Papers - FURUHASHI Masato

Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy

Masato Furuhashi, Ichiro Sakuma, Takeshi Morimoto, Yukimura Higashiura, Akiko Sakai, Megumi Matsumoto, Mio Sakuma, Michio Shimabukuro, Takashi Nomiyama, Osamu Arasaki, Koichi Node, Shinichiro Ueda

Cardiovascular Diabetology ( Springer Science and Business Media {LLC} )  19 ( 1 )  2020.12

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Abstract Background Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. Aim and methods As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. Results The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. Conclusion Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406

DOI

New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity

Masato Furuhashi

American Journal of Physiology-Endocrinology and Metabolism ( American Physiological Society )  319 ( 5 ) E827 - E834  2020.11

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Xanthine oxidoreductase (XOR) consists of two different forms, xanthine dehydrogenase and xanthine oxidase (XO), and is a rate-limiting enzyme of uric acid production from hypoxanthine and xanthine. Uric acid is the end product of purine metabolism in humans and has a powerful antioxidant effect. The lack of ascorbic acid, known as vitamin C, in hominoids has been thought to cause a compensatory increase in uric acid as an antioxidant by unfunctional gene mutation of uricase to a pseudogene. Because XO is involved in an increase in reactive oxygen species (ROS) by generating superoxide and hydrogen peroxide, inadequate activation of XOR promotes oxidative stress-related tissue injury. Plasma XOR activity is associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia, insulin resistance, and adipokines, indicating a novel biomarker of metabolic disorders. However, XOR activity in adipose tissue is low in humans unlike in rodents, and hypoxanthine is secreted from human adipose tissue. The concentration of hypoxanthine, but not xanthine, is independently associated with obesity in a general population, indicating differential regulation of hypoxanthine and xanthine. Treatment with an XOR inhibitor can decrease uric acid for preventing gout, reduce production of XO-related ROS, and promote reutilization of hypoxanthine and ATP production through the salvage pathway. It has recently been suggested that discontinuation of an XOR inhibitor causes adverse cardiovascular outcomes as XOR inhibitor withdrawal syndrome, possibly due to cardiac disturbance of conduction and contraction by reduced ATP production. New insights into purine metabolism, including the role of XOR activity in the past 5 yr, are mainly discussed in this review.

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Independent and Distinct Associations of FABP4 and FABP5 With Metabolic Parameters in Type 2 Diabetes Mellitus

Masato Furuhashi, Ichiro Sakuma, Takeshi Morimoto, Yukimura Higashiura, Akiko Sakai, Megumi Matsumoto, Mio Sakuma, Michio Shimabukuro, Takashi Nomiyama, Osamu Arasaki, Koichi Node, Shinichiro Ueda

Frontiers in Endocrinology ( Frontiers Media {SA} )  11   575557 - 575557  2020.09  [International journal]

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Objective: Among fatty acid-binding proteins (FABPs), secreted forms of FABP4 and FABP5, which are expressed in adipocytes and macrophages, act as bioactive molecules. We investigated concentrations of FABP4 and FABP5 in patients with type 2 diabetes mellitus. Methods: As a sub-analysis study of the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial, 256 patients (male/female: 146/110, age: 68 ± 10 years) with type 2 diabetes mellitus and dyslipidemia who were receiving statin therapy were recruited. Patients who had been treated with a thiazolidinedione were excluded. Results: Several drugs which may modulate FABP4 levels including statins, dipeptidyl peptidase-4 inhibitors and angiotensin II receptor blockers had been administered in 100, 81, and 51% of the recruited patients, respectively. The level of FABP4, but not that of FABP5, was significantly higher in females than in males. Multivariable linear regression analysis demonstrated that waist circumference (β = 0.21), estimated glomerular filtration rate (β = -0.31), triglycerides (β = 0.16), and FABP5 (β = 0.39) were independent predictors of FABP4 level after adjusting age and sex. On the other hand, FABP5 level was independently associated with levels of FABP4 (β = 0.57) and high-density lipoprotein (HDL) cholesterol (β = -0.12). Conclusions: Concentrations of FABP4 and FABP5 are independent predictors of each other in patients with type 2 diabetes mellitus. There are distinct independent associations of FABP4 with renal dysfunction, adiposity and hypertriglyceridemia and there is a distinct independent association of FABP5 with a low HDL cholesterol level in type 2 diabetic patients with dyslipidemia at high risks for cardiovascular disease who are receiving statin therapy.

