2025/11/10 更新

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写真a

トガシ　ユウ
富樫 優
Yu Togashi
所属
医学研究科 医科学専攻 内分泌・糖尿病内科学 講師
医学部 医学科
職名
講師
ホームページ
http://www-user.yokohama-cu.ac.jp/~nai3naib/wp/
外部リンク

学位

  • 医学博士 （ 横浜市立大学 ）

研究キーワード

  • ２型糖尿病

  • 膵β細胞量

研究分野

  • ライフサイエンス / 代謝、内分泌学

経歴

  • 横浜市立大学   大学病院   助教

    2014年

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  • 横浜市立大学 医学部医学科 内分泌・糖尿病内科学   助教

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  • 横浜市立大学 附属病院 内分泌・糖尿病内科

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論文

  • The matricellular protein Fibulin-5 regulates β-cell proliferation in an autocrine/paracrine manner. 国際誌

    Tomoko Okuyama, Takahiro Tsuno, Ryota Inoue, Setsuko Fukushima, Mayu Kyohara, Anzu Matsumura, Daisuke Miyashita, Kuniyuki Nishiyama, Yusuke Takano, Yu Togashi, Makiko Meguro-Horike, Shin-Ichi Horike, Tatsuya Kin, A M James Shapiro, Hiromi Yanagisawa, Yasuo Terauchi, Jun Shirakawa

    iScience   28 ( 2 )   111856 - 111856   2025年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role of Fbln5 in β-cell replication. Fbln5 expression was increased upon glucose stimulation in β-cells of mouse and human islets. β-Cell-specific Fbln5-knockout (βFbln5KO) mice exhibit significantly reduced β-cell proliferation in vivo but not in vitro. Secreted extracellular Fbln5 enhances β-cell replication. Fbln5-deficient β-cells exhibit the downregulated expression of the gene encoding Polo-like kinase 1 (PLK1), which is accompanied by ERK-mediated FoxM1 nuclear export. These data suggest that Fbln5 is secreted from β-cells in response to glucose and plays important roles in the appropriate maintenance of β-cell functions in an autocrine or paracrine manner.

    DOI： 10.1016/j.isci.2025.111856

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  • 多発肝転移に対しTACE施行し一時的に低血糖が改善した悪性インスリノーマの1例

    高柳 りえ, 富谷 蒼, 菊池 香澄, 松浦 彩理裟, 高橋 明裕, 新井 正法, 奥山 朋子, 京原 麻由, 富樫 優, 小林 規俊, 寺内 康夫

    糖尿病   67 ( 7 )   293 - 293   2024年7月

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    記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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  • Protective effects of imeglimin and metformin combination therapy on β-cells in db/db male mice. 国際誌

    Kuniyuki Nishiyama, Masato Ono, Takahiro Tsuno, Ryota Inoue, Ayako Fukunaka, Tomoko Okuyama, Mayu Kyohara, Yu Togashi, Setsuko Fukushima, Takuto Atsumi, Aoi Sato, Asuka Tsurumoto, Chisato Sakai, Yoshio Fujitani, Yasuo Terauchi, Shuichi Ito, Jun Shirakawa

    Endocrinology   164 ( 8 )   2023年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes.

    DOI： 10.1210/endocr/bqad095

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  • Protective effects of S100A8 on sepsis mortality: Links to sepsis risk in obesity and diabetes. 国際誌

    Daisuke Miyashita, Ryota Inoue, Takahiro Tsuno, Tomoko Okuyama, Mayu Kyohara, Chigusa Nakahashi-Oda, Kuniyuki Nishiyama, Setsuko Fukushima, Yutaro Inada, Yu Togashi, Akira Shibuya, Yasuo Terauchi, Jun Shirakawa

    iScience   25 ( 12 )   105662 - 105662   2022年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. Here, we examine the role of S100A8 in sepsis of obesity and diabetes models. Injection of S100A8 prolongs the survival of septic mice induced by lethal endotoxemia, Escherichia coli injection, or cecal ligation and puncture. S100A8 decrease the LPS-induced expression of proinflammatory cytokines in peritoneal macrophages by inhibiting TLR4-mediated signals in an autocrine manner. db/db, ob/ob, and western diet-fed mice demonstrate reduced upregulation of S100A8 induced by LPS treatment in both serum and peritoneal cells. These mice also show shorter survival after LPS injection, and S100A8 supplementation prolonged the survival. While myelomonocytic cells-specific S100A8-deficient mice (Lyz2 cre :S100A8 floxed/floxed ) exhibit shorter survival after LPS treatment, S100A8 supplementation prolonged the survival. Thus, myelomonocytic cell-derived S100A8 is crucial for protection from sepsis, and S100A8 supplementation improves sepsis, particularly in mice with obesity and diabetes.

    DOI： 10.1016/j.isci.2022.105662

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  • Abdominal aortic calcification is associated with Fibrosis-4 index and low body mass index in type 2 diabetes patients: A retrospective cross-sectional study.

