論文 - 上野 浩晶
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Tsuchimochi W., Ueno H., Yamashita E., Tsubouchi C., Sakoda H., Sakoda H., Nakamura S., Nakazato M.
Endocrine Journal 62 ( 1 ) 13 - 20 2015年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Endocrine Journal
© The Japan Endocrine Society.Teneligliptin is a novel peptidomimetic-chemotype prolylthiazolidine-based inhibitor of dipeptidyl peptidase-4 (DPP-4). The aim of this study was to evaluate the effects of teneligliptin on 24 h blood glucose control and gastrointestinal hormone responses to a meal tolerance test, and to investigate the glucose-lowering mechanisms of teneligliptin. Ten patients with type 2 diabetes mellitus (T2DM) were treated for 3 days with teneligliptin (20 mg/day). Postprandial profiles for glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, des-acyl ghrelin, and 24 h glycemic fluctuations were measured via continuous glucose monitoring for 4 days. Once daily teneligliptin administration for 3 days significantly lowered postprandial and fasting glucose levels. Significant elevations of fasting and postprandial active GLP-1 and postprandial active GIP levels were observed. Teneligliptin lowered postprandial glucose elevations, 24 h mean blood glucose levels, standard deviation of 24 h glucose levels and mean amplitude of glycemic excursions (MAGE) without hypoglycemia. Serum insulin levels in the fasting state and 30 min after a meal were similar before and after teneligliptin treatment; however significant reductions at 60 to 180 min after treatment were observed. A significant elevation in early-phase insulin secretion estimated by insulinogenic and oral disposition indices, and a significant reduction in postprandial glucagon AUC were observed. Both plasma ghrelin and des-acyl ghrelin levels were unaltered following teneligliptin treatment. Teneligliptin improved 24 h blood glucose levels by increasing active incretin levels and early-phase insulin secretion, reducing the postprandial insulin requirement, and reducing glucagon secretion. Even short-term teneligliptin treatment may offer benefits for patients with T2DM.
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新規の経鼻投与デバイスおよびGLP-1製剤の開発と臨床応用 招待あり 査読あり
上野浩晶
未病と抗老化 23 59 - 63 2014年7月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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[Cutting-edge of medicine; the prospects of novel anti-obesity drugs].
Ueno H, Nakazato M
Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 ( 3 ) 753 - 9 2014年3月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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上野 浩晶, 中里 雅光
日本内科学会雑誌 103 ( 3 ) 753 - 759 2014年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：The Japanese Society of Internal Medicine
日本を含めた世界中で肥満者が増加しており，その結果として2型糖尿病，脂質異常症，高血圧，脂肪肝，脳卒中，虚血性心疾患などを合併した肥満症患者が増加している．肥満症患者では3%の体重減少でも糖脂質代謝や血圧などの改善がみられるため減量が重要であるが，現実的には食事運動療法のみでは減量できない場合が多く，抗肥満薬の必要性が出てくる．現在，日本ではマジンドールのみが抗肥満薬として認可されているが，リパーゼ阻害薬であるセチリスタットが最近製造承認を受けた．欧米ではリパーゼ阻害薬のオルリスタット，中枢性食欲抑制薬であるロルカセリンやtopiramateとphentermineの合剤などが使用されおり一定の減量効果を認めている．他にも多数の抗肥満薬が開発または治験中であるが，本稿では世界での抗肥満薬の現状と開発状況について概説する．
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Role of central nervous system in the pathogenesis of diabetes
Ueno H., Nakazato M.
Journal of the Japan Diabetes Society 56 ( 7 ) 420 - 423 2013年7月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of the Japan Diabetes Society
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Nighttime blood pressure, nighttime glucose values, and target-organ damages in treated type 2 diabetes patients 査読あり
33. Yano Y, Hayakawa M, Kuroki K, Ueno H, Yamagishi S, Takeuchi M, Eto T, Nagata N, Nakazato M, Shimada K, Kario K
Atherosclerosis 227 135 - 139 2013年6月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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上野 浩晶, 中里 雅光
糖尿病 56 ( 7 ) 420 - 423 2013年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：THE JAPAN DIABETES SOCIETY
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Tamaki N., Tamaki N., Ueno H., Morinaga Y., Shiiya T., Nakazato M.