DOI PubMed

U-shaped relationship between serum uric acid level and decline in renal function during a 10-year period in female subjects: BOREAS-CKD2.

Kazuma Mori, Masato Furuhashi, Marenao Tanaka, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Masayuki Koyama, Arata Osanami, Yukimura Higashiura, Masafumi Inyaku, Megumi Matsumoto, Norihito Moniwa, Hirofumi Ohnishi, Tetsuji Miura

Hypertension research : official journal of the Japanese Society of Hypertension ( Springer Science and Business Media {LLC} )  44 ( 1 ) 107 - 116  2020.08  [Refereed]  [International journal]

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While hyperuricemia is recognized as a risk factor for chronic kidney disease (CKD), the risk of CKD in subjects with a low level of serum uric acid (UA) remains controversial. Here, we examined whether the association of CKD risk with serum UA level differs depending on the sex and age of subjects in a general population. Of subjects who received annual health checkups, we enrolled 6,779 subjects (male/female: 4,454/2,325; age: 45 ± 9 years) with data from a 10-year follow-up after excluding subjects taking anti-hyperuricemic drugs and those with CKD at baseline. During the follow-up period, 11.4% of the males and 11.7% of the females developed CKD. A significant interaction of sex, but not age, with the effect of baseline UA level on CKD risk was found. A restricted cubic spline analysis showed a U-shaped association of the baseline UA level with the risk of CKD in females. Multivariable Cox proportional hazard analyses for females showed that baseline UA levels in the 5th quintile (Q5, ≥5 mg/dL; HR: 1.68) and the 1st quintile (Q1, ≤3.5 mg/dL; HR: 1.73) were independent risk factors for CKD when compared with UA levels in the 4th quintile (Q4, 4.5-4.9 mg/dL). In males, restricted cubic spline analysis indicated increased CKD risk in subjects with a higher baseline UA level but not in those with a low UA level. In conclusion, a low UA level is a significant risk factor for CKD in females, while an elevated UA level increases the risk of CKD in both sexes.

DOI PubMed

Potential differential effects of renin-angiotensin system inhibitors on SARS-CoV-2 infection and lung injury in COVID-19.

Masato Furuhashi, Norihito Moniwa, Hideki Takizawa, Nobuyuki Ura, Kazuaki Shimamoto

Hypertension research : official journal of the Japanese Society of Hypertension    2020.05  [Refereed]  [International journal]

DOI PubMed

糖尿病外来診療における慢性合併症評価の実態調査

小川 俊史, 佐藤 達也, 東浦 幸村, 伊野 祥哉, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三木 隆幸, 斎藤 重幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  63 ( 5 ) 356 - 356  2020.05

Low urine pH predicts new onset of diabetes mellitus during a 10-year period in men: BOREAS-DM1 study.

Yukimura Higashiura, Marenao Tanaka, Masato Furuhashi, Masayuki Koyama, Hirofumi Ohnishi, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Norihito Moniwa, Tetsuji Miura

Journal of diabetes investigation   11 ( 6 ) 1490 - 1497  2020.04  [Refereed]  [Domestic journal]