    Yu Togashi, Daisuke Miyashita, Takahiro Tsuno, Ryota Inoue, Tomoko Okuyama, Mayu Kyohara, Kuniyuki Nishiyama, Masanori Arai, Kenta Kanematsu, Soichiro Kanataki, Yasuo Terauchi, Jun Shirakawa

    Journal of diabetes investigation   13 ( 11 )   1861 - 1872   2022年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    AIMS/INTRODUCTION: This study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus. MATERIALS AND METHODS: This retrospective cross-sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models. RESULTS: The AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis-4 (Fib-4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography-diagnosed fatty liver. There was a significant interaction between BMI and Fib-4 index; lower BMI and Fib-4 index >2.67 showed a synergistic association with high AAC grade. CONCLUSIONS: AAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib-4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.

    DOI： 10.1111/jdi.13883

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  • Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway. 国際誌

    Jinghe Li, Ryota Inoue, Yu Togashi, Tomoko Okuyama, Aoi Satoh, Mayu Kyohara, Kuniyuki Nishiyama, Takahiro Tsuno, Daisuke Miyashita, Tatsuya Kin, A M James Shapiro, Resilind Su Ern Chew, Adrian Kee Keong Teo, Seiichi Oyadomari, Yasuo Terauchi, Jun Shirakawa

    Diabetes   71 ( 3 )   424 - 439   2022年3月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.

    DOI： 10.2337/db21-0123

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  • Effects of Canagliflozin on Hepatic Steatosis, Visceral Fat and Skeletal Muscle among Patients with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease.

    Noriko Nishimiya, Kazuki Tajima, Kento Imajo, Akiko Kameda, Eiko Yoshida, Yu Togashi, Kazutaka Aoki, Tomio Inoue, Atsushi Nakajima, Daisuke Utsunomiya, Yasuo Terauchi

    Internal medicine (Tokyo, Japan)   60 ( 21 )   3391 - 3399   2021年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Objective We assessed the effect of canagliflozin, an sodium-glucose co-transporter type-2 inhibitor, on hepatic steatosis using three imaging modalities: magnetic resonance imaging (MRI), computed tomography, and transient elastography. We further determined factors associated with improving hepatic steatosis by canagliflozin among patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods We conducted a six-month prospective single-arm study between August 2015 and June 2017. The primary outcome was the change in hepatic steatosis assessed using the hepatic proton density fat fraction (PDFF) on MRI before and after treatment with canagliflozin. The secondary outcomes were changes in measures of glucose metabolism, including the hepatic glucose uptake on fluorodeoxyglucose-positron emission tomography, and the inflammation and volumes of visceral and subcutaneous adipose tissue and skeletal muscle. Patients Nine patients with type 2 diabetes and NAFLD completed this study. All participants received canagliflozin at a dose of 100 mg daily. Results Canagliflozin caused a significant reduction in hepatic PDFF from baseline [median 20.6% (interquartile range 11.7%, 29.8%)] after 6 months [10.6% (5.4%, 22.6%), p=0.008]. Canagliflozin also significantly reduced the body weight, glycated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), and volumes of adipose tissue and skeletal muscle (all p<0.05). The reduction in hepatic PDFF was not correlated with changes in the body weight, HOMA-IR, hs-CRP, or volume of adipose tissue and skeletal muscle from baseline after six months. Conclusion Among patients with type 2 diabetes and NAFLD, canagliflozin improved hepatic steatosis. The effect may be independent of reducing adiposity, insulin resistance, inflammation, and skeletal muscle volume.

    DOI： 10.2169/internalmedicine.7134-21

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  • Immediate Glucose-Lowering Effect After the First Administration of Dulaglutide: A Retrospective, Single-Center, Observational Study. 国際誌

    Sakiko Terui, Ryoichi Akamatsu, Masanori Arai, Ryota Inoue, Tomoko Okuyama, Mayu Kyohara, Jinghe Li, Takahiro Tsuno, Daisuke Miyashita, Yu Togashi, Yasuo Terauchi, Jun Shirakawa

    Diabetes therapy : research, treatment and education of diabetes and related disorders   12 ( 11 )   2873 - 2889   2021年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    INTRODUCTION: Dulaglutide is a long-acting glucagon-like peptide 1 receptor agonist that is administered once weekly for the treatment of type 2 diabetes. However, the immediate glucose-lowering effect of dulaglutide after the first administration and the factors affecting the efficacy of the drug remain unclear. METHODS: This study was a retrospective and observational study of 80 subjects with type 2 diabetes conducted in a hospitalized setting. The changes (Δ) in the blood glucose (BG) levels at six time points (6-point BG levels) from the baseline (day - 1) to the day after the first administration of 0.75 mg of dulaglutide (day 1) were evaluated. The associations of the Δ 6-point BG levels with the patients' characteristics and laboratory data were also analyzed. RESULTS: Significant reduction of the fasting BG, preprandial BG, postprandial BG, and standard deviation (SD) of the 6-point BG levels was observed on day 1 as compared to day - 1 (P < 0.0001) and the reduced BG levels were maintained throughout the remaining observation period of 5 days. The baseline serum hemoglobin A1c and glycoalbumin levels were positively correlated with the reduction of the fasting BG. The Δ BG levels were not related to the parameters of insulin-secreting capacity. Insulin treatment was positively associated with the reduction of the 6-point BG levels. Patients without cerebrovascular disease and patients without diabetic retinopathy showed greater improvements of the fasting BG and SD of the 6-point BG levels, respectively. Urinary microalbumin level was positively correlated with improvements of the 6-point BG levels. Dulaglutide reduced the BG levels, irrespective of the previously used class of antidiabetic medication(s). CONCLUSION: Dulaglutide achieved reduction in glucose level within 24 h of the first injection. The improvement in the BG levels remained stable for a week in the hospitalized clinical setting.

