Ectopic fat accumulation and distant organ-specific insulin resistance

• Project/Area Number: 25860744
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: TAKESHITA YUMIE 金沢大学, 大学病院, 助教 (40507042)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 臓器特異的インスリン抵抗性 / ヘパトカイン / セレノプロテインＰ / 肝インスリン抵抗性 / 骨格筋インスリン感受性 / インスリン抵抗性 / 細胞内脂肪蓄積 / 高インスリン正常血糖クランプ検査

Outline of Final Research Achievements

Organ-specific IR in the liver (hepatic glucose production (HGP) × fasting plasma insulin (FPI) and suppression of HGP by insulin [%HGP]), skeletal muscle (insulin-stimulated glucose disposal [Rd]), and adipose tissue (suppression of FFA by insulin [%FFA]) was measured in 69 patients with NAFLD using a euglycemic hyperinsulinemic clamp. Liver fat, intramyocellular lipid (IMCL), and body composition were measured by liver biopsy, proton magnetic resonance spectroscopy, and bioelectrical impedance analysis, respectively. Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organ-specific IR. Instead, liver fat was associated not only with hepatic IR but also with skeletal muscle IR, suggesting a central role of fatty liver in systemic IR and that a network exists between liver and skeletal muscle.

Research Products

• [Journal Article] Bending of a vertical cannula without alarm during insulin pump therapy as a cause of unexpected hyperglycemia: A Japanese issue? (2015)
  • Author(s): Kuroda K, Takeshita Y, Kaneko S, Takamura T.
  • Journal Title: J Diabetes Investig. Volume: 6 Pages: 739-740
  • NAID: 120005689372
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sitagliptin versus mitiglinide switched from mealtime dosing of a rapid-acting insulin analog in patients with type 2 diabetes: a randomized, parallel-group study. (2015)
  • Author(s): Takeshita Y, Takamura T, Kita Y, Takazakura A, Kato K, Isobe Y, Kaneko S.
  • Journal Title: BMJ Open Diabetes Res Care. Volume: 3
  • NAID: 120005774893
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Renoprotective effects of atorvastatin compared with pravastatin on progression of early diabetic nephropathy. (2015)
  • Author(s): Takazakura A, Sakurai M, Bando Y, Misu H, Takeshita Y, Kita Y, Shimizu A, Hayakawa T, Kato K, Kaneko S, Takamura T.
  • Journal Title: J Diabetes Investig Volume: 6 Pages: 346-353
  • NAID: 120005819637
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vildagliptin vs liraglutide as a second-line therapy switched from sitagliptin-based regimens in patients with type 2 diabetes: A randomized, parallel-group study. (2015)
  • Author(s): Takeshita Y, Takamura T, Kita Y, Otoda T, Kato K, Wakakuri H, Yamada M, Misu H, Matsushima Y,Kaneko S; Establishment of Rationale for Antiaging Diabetic Medicine (ERA-DM) Study Chapter 2 Group
  • Journal Title: J Diabetes Investig Volume: 6 Pages: 192-200
  • NAID: 120005774894
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease. (2015)
  • Author(s): Kato K, Takeshita Y, Misu H, Zen Y, Kaneko S, Takamura T
  • Journal Title: J Diabetes Investig. Volume: 6 Pages: 158-163
  • NAID: 120005593987
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis. (2015)