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AIMS/INTRODUCTION: A low level of urine pH (U-pH) has been reported to be associated with metabolic disorders. However, the relationship between the incidence of diabetes mellitus and U-pH has not yet been fully addressed. MATERIALS AND METHODS: We investigated the relationship between U-pH and the development of diabetes mellitus during a 10-year period in a general population of individuals who received annual health examinations in 2006 (n = 28,990). After exclusion of individuals with missing data, and those with diabetes mellitus and/or chronic kidney disease at baseline, a total of 12,476 individuals (men/women: 8,027/4,449) who received health examinations at least once during the period from 2007 to 2016 were recruited. The recruited individuals were divided into four groups according to their U-pH levels: groups of U-pH ≤5.0, 5.5, 6.0 and ≥6.5. RESULTS: During a 10-year period, 521 men (6.5%) and 132 women (3.0%) had new onset of diabetes mellitus. The cumulative incidence of diabetes mellitus was 7.5% (men/women: 9.3%/4.4%) per 100 person-years. The hazard ratios (HRs) in the U-pH ≤5.0 (HR 1.93) and U-pH 5.5 groups (HR 1.46) were significantly higher than that in the U-pH ≥6.5 group as a reference for men, but not for women. After adjustment of age, obesity, fasting glucose, smoking and alcohol drinking habits, family history of diabetes mellitus, and use of drugs for hypertension and dyslipidemia, HR in the U-pH ≤5.0 group (HR 1.39) was significantly higher than that in the U-pH ≥6.5 group for men, but not for women. CONCLUSIONS: Low U-pH predicts new onset of diabetes mellitus in a general population of men.

DOI PubMed

ALT、γGTPの組み合わせによる糖尿病発症リスク評価の向上

宮森 大輔, 田中 希尚, 古橋 眞人, 茂庭 仁人, 三浦 哲嗣, 小山 雅之, 大西 浩文, 沼田 啓太, 久末 章史, 塙 なぎさ

日本内科学会雑誌 ( (一社)日本内科学会 )  109 ( Suppl. ) 241 - 241  2020.02

ALT、γGTPの組み合わせによる糖尿病発症リスク評価の向上

宮森 大輔, 田中 希尚, 古橋 眞人, 茂庭 仁人, 三浦 哲嗣, 小山 雅之, 大西 浩文, 沼田 啓太, 久末 章史, 塙 なぎさ

日本内科学会雑誌 ( (一社)日本内科学会 )  109 ( Suppl. ) 241 - 241  2020.02

Differential regulation of hypoxanthine and xanthine by obesity in a general population.

Masato Furuhashi, Masayuki Koyama, Yukimura Higashiura, Takayo Murase, Takashi Nakamura, Megumi Matsumoto, Akiko Sakai, Hirofumi Ohnishi, Marenao Tanaka, Shigeyuki Saitoh, Norihito Moniwa, Kazuaki Shimamoto, Tetsuji Miura

Journal of diabetes investigation   11 ( 4 ) 878 - 887  2020.01  [Refereed]  [Domestic journal]

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AIMS/INTRODUCTION: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue. MATERIALS AND METHODS: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study. RESULTS: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity. CONCLUSIONS: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.

DOI PubMed

高intact PTH血症、高Ca血症から副甲状腺癌の遠隔再発の診断を得た一例

寺沢 誠, 後町 結, 小山 雅之, 茂庭 仁人, 古橋 眞人, 三浦 哲嗣

日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  95 ( 3 ) 864 - 864  2020.01

Reply to the comment of Hirota et al. on "Accuracy of flash glucose monitoring in insulin-treated patients with type 2 diabetes".

Tatsuya Sato, Hiroto Oshima, Kei Nakata, Yukishige Kimura, Toshiyuki Yano, Masato Furuhashi, Masaya Tannno, Takayuki Miki, Tetsuji Miura

Journal of diabetes investigation   11 ( 1 ) 256 - 256  2020.01  [Domestic journal]

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一般住民においてヒポキサンチンとキサンチンの血中濃度は肥満によって異なった制御を受ける

古橋 眞人, 東浦 幸村, 小山 雅之, 村瀬 貴代, 中村 敬志, 酒井 晶子, 田中 希尚, 茂庭 仁人, 大西 浩文, 斎藤 重幸, 三浦 哲嗣

日本痛風・核酸代謝学会総会プログラム抄録集 ( (一社)日本痛風・尿酸核酸学会 )  53回   74 - 74  2020.01

SAP療法下に多量飲酒を誘因に発症した糖尿病性ケトアシドーシスの1例

東浦 幸村, 中田 圭, 西川 諒, 矢野 俊之, 古橋 眞人, 三木 隆幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  62 ( 12 ) 776 - 776  2019.12