    DOI： 10.1007/s13300-021-01147-2

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  • Asymptomatic meningitis diagnosed by positron emission tomography in a patient with syndrome of inappropriate antidiuretic hormone secretion: a case report. 国際誌

    Masanori Hasebe, Jun Shirakawa, Daisuke Miyashita, Rieko Kunishita, Mayu Kyohara, Tomoko Okuyama, Yu Togashi, Yasuo Terauchi

    Journal of medical case reports   15 ( 1 )   390 - 390   2021年7月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion can be caused by arginine-vasopressin-producing tumors or enhanced arginine vasopressin secretion from the posterior pituitary gland due to central nervous system disorders and intrathoracic diseases. CASE PRESENTATION: A 53-year-old Asian man was hospitalized with complaints of tremor and hiccups. Laboratory examination revealed findings suggestive of hypotonic hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion. The patient did not complain of headache or photophobia, and showed no signs of meningeal irritation. Positron emission tomography-computed tomography revealed 18F-fluoro-deoxy-glucose accumulation along the cervical spinal cord, based on which the patient was diagnosed as having aseptic meningitis. The hyponatremia was treated successfully by fluid restriction, and optimum plasma sodium concentration was maintained by tolvaptan administration. CONCLUSIONS: This case underscores the need to consider the possibility of mild meningitis as the cause of syndrome of inappropriate antidiuretic hormone secretion in patients without other identifiable cause.

    DOI： 10.1186/s13256-021-02956-6

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  • 2型糖尿病患者における腹部大動脈石灰化はFib4-indexおよび低BMIと関連する

    富樫 優, 宮下 大介, 新井 正法, 奥山 朋子, 京原 麻由, 寺内 康夫, 白川 純

    日本内分泌学会雑誌   97 ( 1 )   325 - 325   2021年4月

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    記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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  • Autosomal dominant diabetes associated with a novel ZYG11A mutation resulting in cell cycle arrest in beta-cells. 査読 国際誌

    Chutima Charoensuk, Prapaporn Jungtrakoon Thamtarana, Chutima Chanprasert, Watip Tangjittipokin, Jun Shirakawa, Yu Togashi, Kazuki Orime, Pucharee Songprakhon, Chartchai Chaichana, Zuroida Abubakar, Paweena Ouying, Jatuporn Sujjitjoon, Alessandro Doria, Nattachet Plengvidhya, Pa-Thai Yenchitsomanus

    Molecular and cellular endocrinology   522   111126 - 111126   2021年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Diabetes is a genetically heterogeneous disease, for which we are aiming to identify causative genes. Here, we report a missense mutation (c.T1424C:p.L475P) in ZYG11A identified by exome sequencing as segregating with hyperglycemia in a Thai family with autosomal dominant diabetes. ZYG11A functions as a target recruitment subunit of an E3 ubiquitin ligase complex that plays an important role in the regulation of cell cycle. We demonstrate an increase in cells arrested at G2/mitotic phase among beta-cells deficient for ZYG11A or overexpressing L475P-ZYG11A, which is associated with a decreased growth rate. This is the first evidence linking a ZYG11A mutation to hyperglycemia, and suggesting ZYG11A as a cell cycle regulator required for beta-cell growth. Since most family members were either overweight or obese, but only mutation carriers developed hyperglycemia, our data also suggests the ZYG11A mutation as a genetic factor predisposing obese individuals to beta-cell failure in maintenance of glucose homeostasis.

    DOI： 10.1016/j.mce.2020.111126

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  • Association of the plasma xanthine oxidoreductase activity with the metabolic parameters and vascular complications in patients with type 2 diabetes. 国際誌

    Tomoko Okuyama, Jun Shirakawa, Takashi Nakamura, Takayo Murase, Daisuke Miyashita, Ryota Inoue, Mayu Kyohara, Yu Togashi, Yasuo Terauchi

    Scientific reports   11 ( 1 )   3768 - 3768   2021年2月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine, and of xanthine to uric acid. XOR also enhances the production of reactive oxygen species and causes endothelial dysfunction. In this study, we evaluated the association of XOR and its substrate with the vascular complications in 94 Japanese inpatients with type 2 diabetes (T2DM). The plasma XOR activity and plasma xanthine levels were positively correlated with the body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-GTP, fasting plasma insulin, and the homeostasis model of assessment of insulin resistance (HOMA-IR), and negatively correlated with the high density lipoprotein cholesterol. The plasma XOR activity also showed a positive correlation with the serum triglyceride. Multivariate analyses identified AST, ALT, fasting plasma insulin and HOMA-IR as being independently associated with the plasma XOR activity. The plasma XOR activity negatively correlated with the duration of diabetes, and positively correlated with the coefficient of variation of the R-R interval and sensory nerve conduction velocity. Furthermore, the plasma XOR activity was significantly decreased in patients with coronary artery disease. Thus, the plasma XOR activity might be a surrogate marker for the development of vascular complications, as well as liver dysfunction and insulin resistance, in T2DM.Trial registration: This study is registered at the UMIN Clinical Trials Registry (UMIN000029970; https://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from Nov 15, 2017.

