Reduction of GIP secretion alleviates obesity and insulin resistance under high fat diet condition

• Project/Area Number: 25461344
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: HARADA NORIO 京都大学, 医学(系)研究科(研究院), 助教 (50530169)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: インクレチン / GIP / インスリン分泌 / 耐糖能 / 骨代謝 / 肥満 / インスリン抵抗性 / ＧＩＰ / 骨密度 / エストロゲン

Outline of Final Research Achievements

We generated GIP-deficient mice with reduced and lacking GIP secretion and examine glucose tolerance, bone formation, and high fat diet (HFD)-induced obesity and insulin resistance. During oral glucose tolerance test (OGTT), heterozygous GIP-reduced mice (GIPgfp/+) had significantly decreased GIP levels (~50%) compared to wild-type mice (WT). In homozygous GIP-lacking mice (GIPgfp/gfp), GIP levels were undetectable. Insulin levels during OGTT were significantly lower in GIPgfp/+ and GIPgfp/gfp. Bone volume in GIPgfp/+ was similar to that in WT, while GIPgfp/gfp had decreased bone volume. Body weight gain and total body fat mass after 8 weeks of HFD were decreased in GIPgfp/+ compared to those in WT; GIPgfp/gfp had the lowest body weight and body fat mass. Insulin sensitivity in GIPgfp/+ and GIPgfp/gfp was improved compared to that in WT from data of insulin tolerance test. Thus, chronic reduction of GIP secretion alleviates obesity and insulin resistance under HFD condition.