北海道都市部健診受診者コホートにおける初年度の血圧カテゴリ別の血清尿酸値と高血圧発症との関連

小山 雅之, 樋室 伸顕, 田中 希尚, 茂庭 仁人, 古橋 眞人, 沼田 啓太, 久末 章史, 塙 なぎさ, 齋藤 重幸, 三浦 哲嗣, 大西 浩文

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  42回   300 - 300  2019.10

一般住民において血漿ヒポキサンチン濃度は肥満度および喫煙と関連する

東浦 幸村, 古橋 眞人, 松本 めぐみ, 酒井 晶子, 小山 雅之, 村瀬 貴代, 中村 敬志, 田中 希尚, 茂庭 仁人, 大西 浩文, 斎藤 重幸, 三浦 哲嗣

肥満研究 ( (一社)日本肥満学会 )  25 ( Suppl. ) 279 - 279  2019.10

一般住民におけるキサンチン酸化還元酵素(XOR)活性と高血圧との関連

東浦 幸村, 古橋 眞人, 小山 雅之, 田中 希尚, 茂庭 仁人, 松本 めぐみ, 酒井 晶子, 村瀬 貴代, 中村 敬志, 大西 浩文, 齋藤 重幸, 島本 和明, 三浦 哲嗣

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  42回   279 - 279  2019.10

Annual change in plasma xanthine oxidoreductase activity is associated with changes in liver enzymes and body weight.

Masato Furuhashi, Masayuki Koyama, Megumi Matsumoto, Takayo Murase, Takashi Nakamura, Yukimura Higashiura, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Endocrine journal   66 ( 9 ) 777 - 786  2019.09  [Refereed]  [Domestic journal]

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Xanthine oxidoreductase (XOR), an enzyme of uric acid formation from hypoxanthine and xanthine, is recognized as a source of oxidative stress. Plasma activity of XOR has been reported to be a biomarker of metabolic disorders associated with obesity, liver dysfunction, insulin resistance, hyperuricemia and adipokines. We investigated longitudinal change in plasma XOR activity, which was determined by using mass spectrometry and liquid chromatography to detect [13C2, 15N2]-uric acid using [13C2, 15N2]-xanthine as a substrate, in 511 subjects (male/female: 244/267) of the Tanno-Sobetsu Study in the years 2016 and 2017. Plasma XOR activity in a basal state was significantly higher in men than in women, but no significant sex difference was observed in annual change in plasma XOR activity. Annual change in plasma activity of XOR was positively correlated with changes in each parameter, including body weight (r = 0.203, p < 0.001), body mass index, diastolic blood pressure, aspartate transaminase (AST) (r = 0.772, p < 0.001), alanine transaminase (r = 0.647, p < 0.001), γ-glutamyl transpeptidase, total cholesterol, triglycerides, uric acid, fasting glucose and HbA1c. Multivariate regression analysis demonstrated that change in AST and that in body weight were independent predictors of change in plasma XOR activity after adjustment of age, sex and changes in each variable with a significant correlation without multicollinearity. In conclusion, annual change in plasma XOR activity is independently associated with changes in liver enzymes and body weight in a general population. Improvement of liver function and reduction of body weight would decrease plasma XOR activity and its related oxidative stress as a therapeutic strategy.

DOI PubMed

Anorexia nervosaによるCKDの3症例

後町 結, 茂庭 仁人, 木村 歩, 長南 新太, 菅原 浩仁, 高橋 聖子, 田中 希尚, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  61 ( 6 ) 739 - 739  2019.08

ネフローゼ症候群を呈したシェーグレン症候群による二次性膜性腎症に対しステロイドが奏効した1例

増田 拳, 田中 希尚, 茂庭 仁人, 後町 結, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  61 ( 6 ) 762 - 762  2019.08