    DOI： 10.1038/s41598-021-83234-9

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  • Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor. 国際誌

    Tomoko Okuyama, Jun Shirakawa, Kazuki Tajima, Yoko Ino, Heidrun Vethe, Yu Togashi, Mayu Kyohara, Ryota Inoue, Daisuke Miyashita, Jinghe Li, Nozomi Goto, Taiga Ichikawa, Shingo Yamasaki, Haruka Ohnuma, Rie Takayanagi, Yayoi Kimura, Hisashi Hirano, Yasuo Terauchi

    International journal of molecular sciences   21 ( 21 )   2020年10月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

    DOI： 10.3390/ijms21217815

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  • Luseogliflozin increases beta cell proliferation through humoral factors that activate an insulin receptor- and IGF-1 receptor-independent pathway. 査読 国際誌

    Jun Shirakawa, Kazuki Tajima, Tomoko Okuyama, Mayu Kyohara, Yu Togashi, Dario F De Jesus, Giorgio Basile, Tatsuya Kin, A M James Shapiro, Rohit N Kulkarni, Yasuo Terauchi

    Diabetologia   63 ( 3 )   577 - 587   2020年3月

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    記述言語：英語  

    AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice. METHODS: We treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets. RESULTS: SGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (βIRKO) beta cells with serum from both luseogliflozin- and OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets. CONCLUSIONS/INTERPRETATION: These results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.

    DOI： 10.1007/s00125-019-05071-w

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  • Soluble EGFR, a hepatokine, and adipsin, an adipokine, are biomarkers correlated with distinct aspects of insulin resistance in type 2 diabetes subjects. 国際誌

    Mayu Kyohara, Jun Shirakawa, Tomoko Okuyama, Yu Togashi, Ryota Inoue, Jinghe Li, Daisuke Miyashita, Yasuo Terauchi

    Diabetology & metabolic syndrome   12   83 - 83   2020年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Background: Insulin resistance can occur in all metabolic organs including the liver, adipose tissue, and skeletal muscles. Circulating soluble epidermal growth factor receptor (soluble EGFR) and adipsin levels are altered in obese diabetic mice and are possibly correlated with insulin resistance in both mice and humans. Here, we investigated the significance of soluble EGFR and adipsin as biomarkers for insulin resistance in Japanese subjects with type 2 diabetes. Methods: We measured the soluble EGFR and adipsin levels in sera from 47 non-diabetic subjects and 106 subjects with type 2 diabetes using enzyme-linked immunosorbent assays (ELISAs) and analyzed the correlations between the soluble EGFR or adipsin levels and metabolic parameters in type 2 diabetes subjects. We also measured the gene expression levels of Egfr and Cfd (adipsin) in the liver, adipose tissue, and skeletal muscle in mice with/without obesity or diabetes. Results: The soluble EGFR levels were correlated with the fasting blood glucose level (P = 0.010), HOMA-IR (P = 0.035), HbA1c level (P = 0.007), HDL-cholesterol level (P = 0.044), and FIB-4 index (P = 0.017) after adjustments for age, sex, and total cholesterol levels. These factors are known to be related to hepatic insulin resistance. The serum adipsin levels were correlated with BMI (P < 0.001), waist circumference (P < 0.001), fasting serum insulin level (P = 0.001), HOMA-IR (P = 0.009), CPR-index (P = 0.045), and FIB-4 index (P = 0.007) after adjustments for age, sex and eGFR levels. Abdominal adiposity leads to the potentiation of these factors. The expression of Egfr was abundant in the liver, while Cfd was predominantly expressed in adipose tissue in mice. Conclusions: Soluble EGFR, a hepatokine, is correlated with insulin resistance in the liver, while adipsin, an adipokine, is associated with adipose insulin resistance.Trial registration: UMIN Clinical Trials Registry (www.umin.ac.jp), UMIN000020474. Registered 8 January 2016.

    DOI： 10.1186/s13098-020-00591-7

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  • Influence of Timing of Insulin Initiation on Long-term Glycemic Control in Japanese Patients with Type 2 Diabetes: A Retrospective Cohort Study. 査読

    Miyazaki T, Shirakawa J, Nagakura J, Shibuya M, Kyohara M, Okuyama T, Togashi Y, Nakamura A, Kondo Y, Satoh S, Nakajima S, Taguri M, Terauchi Y

    Internal medicine (Tokyo, Japan)   58 ( 23 )   3361 - 3367   2019年12月

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  • Effects of SGLT2 Inhibition on eGFR and Glomerular and Tubular Damage Markers in Japanese Patients With Type 2 Diabetes

    Hiromi Konishi, Jun Shirakawa, Kazuki Tajima, Tomoko Okuyama, Yu Togashi, Hikaru Takamine, Yoshinobu Kondo, Rieko Kunishita, Yasuo Terauchi