  • Author(s): Yamada K, Mizukoshi E, Sunagozaka H, Arai K, Yamashita T, Takeshita Y, Misu H, Takamura T, Kitamura S, Zen Y, Nakanuma Y, Honda M, Kaneko S.
  • Journal Title: Liver Int. Volume: 35 Pages: 582-590
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum. (2014)
  • Author(s): Tanaka M, Saito Y, Misu H, Kato S, Kita Y, Takeshita Y, Kanamori T, Nagano T, Nakagen M, Urabe T, Takamura T, Kaneko S, Takahashi K, Matsuyama N
  • Journal Title: J Clin Lab Anal. Volume: Dec Pages: 26-26
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. (2014)
  • Author(s): Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T.
  • Journal Title: Diabetologia. Volume: 57 Pages: 1968-1976
  • NAID: 120005463349
  • Peer Reviewed / Open Access
• [Journal Article] Urinary Kim-1 is a sensitive biomarker for the early stage of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats. (2014)
  • Author(s): Hosohata K, Ando H, Takeshita Y, Misu H, Takamura T, Kaneko S, Fujimura A.
  • Journal Title: Diab Vasc Dis Res. Volume: 11 Pages: 243-250
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. (2014)
  • Author(s): Lan F, Misu H, Chikamoto K, Takayama H, Kikuchi A, Mohri K, Takata N, Hayashi H, Matsuzawa-Nagata N, Takeshita Y, Noda H, Matsumoto Y, Ota T, Nagano T, Nakagen M, Miyamoto K, Takatsuki K, Seo T, Iwayama K, Tokuyama K, Matsugo S, Tang H, Saito Y, Yamagoe S, Kaneko S,Takamura T.
  • Journal Title: Diabetes. Volume: 63 Pages: 1649-1664
  • NAID: 120005440333
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic Fatty liver disease. (2014)
  • Author(s): Kato K, Takamura T, Takeshita Y, Ryu Y, Misu H, Ota T, Tokuyama K, Nagasaka S, Matsuhisa M, Matsui O, Kaneko S.
  • Journal Title: PLoS One Volume: 9 (3)
  • NAID: 120005440398
  • Peer Reviewed
• [Journal Article] The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. (2014)
  • Author(s): Takeshita Y, Takamura T, Honda M, Kita Y, Zen Y, Kato KI, Misu H, Ota T, Nakamura M, Yamada K, Sunagozaka H, Arai K, Yamashita T, Mizukoshi E, Kaneko S.
  • Journal Title: Diabetologia Volume: 57 Pages: 878-890
  • Peer Reviewed
• [Journal Article] Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver. (2013)
  • Author(s): Otoda T, Takamura T, Misu H, Ota T, Murata S, Hayashi H, Takayama H, Kikuchi A, Kanamori T, Shima KR, Lan F, Takeda T, Kurita S, Ishikura K, Kita Y, Iwayama K, Kato K, Uno M, Takeshita Y, Yamamoto M, Tokuyama K, Iseki S, Tanaka K, Kaneko S.
  • Journal Title: Diabetes. Volume: 62 Pages: 811-824
  • Peer Reviewed
• [Journal Article] Quantitative analysis of hepatic fat fraction by single-breath-holding MR spectroscopy with T₂ correction: phantom and clinical study with histologic assessment. (2013)
  • Author(s): Hayashi N, Miyati T, Minami T, Takeshita Y, Ryu Y, Matsuda T, Ohno N, Hamaguchi T, Kato K, Takamura T, Matsui O.
  • Journal Title: Radiol Phys Technol. Volume: 6 Pages: 219-225
  • Peer Reviewed
• [Presentation] 前向き薬剤介入試験における血管内皮機能と臨床検査データの関連 (2015)
  • Author(s): 中田晶子，竹下有美枝，南部裕子，大江宏康，長原三輝雄、酒井佳夫，御簾博文，篁俊成，和田隆志
  • Organizer: 第58回 日本糖尿病学会年次学術集会
  • Place of Presentation: 山口県下関市
