzeta/lambda without insulin stimulation but showed only the minimum effects to stimulate phosphorylation of Akt and GSK-3. In contrast, the overexpression of PDK-1CAAX caused phosphorylation of Akt and GSK-3 more strongly without insulin stimulation. However, PDK-1CAAX did not affect 2-deoxyglucose uptake and inhibited glycogen synthesis, surprisingly. Finally, PDK-1CAAX expression inhibited insulin-induced ERK1/2 phosphorylation in a dose-dependent manner. Taken together, the translocation of PDK-1 from cytosol to the plasma membrane is critical for Akt and GSK-3 activation. On the other hand, only atypical PKC and Akt activation was insufficient for stimulation of glucose transport, and constitutive activation of Akt-GSK-3 pathway may inhibit glycogen synthesis and MAPK cascade in 3T3-L1 adipocytes.

DOI： 10.1074/jbc.M203132200

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

We investigated the role of protein kinase C (PKC) in insulin-induced c-Jun N-terminal kinase (JNK) activation in rat 1 fibroblasts expressing human insulin receptors. Insulin treatment led to increased SAP/ERK kinase 1 (SEK1) phosphorylation, and then stimulated JNK activity in a dose- and time-dependent manner, as measured either by a solid-phase kinase assay using glutathione S-transferase (GST)-c-Jun fusion protein as a substrate, or by quantitation of the levels of phosphorylated JNK by Western blotting using anti-phospho-JNK antibody. Insulin-induced JNK activation was potentiated by either preincubating cells with 2 nM GF109203X (PKC inhibitor) or down-regulation of PKC by overnight treatment with 100 nM tetradecanoyl phorbol acetate. In contrast, brief preincubation with 100 nM tetradecanoyl phorbol acetate inhibited the insulin-induced JNK activation. Furthermore, we found that 5 muM rottlerin, a PKC delta inhibitor, enhanced insulin-induced JNK activation, but a PKC beta inhibitor, LY333531, had no effect. Consistent with these findings, overexpression of PKC delta led to decreased insulin-induced JNK activation, whereas overexpression of PKC beta had no effect. Although overexpression of wild-type PKC delta attenuated insulin-induced JNK activation, a kinase-dead PKC delta mutant did not cause such attenuation. Finally, we found that the magnitude of insulin-induced JNK activation was inversely correlated with the expression level of PKC delta among different cell lines. In conclusion, the expression of PKC delta may negatively regulate insulin-induced JNK activation.

DOI： 10.1210/endo.142.6.8189

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Scopus

PubMed

Language：Japanese   Publisher：順天堂医学会  

J-GLOBAL

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Insulin signaling is regulated by tyrosine phosphorylation of the signaling molecules, such as the insulin receptor and insulin receptor substrates (IRSs), Therefore, the balance between protein-tyrosine kinases and protein-tyrosine phosphatase activities is thought to be important in the modulation of insulin signaling in insulin-resistant states. We thus employed the adenovirus-mediated gene transfer technique, and we analyzed the effect of overexpression of a wild-type protein-tyrosine phosphatase-1B (PTP1B) on insulin signaling in both L6 myocytes and Fao cells. In both cells, PTP1B overexpression blocked insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 by more than 70% and resulted in a significant inhibition of the association between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase and Akt phosphorylation as well as mitogen-activated protein kinase phosphorylation, Moreover, insulin-stimulated glycogen synthesis was also inhibited by PTP1B overexpression in both cells. These effects were specific for insulin signaling, because platelet-derived growth factor (PDGF)-stimulated PDGF receptor tyrosine phosphorylation and Akt phosphorylation were not inhibited by PTP1B overexpression. The present findings demonstrate that PTP1B negatively regulates insulin signaling in L6 and Fao cells, suggesting that PTP1B plays an important role in insulin resistance in muscle and liver.