    JOURNAL OF ENDOCRINOLOGY AND METABOLISM   8 ( 5 )   106 - 112   2018年10月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.14740/jem531w

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  • Signaling between pancreatic β cells and macrophages via S100 calcium-binding protein A8 exacerbates β-cell apoptosis and islet inflammation. 査読 国際誌

    Inoue H, Shirakawa J, Togashi Y, Tajima K, Okuyama T, Kyohara M, Tanaka Y, Orime K, Saisho Y, Yamada T, Shibue K, Kulkarni RN, Terauchi Y

    The Journal of biological chemistry   293 ( 16 )   5934 - 5946   2018年4月

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  • Serum Quantitative Proteomic Analysis Reveals Soluble EGFR To Be a Marker of Insulin Resistance in Male Mice and Humans. 査読 国際誌

    Kyohara M, Shirakawa J, Okuyama T, Kimura A, Togashi Y, Tajima K, Hirano H, Terauchi Y

    Endocrinology   158 ( 12 )   4152 - 4164   2017年12月

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    記述言語：英語  

    DOI： 10.1210/en.2017-00339

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  • Effects of metformin on compensatory pancreatic β-cell hyperplasia in mice fed a high-fat diet. 査読 国際誌

    Tajima K, Shirakawa J, Okuyama T, Kyohara M, Yamazaki S, Togashi Y, Terauchi Y

    American journal of physiology. Endocrinology and metabolism   313 ( 3 )   E367-E380 - E380   2017年9月

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  • Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic β cell proliferation after the withdrawal of OSI-906. 査読 国際誌

    Tajima K, Shirakawa J, Togashi Y, Yamazaki S, Okuyama T, Kyohara M, Konishi H, Terauchi Y

    Scientific reports   7 ( 1 )   4119 - 4119   2017年6月

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  • Identification of the matricellular protein Fibulin-5 as a target molecule of glucokinase-mediated calcineurin/NFAT signaling in pancreatic islets. 査読 国際誌

    Okuyama T, Shirakawa J, Yanagisawa H, Kyohara M, Yamazaki S, Tajima K, Togashi Y, Terauchi Y

    Scientific reports   7 ( 1 )   2364 - 2364   2017年5月

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  • GHRP-2負荷試験による視床下部 下垂体副腎系機能評価に関する検討

    近藤 義宣, 新井 正法, 室橋 祐子, 細川 紗帆, 田島 一樹, 富樫 優, 伊藤 譲, 寺内 康夫

    日本内分泌学会雑誌   93 ( 1 )   264 - 264   2017年4月

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    記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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  • Evaluation of the appropriateness of using glucometers for measuring the blood glucose levels in mice. 査読 国際誌

    Togashi Y, Shirakawa J, Okuyama T, Yamazaki S, Kyohara M, Miyazawa A, Suzuki T, Hamada M, Terauchi Y

    Scientific reports   6   25465 - 25465   2016年5月

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    記述言語：英語  

    DOI： 10.1038/srep25465

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  • Lipid-lowering agents inhibit hepatic steatosis in a non-alcoholic steatohepatitis-derived hepatocellular carcinoma mouse model. 査読 国際誌

    Orime K, Shirakawa J, Togashi Y, Tajima K, Inoue H, Nagashima Y, Terauchi Y

    European journal of pharmacology   772   22 - 32   2016年2月

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  • DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid. 査読 国際誌

    Shirakawa J, Okuyama T, Kyohara M, Yoshida E, Togashi Y, Tajima K, Yamazaki S, Kaji M, Koganei M, Sasaki H, Terauchi Y

    Diabetology & metabolic syndrome   8   16 - 16   2016年

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  • 著明な高Na血症を呈した糖尿病性ケトーシスの1例

    原田 万里奈, 白川 純, 奥山 朋子, 吉井 大司, 野上 麻子, 室橋 祐子, 酒井 里菜, 山崎 俊介, 富樫 優, 伊藤 譲, 寺内 康夫

    糖尿病   57 ( 6 )   486 - 486   2014年6月

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    記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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  • 混合型インスリン製剤1日2回注射で血糖コントロール不十分な際の段階的治療法の検討

    小野 香奈子, 中村 昭伸, 川口 順子, 瀧端 正博, 井上 雄一郎, 白川 純, 亀田 晶子, 富樫 優, 林 勉, 古木 隆元, 伊藤 俊, 高野 達朗, 河崎 さつき, 武田 浩, 金子 徹治, 木村 真理, 水嶋 春朔, 寺内 康夫

    糖尿病   56 ( Suppl.1 )   S - 152   2013年4月

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    記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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  • Mosapride citrate, a 5-HT4 receptor agonist, increased the plasma active and total glucagon-like peptide-1 levels in non-diabetic men 査読

    Kazutaka Aoki, Hiroshi Kamiyama, Kiyomi Masuda, Yu Togashi, Yasuo Terauchi

    ENDOCRINE JOURNAL   60 ( 4 )   493 - 499   2013年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

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  • Trefoil factor 2 promotes cell proliferation in pancreatic β-cells through CXCR-4-mediated ERK1/2 phosphorylation. 査読 国際誌