Research Products

• [Journal Article] Sitagliptin monotherapy has better effect on insulinogenic index than glimepiride monotherapy in Japanese patients with type 2 diabetes mellitus: a 52-week, multicenter, parallel-group randomized controlled trial. (2016)
  • Author(s): Kondo Y, Harada N, Hamasaki A, Kaneko S, Yasuda K, Ogawa E, Harashima S, Yoneda H, Fujita Y, Kitano N, Nakamura Y, Matsuo F, Shinji M, Hinotsu S, Nakayama T, Inagaki N
  • Journal Title: Diabetol Metab Syndr. Volume: 8 Issue: 1 Pages: 1-5
  • DOI: 10.1186/s13098-016-0131-y
  • NAID: 120005758426
  • Peer Reviewed / Open Access
• [Journal Article] Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K-cells of upper small intestine and has a critical role in GIP secretion after fat ingestion. (2015)
  • Author(s): Iwasaki K, Harada N, Sasaki K, Yamane S, Iida K, Suzuki K, Hamasaki A, Joo E, Nasteska D, Shibue K, Harada T, Hashimoto T, Asakawa Y, Hirasawa A, Inagaki N.
  • Journal Title: Endocrinology Volume: 156 Issue: 3 Pages: 837-837
  • DOI: 10.1210/en.2014-1653
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fatty acid binding protein 5 (FABP5) regulates diet-induced obesity (DIO) via GIP secretion from enteroendocrine K-cells in response to fat ingestion. (2015)
  • Author(s): Shibue, K., Yamane, S., Harada, N., Hamasaki, A., Suzuki, K., Joo, E., Iwasaki, K., Nasteska, D., Harada, T., Hayashi, Y., Adachi, Y., Owada, Y., Takayanagi, R. and Inagaki, N.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 308 Issue: 7 Pages: 583-591
  • DOI: 10.1152/ajpendo.00543.2014
  • Peer Reviewed / Open Access
• [Journal Article] Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients (2015)
  • Author(s): Yabe D, Kuroe A, Watanabe K, Iwasaki M, Hamasaki A, Hamamoto Y, Harada N, Yamane S, Lee S, Murotani K, Deacon CF, Holst JJ, Hirano T, Inagaki N, Kurose T, Seino Y
  • Journal Title: J Diabetes Complications Volume: 29 Issue: 3 Pages: 413-421
  • DOI: 10.1016/j.jdiacomp.2014.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fructose induces glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and insulin secretion: Role of adenosine triphosphate-sensitive K+ channels (2015)
  • Author(s): Seino Y, Ogata H, Maekawa R, Izumoto T, Iida A, Harada N, Miki T, Seino S, Inagaki N, Tsunekawa S, Oiso Y, Hamada Y
  • Journal Title: J Diabetes Investig Volume: 6 Issue: 5 Pages: 522-526
  • DOI: 10.1111/jdi.12356
  • NAID: 120005770745
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enteral supplement enriched with glutamine, fiber, and oligosaccharide modulates incretin and glucagon-like peptide-2 secretion. (2015)
  • Author(s): Joo E., Muraoka A., Hamasaki A., Harada N., Yamane S., Kondo Y., Suzuki K., Nasteska D., Shibue K., Harada T., Iwasaki K., Tsuji H., Shide K., Inagaki N.
  • Journal Title: J Diabetes Investig. Volume: 6 Issue: 3 Pages: 302-308
  • DOI: 10.1111/jdi.12289
  • Peer Reviewed / Open Access
• [Journal Article] Chronic reduction of GIP secretion alleviates obesity and insulin resistance under high fat diet condition. (2014)
  • Author(s): Nasteska, D., Harada, N., Suzuki, K., Yamane, S., Hamasaki, A., Joo, E., Mori, K., Shibue, K., Harada, T., Inagaki, N.
  • Journal Title: Diabetes Volume: 63 Issue: 7 Pages: 2332-2343
  • DOI: 10.2337/db13-1563
  • NAID: 120005458283
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state (2014)
  • Author(s): Ogata H, Seino Y, Harada N, Iida A, Suzuki K, Izumoto T, Ishikawa K, Uenishi E, Ozaki N, Hayashi Y, Miki T, Inagaki N, Tsunekawa S, Hamada Y, Seino S, Oiso Y
  • Journal Title: J Endocrinol Volume: 222 Issue: 2 Pages: 191-200
  • DOI: 10.1530/joe-14-0161
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transcriptional regulatory factor X6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-cells and is involved in GIP hypersecretion in high fat diet-induced obesity. (2013)
  • Author(s): Suzuki K, Harada N, Yamane S, Nakamura Y, Sasaki K, Nasteska D, Joo E, Shibue K, Harada T, Hamasaki A, Toyoda K, Nagashima K, Inagaki N.
  • Journal Title: J Biol Chem. Volume: 288 Issue: 3 Pages: 1929-1938
  • DOI: 10.1074/jbc.m112.423137
  • NAID: 120005373090
  • Peer Reviewed
• [Journal Article] Hospital-based cross-sectional study to develop an estimation formula for 2-hours post-challenge plasma glucose for screening impaired glucose tolerance. (2013)
  • Author(s): Kondo Y, Harada N, Sozu T, Hamasaki A, Yamane S, Muraoka A, Harada T, Shibue K, Nasteska D, Joo E, Sasaki K, Inagaki N.
  • Journal Title: Diabetes Res Clin Pract. Volume: 101 Issue: 2 Pages: 218-225
  • DOI: 10.1016/j.diabres.2013.05.013
  • Peer Reviewed
• [Journal Article] Enteral supplement enriched with glutamine, fiber, and oligosaccharide attenuates experimental colitis in mice (2013)