DOI： 10.1074/jbc.M009489200

Web of Science

Language：Japanese   Publisher：(一社)滋賀県医師会  

J-GLOBAL

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

To elucidate the roles of SHP-2 genic (Tg) mice expressing a dominant negative mutant lacking protein tyrosine phosphatase domain (Delta PTP). On examining two lines of Tg mice identified by Southern blot, the transgene product Tvas expressed in skeletal muscle, liver, and adipose tissues, and insulin-induced association of insulin receptor substrate 1 with endogenous SHP-2 was inhibited, confirming that Delta PTP has a dominant negative property. The intraperitoneal glucose loading test demonstrated an increase in blood glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fasting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin, and somatostatin infusion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore, we observed the impairment of insulin-stimulated glucose uptake in muscle and adipocytes in the presence of physiological concentrations of insulin. Moreover, tyrosine phosphorylation of insulin receptor substrate-1 and stimulation of phosphatidylinositol 3-kinase and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insulin sensitivity of glucose metabolism, and thus SHP-2 may function to modulate insulin signaling in target tissues.

Web of Science

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

A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of JTT-501 (100 mg . kg(-1) . day(-1)) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40% of non-treated) and hypertriglyceridaemia (23% of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501 (5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min, We found that this treatment increased the glucose infusion rate by 33% during the last 30 min in SD rats, After the clamp had been initiated for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles. Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501 stimulated the glucose infusion rate by 30% and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin signalling and could be useful for the treatment of insulin-resistant diabetic subjects.

DOI： 10.1007/s001250051133

Web of Science

Language：Japanese   Publisher：皮膚科紀要編集部  

57歳男,慢性膵炎による消化吸収障害のために全身性紅斑を生じた.皮膚病変は特に両下腿,殿部及び肢端部に認められた.中心性治癒を伴った環状の落屑性紅斑,丘疹及び魚鱗癬様病変の如き様々な種類の病変が存在した.平滑な舌,爪甲変形及び口角炎も見られた.殿部の落屑性紅斑性病変の皮膚生検は,不全角化,顆粒層消失及び表皮細胞の空胞化を示した.アルブミン,ビタミン,金属及び数種類の必須アミノ酸を含む各種栄養素の血清値が減少していた.膵酵素の経口投与により病変は急速に改善した

J-GLOBAL

Language：Japanese  

J-GLOBAL

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

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

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

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

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

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

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

Language：Japanese   Publisher：(一社)日本病態栄養学会  

Language：Japanese   Publisher：(株)先端医学社  

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

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

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

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

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

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

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

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

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

Language：Japanese   Publisher：(一社)日本循環器病予防学会  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

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

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

Language：English   Publisher：(公社)日本生化学会  

Language：English   Publisher：(公社)日本生化学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

Language：Japanese   Publisher：(株)医学出版  

糖尿病が歯周病の悪化因子であり,逆に歯周病が糖尿病の悪化因子となることは,これまでも多くの研究が報告されている.そのメカニズムに関して,本誌の各記事で解説される.本特集記事では,レセプトデータと健診データを突合して作成されたデータベースを用いて,HbA1cや空腹時血糖と残歯の関係を調べた論文を解説する.残歯への影響は50代以降に顕著であるが,30代・40代でも確認されており,歯周病・糖尿病両者にとって予防の大切さが必要と思われる.口腔状態の定期的確認と医科・歯科の連携がますます重要であると示唆される.(著者抄録)

Language：Japanese   Publisher：(株)医学出版  

糖尿病が歯周病の悪化因子であり,逆に歯周病が糖尿病の悪化因子となることは,これまでも多くの研究が報告されている.そのメカニズムに関して,本誌の各記事で解説される.本特集記事では,レセプトデータと健診データを突合して作成されたデータベースを用いて,HbA1cや空腹時血糖と残歯の関係を調べた論文を解説する.残歯への影響は50代以降に顕著であるが,30代・40代でも確認されており,歯周病・糖尿病両者にとって予防の大切さが必要と思われる.口腔状態の定期的確認と医科・歯科の連携がますます重要であると示唆される.(著者抄録)