    Orime K, Shirakawa J, Togashi Y, Tajima K, Inoue H, Ito Y, Sato K, Nakamura A, Aoki K, Goshima Y, Terauchi Y

    Endocrinology   154 ( 1 )   54 - 64   2013年1月

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    記述言語：英語  

    DOI： 10.1210/en.2012-1814

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  • AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration. 査読 国際誌

    Kazuki Tajima, Jun Shirakawa, Yu Togashi, Hideaki Inoue, Koichiro Sato, Kazuki Orime, Yuzuru Ito, Mitsuyo Kaji, Eri Sakamoto, Akinobu Nakamura, Kazutaka Aoki, Yoshio Goshima, Tatsuya Atsumi, Yasuo Terauchi

    PloS one   8 ( 5 )   e64633   2013年

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    記述言語：英語  

    The precise role of AMP-activated protein kinase (AMPK), a target of metformin, in pancreatic β cells remains controversial, even though metformin was recently shown to enhance the expression of incretin receptors (GLP-1 and GIP receptors) in pancreatic β cells. In this study, we investigated the effect of AMPK in the regulation of incretin receptors expression in pancreatic islets. The phosphorylation of AMPK in the mouse islets was decreased by increasing glucose concentrations. We showed the expression of incretin receptors in bell-shaped response to glucose. Expression of the incretin receptors in the isolated islets showed higher levels under a medium glucose concentration (11.1 mM) than that under a low glucose concentration (2.8 mM), but was suppressed under a high glucose concentration (22.2 mM). Both treatment with an AMPK inhibitor and DN-AMPK expression produced a significant increase of the incretin receptors expression under a low glucose concentration. By contrast, in hyperglycemic db/db islets, the enhancing effect of the AMPK inhibitor on the expression of incretin receptors was diminished under a low glucose concentration. Taken together, AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.

    DOI： 10.1371/journal.pone.0064633

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  • Plasminogen activator inhibitor-1 is associated with renal dysfunction independent of BMI and serum lipid levels in patients with type 2 diabetes. 査読 国際誌

    Shirakawa J, Togashi Y, Tajima K, Orime K, Kikuchi K, Miyazaki T, Sato K, Kimura M, Goshima Y, Terauchi Y

    Diabetes research and clinical practice   97 ( 1 )   e9-12 - e10   2012年7月

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    記述言語：英語   出版者・発行元：1  

    DOI： 10.1016/j.diabres.2012.03.017

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  • Effects of Liraglutide on β-Cell-Specific Glucokinase-Deficient Neonatal Mice. 査読 国際誌

    Shirakawa J, Tanami R, Togashi Y, Tajima K, Orime K, Kubota N, Kadowaki T, Goshima Y, Terauchi Y

    Endocrinology   153 ( 7 )   3066 - 75   2012年7月

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    記述言語：英語   出版者・発行元：7  

    DOI： 10.1210/en.2012-1165

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  • Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions. 査読

    Nakamura A, Togashi Y, Orime K, Sato K, Shirakawa J, Ohsugi M, Kubota N, Kadowaki T, Terauchi Y

    Diabetologia   55 ( 6 )   1745 - 1754   2012年6月

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    出版者・発行元：6  

    DOI： 10.1007/s00125-012-2521-5

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  • Impact of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance and β-cell function and mass in insulin receptor substrate-2-knockout mice fed a high-fat diet. 査読 国際誌

    Sato K, Nakamura A, Shirakawa J, Muraoka T, Togashi Y, Shinoda K, Orime K, Kubota N, Kadowaki T, Terauchi Y

    Endocrinology   153 ( 3 )   1093 - 102   2012年3月

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    記述言語：英語   出版者・発行元：3  

    DOI： 10.1210/en.2011-1712

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  • Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased β cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes. 査読 国際誌

    Shirakawa J, Amo K, Ohminami H, Orime K, Togashi Y, Ito Y, Tajima K, Koganei M, Sasaki H, Takeda E, Terauchi Y

    The Journal of biological chemistry   286 ( 29 )   25467 - 76   2011年7月

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  • Comparison of short-term effectiveness of introducing insulin treatment between intensive and thrice-daily lispro 50/50 therapy

    Kiyomi Masuda, Kazutaka Aoki, Yu Togashi, Mayumi Takahashi, Yasuo Terauchi

    Yokohama Medical Journal   62 ( 4 )   487 - 493   2011年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

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  • Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men 査読

    Kazutaka Aoki, Kiyomi Masuda, Takashi Miyazaki, Yu Togashi, Yasuo Terauchi

    ENDOCRINE JOURNAL   57 ( 8 )   667 - 672   2010年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

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  • Effects of pre-meal versus post-meal administration of miglitol on plasma glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide levels in healthy men. 査読

    Aoki K, Miyazaki T, Nagakura J, Orime K, Togashi Y, Terauchi Y

    Endocr J.   57 ( 8 )   673 - 677   2010年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.1507/endocrj.K10E-064

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  • Comparison of Adverse Gastrointestinal Effects of Acarbose and Miglitol in Healthy Men: A Crossover Study 査読

    Kazutaka Aoki, Tomonori Muraoka, Yuzuru Ito, Yu Togashi, Yasuo Terauchi

    INTERNAL MEDICINE   49 ( 12 )   1085 - 1087   2010年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.2169/internalmedicine.49.3218