Journal of Atherosclerosis and Thrombosis 19 ( 6 ) 532 - 538 2012年7月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Atherosclerosis and Thrombosis
Aim: Ezetimibe reduces serum low-density lipoprotein cholesterol (LDL-C) levels by inhibiting intestinal cholesterol absorption; however, the effects of ezetimibe, including its pleiotropic effects, have not been fully clarified. The aims of our study were to examine the efficacy of ezetimibe for hypercholesterolemia and its pleiotropic effects. Methods: Outpatients with hyper LDL-C levels were treated with 10 mg ezetimibe once a day for 12 weeks. Serum lipid profiles, atherosclerotic and inflammatory markers, glucose, insulin, liver function, and cholesterol absorption and synthesis markers were measured before and after treatment. Results: Seventy-five patients treated with ezetimibe monotherapy and 16 patients treated with combined therapy of ezetimibe with different statins completed this study. Following 12 weeks of ezetimibe monotherapy, serum LDL-C, triglyceride, remnant-like particles cholesterol, matrix metalloproteinase- 9, insulin, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, the relative mobility of the peak of the LDL fraction, and cholesterol absorption markers were significantly decreased, and high-density lipoprotein cholesterol and lathosterol were significantly increased. In the combined therapy group, LDL-C and cholesterol absorption markers were significantly decreased after treatment. In patients with a high basal ALT level that were treated with monotherapy, ALT and the AST/ALT ratio were significantly decreased and increased, respectively, after treatment. Conclusion: Ezetimibe ameliorated not only atherogenic lipid profiles but also atherosclerotic and inflammatory markers, insulin sensitivity, and liver dysfunction in Japanese hypercholesterolemia patients, suggesting that ezetimibe treatment is a beneficial and effective strategy for the treatment of hypercholesterolemia, especially patients with obesity, metabolic syndrome, and/or fatty liver.
DOI： 10.5551/jat.10835
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[Mechanism of feeding regulation by gut hormones].
Morinaga Y, Ueno H, Nakazato M
Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 3 85 - 9 2012年5月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Ueno H., Saitoh Y., Mizuta M., Shiiya T., Noma K., Mashiba S., Kojima S., Nakazato M.
Obesity Research and Clinical Practice 5 ( 4 ) e267 - 360 2011年10月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Obesity Research and Clinical Practice
Objective: The benefits of fenofibrate, a peroxisome proliferator-activated receptor α agonist, against cardiovascular risk factors have been established. To clarify the underlying mechanisms of these benefits, we examined the effects of fenofibrate on insulin resistance, hypertension, inflammation, oxidative stress and coagulation markers in patients with metabolic syndrome. Methods: Eleven Japanese patients with metabolic syndrome underwent physical examinations and blood tests before and after treatment with fenofibrate 200 mg daily for 8 weeks. Results: Fenofibrate significantly decreased systolic blood pressure, pulse wave velocity, serum insulin, insulin resistance (calculated from the homeostasis model assessment), total cholesterol, triglyceride, remnant-like particles cholesterol, uric acid, D-dimer, fibrinogen, serum amyloid A/low-density lipoprotein (LDL) and apoA1/LDL levels. It also significantly increased levels of high molecular weight adiponectin, thrombomodulin and high-density lipoprotein cholesterol in these patients. Plasminogen activator inhibitor-1, C-reactive protein, fasting plasma glucose and thrombin-antithrombin complex levels did not change. Limitation: Small sample size. Conclusion: Short-term fenofibrate administration not only improved lipid profiles, but also ameliorated insulin resistance, hypertension and oxidative stress markers in patients with metabolic syndrome, suggesting that fenofibrate can decrease the risk of arteriosclerosis through various pathways. © 2011 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
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Therapeutic potential of ghrelin treatment for unloading-induced muscle atrophy in mice
Koshinaka K., Toshinai K., Mohammad A., Noma K., Oshikawa M., Ueno H., Yamaguchi H., Nakazato M.