  • Year and Date: 2015-05-23
• [Presentation] ビルダグリプチンとリラグルチドのランダム化 比較試験(ERA-DM Study-Chapter 2)における治療満足度とQOLの解析 (2015)
  • Author(s): 吉村かおり、小柴美紀恵、竹下有美枝、金森岳広、 御簾博文、石井 均、篁 俊成
  • Organizer: 第58回 日本糖尿病学会年次学術集会
  • Place of Presentation: 山口県下関市
  • Year and Date: 2015-05-23
• [Presentation] ２型糖尿病患者におけるアログリプチンとメトフォルミンの無作為割り付けクロスオーバー試験（最終評価） (2015)
  • Author(s): 竹下有美枝 金森岳広 加藤健一郎 喜多裕樹 太田嗣人 御簾博文 篁俊成
  • Organizer: 第58回 日本糖尿病学会年次学術集会
  • Place of Presentation: 山口県下関市
  • Year and Date: 2015-05-22
• [Presentation] インクレチンの多面的作用―NASH・NAFLDを改善するか？ (2015)
  • Author(s): 篁俊成、竹下有美枝
  • Organizer: 第58回 日本糖尿病学会年次学術集会
  • Place of Presentation: 山口県下関市
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] 2型糖尿病患者に対するアログリプチンとメトホルミンの無作為割付クロスオーバー比較試験 (2014)
  • Author(s): 竹下有美枝、御簾博文、金森岳広、喜多裕樹、太田嗣人、篁俊成
  • Organizer: 第29回糖尿病合併症学会
  • Place of Presentation: 都市センターホテル（東京）
  • Year and Date: 2014-10-03
• [Presentation] 2型糖尿病患者に対するインスリンーGLP-1アナログ（Liraglutide vs. Exenatide)リレー療法 (2014)
  • Author(s): 若栗ひとみ、竹下有美枝、山田雅之、金森岳広、加藤健一郎、御簾博文、篁俊成
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪）
  • Year and Date: 2014-05-25
• [Presentation] 2型糖尿病患者に対するアログリプチンとメトホルミンの無作為割付クロスオーバー比較試験 (2014)
  • Author(s): 竹下有美枝、御簾博文、金森岳広、加藤健一郎、喜多裕樹、篁俊成
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪）
  • Year and Date: 2014-05-24
• [Presentation] コレステロール吸収阻害がヒトの糖・脂質代謝と肝病理におよぼすパラドックス (2014)
  • Author(s): 篁俊成、竹下有美枝、金森岳広、加藤健一郎、喜多裕樹、御簾博文、金子周一
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪）
  • Year and Date: 2014-05-24
• [Presentation] 通常食および低炭水化物食下での持続血糖モニター結果をかーぼカウント法へフィードバックした1型糖尿病の1例 (2014)
  • Author(s): 畑千尋、中田裕佳、土本千春、櫻井吾郎、古市素江、八幡陽子、竹下有美枝、篁俊成、徳丸季聡
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪）
  • Year and Date: 2014-05-24
• [Presentation] 脂肪肝患者における ヘパトカインセレノプロテインP血中濃度と 臓器別インスリン感受性の関連 (2014)
  • Author(s): 加藤健一郎, 御簾博文, 田中睦, 斎藤芳郎, 竹下有美枝, 金子周一 , 篁俊成
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪）
  • Year and Date: 2014-05-23
• [Presentation] ビルダグリプチンとリラグルチドの無作為割り付けクロスオーバー研究（ERA-DM Study-Chapter 2）
  • Author(s): 竹下有美枝、喜多裕樹、松嶋由紀子、山田雅之、加藤健一郎、御簾博文、金子周一、篁俊成
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本）
• [Presentation] 臓器特異的インスリン抵抗性から単純性脂肪肝と非アルコール性脂肪肝炎を鑑別可能か？
  • Author(s): 加藤健一郎、圓山泰史、山田雅之、竹下有美枝、御簾博文、太田嗣人、金子周一、篁俊成
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本）
• [Presentation] インスリン抵抗性誘導ヘパトカインセレノプロテインＰによる高血糖発症予知に関する検討
  • Author(s): 御簾博文、田中睦、斉藤芳郎、竹下有美枝、喜多裕樹、中源雅俊、長野亨、金子周一、篁俊成
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本）
• [Presentation] Circulating levels of selenoprotein P predict future hyperglycemia in nondiabetic Japanese people
  • Author(s): H Misu, T Kanamori, Y Takeshita, Y Saito, M Tanaka, S Kaneko, T Takamura
  • Organizer: 49th annual Meeting of EASD
  • Place of Presentation: バルセロナ(スペイン)
• [Book] 糖尿病診療マスター (2015)
  • Author(s): 竹下有美枝 篁俊成
  • Publisher: 医学書院
• [Book] 最新インスリン療法第2版 (2015)
  • Author(s): 竹下有美枝 篁俊成
  • Publisher: 中山書店
• [Book] 糖尿病 研修ノート (2014)
  • Author(s): 竹下有美枝、篁俊成
  • Total Pages: 4
  • Publisher: 診断と治療社
• [Book] 糖尿病 最新の治療 (2013)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 4
  • Publisher: 南江堂