Language：Japanese   Publisher：(公社)日本糖尿病協会  

Language：Japanese   Publisher：(公社)日本糖尿病協会  

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

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

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

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

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

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

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

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

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

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

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

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

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DOI： 10.2337/db20-1713-P

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DOI： 10.2337/db20-1607-P

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CiNii Books

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Language：Japanese   Publisher：(株)メディカ出版  

J-GLOBAL

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

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

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

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

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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DOI： 10.2337/db19-1192-P

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

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Language：Japanese   Publisher：日本肥満症治療学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

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

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Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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CiNii Books

Other Link： https://search.jamas.or.jp/link/ui/2017318215

Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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Language：Japanese   Publisher：日本肥満症治療学会  

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

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

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

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Other Link： http://search.jamas.or.jp/link/ui/2016378095

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

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

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

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

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

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

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

Language：Japanese   Publisher：日本肥満症治療学会  

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

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

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

代謝疾患と心血管疾患のリスクは密接に関係しており、その背景には共通した要因が存在すると思われる。我々はその中でもインスリン抵抗性に注目し研究を行ってきた。インスリン抵抗性は糖尿病の基本病態であるのみならず、合併症進展の一因と考えられている。インスリン抵抗性の分子メカニズムにおけるインスリン細胞内情報伝達の異常とミトコンドリア機能異常が関係することを見出した。またミトコンドリアを調節する因子として、non-coding RNAであるmicroRNA-494を見出した。(著者抄録)

Language：Japanese   Publisher：日本肥満症治療学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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

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Language：Japanese   Publisher：(株)ライフメディコム  

Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

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

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

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(公社)日本糖尿病協会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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

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

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

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

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

Language：Japanese   Publisher：(株)メディカルレビュー社  

J-GLOBAL

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

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Language：Japanese   Publisher：日本肥満症治療学会  

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

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Language：Japanese   Publisher：日本肥満症治療学会  

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Language：Japanese   Publisher：日本肥満症治療学会  

J-GLOBAL

Language：Japanese   Publisher：日本肥満症治療学会  

Language：Japanese   Publisher：(一社)日本抗加齢医学会  

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

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

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

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

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

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

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

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CiNii Books

Language：Japanese   Publisher：滋賀医科大学雑誌刊行会  

Background: The bariatric surgery is the most efficacious therapy for morbid obesity today. We have performed bariatric surgeryand have taken a multidisciplinary approach since 2008. The excess weight loss (%EWL) at 1 year after laparoscopic sleeve gastrectomy(LSG) at our institute is 73%, which is better than that of LSGs at the Fourth International Consensus Summit on Sleeve Gastrectomy. On theother hand, there are some patients with less effect after LSG in our series. We investigated the causes of less effectiveness of weight lossafter LSG with a multidisciplinary approach. Methods: The twenty patients were performed LSG at our institute between October 2008 andMay 2014 and followed up with nutritional guidance more than 1 year. Method 1: The shape of a sleeve after LSG was classified accordingto four types of a shape, and evaluated weight loss effect of each type. Method 2: The twenty patients were divided into two groups: Betterweight loss group, which %EWL was more than 50%, and Less weight loss group, which %EWL was less than 50%. Lifestyles werecompared between the two groups. Method 3: Depression before and after LSG were evaluated with Beck Depression Inventory-II (BDI-II).Results: There was no difference in weight loss among types of sleeve shape. The amount of taking calories 1 year after LSG and %EWL 3months after LSG were different between the two groups. Depression was not severe in two groups. Conclusions: We describe ourmultidisciplinary approach for less effectiveness of weight loss after LSG for morbid obesity. The amount of taking calories 1 year after LSGwas more and %EWL 3 months after LSG was less in Less weight loss group than in Better weight loss group.

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

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Language：Japanese   Publisher：(公社)日本理学療法士協会  

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

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

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

Language：Japanese   Publisher：(一社)日本内分泌学会  

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

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