  • Author(s): Joo E, Yamane S, Hamasaki A, Harada N, Matsunaga T, Muraoka A, Suzuki K, Nasteska D, Fukushima T, Hayashi T, Tsuji H, Shide K, Tsuda K, Inagaki N
  • Journal Title: Nutrition Volume: 29(3):549-55 Issue: 3 Pages: 549-555
  • DOI: 10.1016/j.nut.2012.09.007
  • NAID: 120005242568
  • Peer Reviewed
• [Presentation] 高脂肪食摂取によるGIP分泌亢進と肥満誘導の機序 (2015)
  • Author(s): 原田 範雄
  • Organizer: 第21回Hind Gut Japan symposium
  • Place of Presentation: 東京
  • Year and Date: 2015-12-05
  • Invited
• [Presentation] 脂肪酸受容体GPR120は上部小腸K細胞に高発現し脂肪摂取後のGIP分泌に深く関与する. (2015)
  • Author(s): 原田範雄, 岩崎可南子，佐々木香月，山根俊介，飯田桂子，濱崎暁洋，鈴木和代，城尾恵里奈，ナステスカダニエラ，渋江公尊，原田貴成，平澤明，稲垣暢也.
  • Organizer: 第29回糖尿病・肥満動物学会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-13 – 2015-02-15
• [Presentation] Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K cells of upper small intestine and has a critical role in GIP secretion after fat ingestion. (2014)
  • Author(s): Iwasaki K, Harada N, Sasaki K, Yamane S, Iida K, Suzuki K, Hamasaki A, Joo E, Nasteska D, Shibue K, Harada T, Hirasawa A, Inagaki N.
  • Organizer: 50th EASD Annual Meeting
  • Place of Presentation: Vienna, Austria.
  • Year and Date: 2014-09-15 – 2014-09-17
• [Presentation] Inhibition of GIP receptor signalling in adipose tissue reduces insulin resistance in high fat diet-induced obesity. (2014)
  • Author(s): Joo E, Harada N, Fukushima T, Hamasaki A, Yammane S, Iwasaki K, Nasteska D, Shibue K, Harada T, Suzuki K, Inagaki N.
  • Organizer: 50th EASD Annual Meeting
  • Place of Presentation: Vienna, Austria.
  • Year and Date: 2014-09-15 – 2014-09-17
• [Presentation] The role of GIP in high fat diet-induced obesity. (2014)
  • Author(s): Harada N, Yamane S, Inagaki N.
  • Organizer: 9th Metabolic Syndrome, Type 2 Diabetes, Atherosclerosis Congress
  • Place of Presentation: Ｋｙｏｔｏ， Ｊａｐａｎ
  • Year and Date: 2014-09-12 – 2014-09-14
  • Invited
• [Presentation] 脂肪組織におけるGIPシグナルが高脂肪食摂取下の肥満やインスリン抵抗性に及ぼす影響. (2014)
  • Author(s): 原田貴成, 原田範雄, 城尾恵里奈, 福島徹, 岩崎可南子, 浜崎暁洋, 山根俊介, Nasteska Daniela, 渋江公尊, 鈴木和代, 稲垣暢也.
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] GIP-GFPノックインマウスを用いたGIP分泌K細胞の局在と遺伝子発現の検討. (2014)
  • Author(s): 岩崎可南子, 原田範雄, 佐々木香月, 鈴木和代, 山根俊介, 浜崎暁洋, 城尾恵里奈, Nasteska Daniela, 渋江公尊, 原田貴成, 稲垣暢也.
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] GIP and high-fat diet-induced obesity. (2013)
  • Author(s): Harada N and Inagaki N.
  • Organizer: 5th Scientific Meeting of AASD in conjunction with 2013 ICDM.
  • Place of Presentation: Seoul, Korea.
  • Invited
• [Presentation] Distribution of fatty acid binding receptors in GIP-secreting K cells in the small intestine. (2013)
  • Author(s): Mori K, Harada N, Suzuki K, Yamane S, Hamasaki A, Sasaki K, Nasteska D, Joo E, Shibue T, Harada T, Inagaki N.
  • Organizer: The 49th EASD Annual Meeting
  • Place of Presentation: Barcelona, Spain.
• [Presentation] Lowering GIP secretion has beneficial role in reducing obesity and insulin resistance without impairing glucose tolerance and osteogenesis. (2013)
  • Author(s): Daniela N, Harada N, Yamane S, Suzuki K, Hamasaki A, Joo E, Sasaki K, Shibue K, Harada T, Inagaki N.
  • Organizer: The 73th American Diabetes Association's scientific sessions
  • Place of Presentation: Chicago, USA.
• [Presentation] The effect of GIP on high-fat induce obesity. (2013)
  • Author(s): Harada N, Yamane S, Hamasaki A, Inagaki N.
  • Organizer: 26th Spring Congress of Korean Diabetes Association/1st Korea-Japan Diabetes Forum
  • Place of Presentation: Jeju, Korea.
  • Invited
• [Presentation] 脂肪摂取と肥満. (2013)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Organizer: 第50回日本糖尿病学会近畿地方会
  • Place of Presentation: 京都
  • Invited
• [Book] 【糖尿病 基礎分野での進歩】 糖尿病治療標的としてのGタンパク質共役脂肪酸受容体 (2016)
  • Author(s): 三小田 亜希子, 原田 範雄, 稲垣 暢也
  • Total Pages: 6
  • Publisher: Annual Review糖尿病・代謝・内分泌 2016巻
• [Book] 【インクレチン薬による糖尿病治療の革新-基礎と臨床の架け橋-】 (2016)
  • Author(s): 原田 範雄, 稲垣 暢也
  • Total Pages: 6
  • Publisher: 最新医学 71巻1号
• [Book] 【糖尿病治療新時代-糖尿病治療のupdate-】 新しい糖尿病治療薬の現状と開発動向 週1回投与DPP-4阻害薬 (2015)
  • Author(s): 原田 範雄, 稲垣 暢也
  • Total Pages: 6
  • Publisher: 日本臨床 73巻12号
• [Book] 【糖尿病の療養指導Q&A】 週1回投与型DPP-4阻害薬の特徴と利便性. (2015)
  • Author(s): 原田 範雄, 稲垣 暢也
  • Total Pages: 2
  • Publisher: プラクティス 32巻5号
• [Book] 【グルカゴンの分泌調節と作用】 GLP-1の生成と分泌について. (2014)
  • Author(s): 原田範雄, 稲垣暢也.
  • Publisher: 内分泌・糖尿病・代謝内科
• [Book] 【DPP-4阻害薬登場後の糖尿病治療の変化】 インクレチン関連薬の作用機序, カレントテラピー (2014)
  • Author(s): 原田範雄, 稲垣暢也.
  • Publisher: ライフメディコム
• [Book] 【糖尿病-診断・治療Update-】 GLP-1受容体作動薬による治療, 最新医学 (2014)
  • Author(s): 原田範雄, 稲垣暢也.
  • Publisher: 最新医学社
• [Book] 【糖尿病治療薬Q&A-最新のSGLT-2阻害薬を含め賢く使い分ける-】 DPP-4阻害薬の作用機序、種類、代謝・排泄について. (2014)
  • Author(s): 原田範雄, 稲垣暢也.
  • Publisher: 南山堂
• [Book] 糖尿病 (2013)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Total Pages: 3
  • Publisher: 日本糖尿病学会