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  • Correlations of fasting and postprandial blood glucose increments to the overall diurnal hyperglycemic status in type 2 diabetic patients: variations with levels of HbA1c. 査読

    Kikuchi K, Nezu U, Shirakawa J, Sato K, Togashi Y, Kikuchi T, Aoki K, Ito Y, Kimura M, Terauchi Y

    Endocrine journal   57 ( 3 )   259 - 266   2010年

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  • Comparison of pre- versus post-meal administration of voglibose in men with or without impaired glucose tolerance. 査読 国際誌

    Kazutaka Aoki, Yuzuru Ito, Kaori Saito, Jun Shirakawa, Yu Togashi, Kouichiro Satoh, Tomonori Muraoka, Kazuaki Shinoda, Kiyomi Masuda, Mari Kimura, Yasuo Terauchi

    Diabetes research and clinical practice   83 ( 2 )   e31-2 - 2   2009年2月

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共同研究・競争的資金等の研究課題

  • 機能的な膵β細胞量を増加させる「膵β細胞のhealthy expansion」の分子機構の解明

    研究課題/領域番号：23K27652  2023年4月 - 2026年3月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    寺内 康夫, 富樫 優, 京原 麻由, 白川 純, 奥山 朋子

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    配分額：18850000円 （ 直接経費：14500000円 、 間接経費：4350000円 ）

    新規蛍光指示薬を用いて、膵β細胞株や膵島において、慢性的なグルコキナーゼの活性化で誘導されるUCP2およびAldBの過剰発現やノックダウンが、細胞内小器官を介して、インスリン分泌障害を誘導する新規の糖尿病機構を検討した。
    膵β細胞においては、グルコース刺激時のATP 感受性 K+ チャネル閉鎖に伴う脱分極を介した細胞外からのCa2+ 流入がインスリン分泌に重要である。Multi-Electrode Array (MEA) は、培養細胞の活動電位を多点で同時計測でき、かつ膵島細胞間のネットワークの評価も可能とする技術である。これにより、膵島の電気生理的解析が可能となり、UCP2およびAldBの過剰発現やノックダウンが膵β細胞の活動電位へ与える影響の解析を行った。
    また、UCP2およびAldBが膵島の活動電位に変化をおよぼす場合、膵β細胞の活動電位へ影響する既存の経口血糖降下薬（SU薬、インクレチン関連薬、イメグリミンなど）との関連を解析し、1編論文化した。
    Phos-tag 二次元電気泳動というリン酸化状態の異なる同一蛋白を定量する技術、mRNAに会合する複数のリボソームを検出するポリソームプロファイリングという手法により、遺伝子の転写から翻訳および翻訳後調節に至るまでの網羅的な解析が可能となり、糖尿病下の膵β細胞におけるUCP2やAldBの膵β障害機構を詳細に解析した。
    UCP2の過剰発現によるインスリン分泌障害がAldBの誘導に起因しているのか、膵β細胞特異的AldB欠損マウスを作成し検証する。また、膵β細胞特異的UCP2過剰発現AldB欠損マウスを樹立した。膵β細胞でAldBが発現上昇する他の糖尿病モデルマウス（db/dbマウスなど）においても、膵β細胞特異的AldB欠損による抗糖尿病効果を検討した。

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  • リン酸化プロテオミクスによる膵切除後膵β細胞増殖機構の解明

    研究課題/領域番号：22K08659  2022年4月 - 2025年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    富樫 優, 京原 麻由, 寺内 康夫, 奥山 朋子

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    配分額：4160000円 （ 直接経費：3200000円 、 間接経費：960000円 ）

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  • 糖脂肪毒性下の膵島ミトコンドリア機能障害・炎症の病態解明と治療法の創出

    研究課題/領域番号：20H03733  2020年4月 - 2023年3月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    寺内 康夫, 富樫 優, 白川 純

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    配分額：17810000円 （ 直接経費：13700000円 、 間接経費：4110000円 ）

    膵β細胞特異的UCP2過剰発現マウス（βUCP2Tg）膵島においてATP 産生およびミトコンドリア酸素消費速度は抑制，電子伝達系Complex1 の蛋白発現は低下．遺伝子発現解析にて，βUCP2Tg で約77 倍に上昇する解糖系酵素のアルドラーゼB（AldB）を同定．AldB 過剰発現MIN6-M9 細胞ではGSISが低下，AldB 過剰発現マウス膵島ではComplex 2，4 の蛋白発現が低下．βUCP2Tg 膵島ではGPR40 作動薬によるインスリン分泌増強および細胞内Ca濃度上昇が抑制，これはAldB 過剰発現膵島でも同様．UCP2 過剰発現INS1 細胞株では高グルコース刺激後の小胞体Ca濃度が低下，GPR40 作動薬刺激時の小胞体Ca濃度低下が消失．一方，UCP2 過剰発現膵β 細胞でAldB をノックダウンするとUCP2 過剰発現によるGSIS 低下，ミトコンドリア呼吸障害およびグルコース刺激時の細胞内Ca濃度低下がいずれも改善．
    炎症関連タンパク質S100A8の敗血症における役割を解析．LPSを腹腔内注射後にS100A8をマウスに投与すると，腹腔細胞および血清の炎症性サイトカイン産生が低下，生存率が改善．大腸菌投与，盲腸結紮穿刺による敗血症モデルでもS100A8投与により生存率が改善．TLR4を介したシグナルがS100A8を誘導，S100A8はMφのTLR4を介してLPSによる炎症を抑制．顆粒球単球特異的S100A8ノックアウトマウスではLPSによるS100A8の上昇が消失，生存率が低下，S100A8補充により生存率改善．西洋食（WD）負荷肥満・糖尿病マウスでも，LPS投与によるS100A8誘導が障害され，生存率が低下．WDマウスにS100A8を補充したところLPSによる致死率が改善．肥満・糖尿病ではS100A8の補充が感染症治療に有用となる可能性が示唆された．