Biochemical and Biophysical Research Communications 412 ( 2 ) 296 - 301 2011年8月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Ghrelin is a growth hormone (GH) secretagogue secreted mainly from the stomach that functions in controlling muscle volume and energy homeostasis. We here studied the effects of ghrelin on unloading-induced muscle atrophy using a mouse model of hindlimb suspension (HS). Ghrelin administration during 2-week HS alleviated reductions of muscle mass in the fast-twitch fiber-rich plantaris muscle and the slow-twitch fiber-rich soleus muscle of the hindlimb. Ghrelin administration during a 5-day recovery period following 2-week HS enhanced food intake and facilitated recovery from atrophy in both muscles. Ghrelin administration normalized hypercorticosteronemia in these studies. Ghrelin's anti-muscle atrophy effect was found even under pair-feeding condition, but not in mice given des-acyl ghrelin. Insulin-like growth factor (IGF)-1 mRNA expression was significantly reduced in the atrophied plantaris muscle compared with control muscles. A single ghrelin administration to HS mice acutely increased plasma GH and also amplified phosphorylation of signal transducer and activator of transcription (STAT) 5 and increased IGF-1 mRNA expression in the plantaris muscle, but not in the soleus muscle. This study demonstrated that ghrelin stimulated the GH-STAT5-IGF-1 axis in the locally atrophied plantaris muscle, and its administration alleviated muscle atrophy and facilitated recovery from muscle atrophy. Ghrelin's effects represent a novel therapeutic paradigm for the treatment of unloading-induced muscle atrophy induced by factors such as bed rest, injury, and joint immobilization. © 2011 Elsevier Inc.
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Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic β-cells
Wang H., Mizuta M., Saitoh Y., Noma K., Ueno H., Nakazato M.
Metabolism: Clinical and Experimental 60 ( 8 ) 1081 - 1089 2011年8月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Metabolism: Clinical and Experimental
Glucagon-like peptide-1 (GLP-1) and angiotensin II type 1 receptor blocker reduce β-cell apoptosis in diabetes, but the underlying mechanisms are not fully understood. We examined the combination effects of GLP-1 and candesartan, an angiotensin II type 1 receptor blocker, on glucolipotoxicity-induced β-cell apoptosis; and we explored the possible mechanisms of the antiapoptotic effects. The effects of GLP-1 and/or candesartan on glucolipotoxicity-induced apoptosis and the phosphorylation of insulin receptor substrate-2 (IRS-2), protein kinase B (PKB), and forkhead box O1 (FoxO1) were evaluated by using MIN6 cells and isolated mouse pancreatic islets. Although palmitate significantly enhanced the high-glucose-induced apoptosis in both islets and MIN6 cells, GLP-1 and candesartan significantly inhibited apoptosis; and combination treatment additively prevented apoptosis. Whereas palmitate significantly decreased the phosphorylation of IRS-2, PKB, and FoxO1 in MIN6 cells, these changes were significantly inhibited by treatment with GLP-1 and/or candesartan. In addition, wortmannin, an inhibitor of phosphoinositide 3-kinase, markedly inhibited GLP-1- and/or candesartan-mediated PKB and FoxO1 phosphorylation. The present results suggest that GLP-1 and candesartan additively prevent glucolipotoxicity-induced apoptosis in pancreatic β-cells through the IRS-2/phosphoinositide 3-kinase/PKB/FoxO1 signaling pathway. © 2011 Elsevier Inc.
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Significant lowering of plasma ghrelin but not des-acyl ghrelin in response to acute exercise in men
Shiiya T., Ueno H., Toshinai K., Kawagoe T., Naito S., Tobina T., Nishida Y., Shindo M., Kangawa K., Tanaka H., Nakazato M.
Endocrine Journal 58 ( 5 ) 335 - 342 2011年6月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Endocrine Journal
Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and growth hormone (GH) secretion via interaction with the GH secretagogue receptor. Ghrelin molecules are present in two major endogenous forms, an acylated form (ghrelin) and a des-acylated form (des-acyl ghrelin). Recent studies indicated that aerobic exercise did not change plasma total ghrelin levels, however, dynamics of circulating ghrelin and des-acyl ghrelin during aerobic exercise remains unclear. The purpose of this study is to examine the effects of moderate intensity exercise on plasma ghrelin and des-acyl ghrelin concentrations, and to investigate the relationship between ghrelin molecules and other hormonal and metabolic parameters during exercise. Nine healthy males (25.2 ± 0.5 years) exercised for 60 min at 50% of their maximal oxygen consumptions. We measured the plasma concentrations of ghrelin, des-acyl ghrelin, GH, norepinephrine (NE), epinephrine (E), dopamine (DA), insulin, and glucose. Plasma ghrelin level significantly decreased during exercise, whereas plasma des-acyl ghrelin and total ghrelin levels did not change. Plasma NE, E, DA and GH levels were significantly increased during exercise. Plasma insulin level significantly decreased during exercise, and plasma glucose levels remained steady during exercise. NE, E, DA, and GH were correlated negatively with plasma ghrelin levels. These findings suggest that acute moderate exercise may suppress ghrelin release from the stomach, decrease ghrelin O-acyltransferase activity, and/or activate ghrelin utilization in peripheral tissues and that exercise-induced ghrelin suppression may be mediated by activated adrenergic system. © The Japan Endocrine Society.
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Translational research of ghrelin
Ueno H, Nakazato M
Peptide Science 2010: Proceedings of the fifth international peptide symposium 34 - 34 2011年6月
記述言語：英語 掲載種別：研究論文（国際会議プロシーディングス）
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Fenofibrate ameliorates insulin resistance, hypertension and novel oxidative stress markers in patients with metabolic syndrome 査読あり
Ueno H, Saitoh Y, Mizuta M, Shiiya T, Noma K, Mashiba S, Kojima S, Nakazato M
Obes Res Clin Pract 2011年4月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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[The crosstalk of feeding signals between gut and hypothalamus].
Shiiya T., Ueno H., Nakazato M.
Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1 115 - 120 2011年1月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Nihon rinsho. Japanese journal of clinical medicine
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Saitoh Y., Hongwei W., Ueno H., Mizuta M., Nakazato M.
Diabetes Research and Clinical Practice 90 ( 1 ) 54 - 59 2010年10月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Diabetes Research and Clinical Practice
Angiotensin II receptor blockers (ARBs) have been shown to decrease insulin resistance in obese diabetic animal models and reduce the risk of new-onset diabetes in hypertensive patients. In the present study, we studied whether candesartan, an ARB, can exert a direct effect against fatty acid-induced oxidative stress in pancreatic β-cells. The effect of candesartan on lipotoxicity was evaluated using mouse insulin-secreting clonal cell, MIN6 and isolated mouse pancreatic islets. Intracellular insulin and triglyceride content, uncoupling protein-2 (UCP-2) mRNA expression, reactive oxygen species, protein kinase C (PKC) and NAD(P)H oxidase activity were examined. Candesartan recovered decreased insulin content in MIN6 exposed to 25. mM glucose with 0.5. mM palmitate (P< 0.01). Candesartan tended to decrease intracellular triglyceride accumulation in cells exposed to 25. mM glucose with 0.5. mM palmitate. Palmitate-induced up-regulation of UCP-2 mRNA levels was suppressed by candesartan in a dose-dependent manner. Candesartan decreased palmitate-induced reactive oxygen species accumulation in MIN6 cells by 23% and in mouse islets by 59%. Candesartan also decreased palmitate-induced PKC activity by 21% and NAD(P)H oxidase activity by 37% in MIN6 cells. These findings indicated that candesartan attenuated fatty acid-induced oxidative stress and NAD(P)H oxidase activity in pancreatic β-cells. © 2010.
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多数のcerebral microbleedsを認めた若年女性の1例 査読あり
塩見一剛, 荒沢麻衣, 京楽 格, 椎屋智美, 上野浩晶, 山下秀一, 中里雅光
宮崎県医師会医学会誌 34 116 - 120 2010年7月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Translational research of ghrelin. 査読あり
Ueno H, Shiiya T, Nakazato M
Ann N Y Acad Sci 2010年5月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Saitoh Y., Hongwei W., Ueno H., Mizuta M., Nakazato M.
Diabetes and Metabolism 35 ( 5 ) 392 - 397 2009年11月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Diabetes and Metabolism
Aim: Angiotensin II receptor blockers (ARB) have been shown to lower insulin resistance in obese diabetic animal models and to reduce the risk of new-onset diabetes in hypertensive patients. In the present study, we studied whether telmisartan, an ARB with partial peroxisome proliferator-activated receptor-γ (PPARγ) activity, can exert a direct effect against fatty-acid-induced oxidative stress in pancreatic β-cells. Methods: The effect of telmisartan on lipotoxicity was evaluated using mouse insulin-secreting clonal MIN6 and isolated mouse pancreatic islet cells. Reactive oxygen species, protein kinase-C (PKC) activity and NAD(P)H oxidase activity were examined to clarify the underlying mechanisms. Result: Telmisartan decreased the accumulation of palmitate-induced reactive oxygen species in MIN6 cells by 25% and in mouse islet cells by 55%. Telmisartan also decreased palmitate-induced PKC activity by 36% and NAD(P)H oxidase activity by 32% in MIN6 cells. Conclusion: These findings indicate that telmisartan attenuated fatty-acid-induced oxidative stress and NAD(P)H oxidase activity in pancreatic β-cells. Our observations pave the way to the possible use of ARB as a means of protecting β-cell survival and preserving insulin secretion capacity in patients with diabetes mellitus. © 2009 Elsevier Masson SAS.