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  • インスリン/IGF-1両受容体阻害による新規サルコペニアモデルの解析

    研究課題/領域番号：18K08484  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    富樫 優, 寺内 康夫, 白川 純, 奥山 朋子

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    配分額：4420000円 （ 直接経費：3400000円 、 間接経費：1020000円 ）

    インスリン受容体(IR)/IGF-1受容体(IFG1R)を阻害するOSI-906投与動物モデルにより、2型糖尿病患者のサルコペニアの機構を解析した。OSI-906を14日間投与後、OSI-906群は高血糖と体重減少、四頭筋、腓腹筋の重量低下を認めた。前脛骨筋の組織では、OSI-906投与後に、oxidative fiber の数および割合が有意に増加していたことから、完全に分化した骨格筋におけるIRおよびIGF1Rの阻害が骨格筋の可塑的な変化を誘導することが示唆された。遺伝子解析では、骨格筋のグルコース取り込み促進、細胞周期の抑制的制御、蛋白分解促進、オートファジー亢進の可能性が示唆された。

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  • グルコキナーゼ活性化による膵β細胞の運命決定

    研究課題/領域番号：16H05329  2016年4月 - 2019年3月

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    寺内 康夫, 伊藤 譲, 富樫 優, 白川 純, 田島 一樹, 田島 一樹

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    配分額：17290000円 （ 直接経費：13300000円 、 間接経費：3990000円 ）

    解糖系の酵素であるグルコキナーゼを介した糖代謝シグナルが、膵β細胞の機能のみならず増殖と関与することを私たちは示してきたが、今回、グルコキナーゼを活性化することで、糖代謝が活性化された時に膵β細胞に起こる変化を網羅的に観察した。発現が上昇するタンパクの中でもFlbn5、EGFR、S100A8に焦点を当て、糖代謝における役割を論文化した。興味深いことに、S100A8は高血糖および高遊離脂肪酸により惹起される膵β細胞とマクロファージとの相互作用を介した膵島炎症の悪循環の形成に関わっていた。

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  • インスリン受容体およびIGF-1受容体阻害後の膵β細胞、肝臓、脂肪組織の回復機構

    研究課題/領域番号：16K19542  2016年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業  若手研究(B)

    富樫 優, 寺内 康夫, 白川 純, 田島 一樹, 折目 和基, 奥山 朋子

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    配分額：3900000円 （ 直接経費：3000000円 、 間接経費：900000円 ）

    インスリン受容体・IGF-1受容体遮断薬OSI-906投与モデルを用い、インスリン抵抗性下および解除後の膵β細胞、肝臓、脂肪組織の可塑的変化の分子機構を解析した。
    OSI-906投与により、インスリン/IGF-1に非依存的な膵β細胞増殖、内臓脂肪の著明な萎縮、脂肪肝を認め、OSI-906投与中止後に対照群と同等となった。本モデルでは、脂肪萎縮糖尿病の治療薬として用いられるレプチンや経口糖尿病薬のDPP-4阻害薬の投与は、脂肪肝を改善し、経口糖尿病薬SGLT-2阻害薬の投与は耐糖能の改善および膵β細胞量の増大効果を認め、インスリン/IGF-1に非依存的な臓器特異的作用を有する可能性が示唆された。

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  • 膵切除モデルにおける新規膵β細胞増殖機構の解明

    研究課題/領域番号：26860698  2014年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業  若手研究(B)

    富樫 優, 寺内 康夫, 白川 純, 田島 一樹, 折目 和基

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    配分額：3770000円 （ 直接経費：2900000円 、 間接経費：870000円 ）

    膵切除後の膵β細胞増殖におけるIRS-2の役割を検討するため、野生型およびIRS-2欠損マウスに膵部分切除を行った。膵切除後IRS-2欠損マウスは高血糖とインスリン分泌障害を認め、高血糖是正によりインスリン分泌能が改善した。一方、単離膵島のインスリン分泌能は高血糖是正の有無に関わらず膵切除IRS-2欠損マウスにおいても障害を認めなかった。さらに、膵切除IRS-2欠損マウスの膵β細胞増殖能は高血糖是正により低下しなかった。以上より、膵部分切除後の膵β細胞増殖はIRS-2を介したインスリンシグナル非依存的であり、高血糖にも依存せず、膵β細胞増殖後のインスリン分泌能は正常に保たれることが示唆された。

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