Hepatic glucose and lipid homeostasis in type 2 diabetes with obesity

• Project/Area Number: 15H04847
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: Kubota Naoto 東京大学, 医学部附属病院, 准教授 (50396719)
• Co-Investigator(Renkei-kenkyūsha): Kadowaki Takashi 東京大学, 医学部附属病院, 教授 (30185889)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2015: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: インスリン受容体基質 / エネルギー / 糖質代謝異常 / 糖尿病 / 糖代謝異常 / エネルギー・糖質代謝異常

Outline of Final Research Achievements

By investigating differential insulin signaling in the periportal (PP) zone, the site of gluconeogenesis, and perivenous (PV) zone, the site of lipogenesis, of the liver, we found that insulin signaling mediated by Irs1 and Irs2 was impaired in the PP zone, but rather enhanced in the PV zone, caused by the downregulation by hyperinsulinemia of Irs2, which is similarly expressed in both the PP and PV zones, coupled with intact expression of Irs1, which is predominantly expressed in the PV zone and is not affected by hyperinsulinemia. These data suggest that “selective insulin resistance” is induced by the differential distribution and alterations of hepatic Irs1 and Irs2 expressions in type 2 diabetes and obesity.

Research Products

• [Journal Article] Role of insulin receptor substrates in the progression of hepatocellular carcinoma (2017)
  • Author(s): Sakurai Yoshitaka、Kubota Naoto、Takamoto Iseki、Obata Atsushi、Iwamoto Masahiko、Hayashi Takanori、Aihara Masakazu、Kubota Tetsuya、Nishihara Hiroshi、Kadowaki Takashi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 5387-5387
  • DOI: 10.1038/s41598-017-03299-3
  • Peer Reviewed / Open Access
• [Journal Article] Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney (2017)
  • Author(s): Sasaki Motohiro、Sasako Takayoshi、Kubota Naoto、Sakurai Yoshitaka、Takamoto Iseki、Kubota Tetsuya、Inagi Reiko、Seki George、Goto Moritaka、Ueki Kohjiro、Nangaku Masaomi、Jomori Takahito、Kadowaki Takashi
  • Journal Title: Diabetes Volume: 66 Issue: 9 Pages: 2339-2350
  • DOI: 10.2337/db16-1602
  • Peer Reviewed / Open Access
• [Journal Article] Imbalanced Insulin Actions in Obesity and Type 2 Diabetes: Key Mouse Models of Insulin Signaling Pathway (2017)
  • Author(s): Kubota Tetsuya、Kubota Naoto、Kadowaki Takashi
  • Journal Title: Cell Metab. Volume: 25 Issue: 4 Pages: 797-810
  • DOI: 10.1016/j.cmet.2017.03.004
  • Peer Reviewed / Open Access
• [Journal Article] Novel and Simple Ultrasonographic Methods for Estimating the Abdominal Visceral Fat Area (2017)
  • Author(s): Asano Takeharu、Kubota Naoto、Koizumi Norihiro、Itani Kazunori、Mitake Tsuyoshi、Yuhashi Kazuhito、Liao Hongen、Mitsuishi Mamoru、Takeishi Shigemi、Takahashi Toshiaki、Ohnishi Shin、Sasaki Shiro、Sakuma Ichiro、Kadowaki Takashi
  • Journal Title: Int J Endocrinol. Volume: 2017 Pages: 1-12
  • DOI: 10.1155/2017/8796069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adiponectin at physiological level glucose-independently enhances inhibitory postsynaptic current onto NPY neurons in the hypothalamic arcuate nucleus (2017)
  • Author(s): Suyama Shigetomo、Lei Wang、Kubota Naoto、Kadowaki Takashi、Yada Toshihiko
  • Journal Title: Neuropeptides Volume: 65 Pages: 1-9
  • DOI: 10.1016/j.npep.2017.03.003
  • Peer Reviewed
• [Journal Article] Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways. (2016)
  • Author(s): Kubota T, Kubota N, Sato H, Inoue M, Kumagai H, Iwamura T, Takamoto I, Kobayashi T, Moroi M, Terauchi Y, Tobe K, Ueki K, Kadowaki T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34707-34707
  • DOI: 10.1038/srep34707
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice. (2016)
  • Author(s): Sato H, Kubota N, Kubota T, Takamoto I, Iwayama K, Tokuyama K, Moroi M, Sugi K, Nakaya K, Goto M, Jomori T, Kadowaki T.
  • Journal Title: Diabetologia Volume: 59 Issue: 11 Pages: 2426-2434
  • DOI: 10.1007/s00125-016-4071-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity. (2016)
  • Author(s): Kubota N, Kubota T, Kajiwara E, Iwamura T, Kumagai H, Watanabe T, Inoue M, Takamoto I, Sasako T, Kumagai K, Kohjima M, Nakamuta M, Moroi M, Sugi K, Noda T, Terauchi Y, Ueki K, Kadowaki T.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 12977-12977
  • DOI: 10.1038/ncomms12977
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion. (2015)
  • Author(s): ・Hashimoto S, Kubota N, Sato H, Sasaki M, Takamoto I, Kubota T, Nakaya K, Noda M, Ueki K, Kadowaki T
  • Journal Title: Diabetes Volume: 64 Pages: 876-886
  • NAID: 40020753201
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2. (2015)
  • Author(s): ・Nakatsu D, Horiuchi Y, Kano F, Noguchi Y, Sugawara T, Takamoto I, Kubota N, Kadowaki T, Murata M
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Pages: 1067-1076
  • Peer Reviewed
• [Journal Article] Effects of beraprost sodium, an oral prostacyclin analog, on insulin resistance in patients with type 2 diabetes. (2015)
  • Author(s): ・Katsuyama H, Kubota N, Kubota T, Haraguchi M, Obata A, Takamoto I, Shigematsu K, Miyata T, Ueki K, Kadowaki T
  • Journal Title: Diabetol. Int. Volume: 6 Pages: 39-45
  • NAID: 40020406077
  • Peer Reviewed
• [Journal Article] Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells. (2015)
  • Author(s): ・Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M, Asano Y, Sugaya M, Kadono T, Masamoto Y, Kurokawa M, Yamauchi T, Kubota N, Kadowaki T, Sato S
  • Journal Title: Nat Commun Volume: 6 Pages: 7687-7687
  • Peer Reviewed / Open Access
• [Journal Article] Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes. (2015)
  • Author(s): ・Motonishi S, Nangaku M, Wada T, Ishimoto Y, Ohse T, Matsusaka T, Kubota N, Shimizu A, Kadowaki T, Tobe K, Inagi R
  • Journal Title: J Am Soc Nephrol Volume: 26 Pages: 1939-1959
  • Peer Reviewed
• [Presentation] 肝臓のエネルギー代謝：センシングと病態（シンポジウム）「インスリン抵抗性の新視点―肝臓のmetabolic zonation―」 (2017)
  • Author(s): 窪田直人，窪田哲也，門脇孝
  • Organizer: 第60回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] エネルギー代謝と心血管病 糖尿病と心血管病 糖尿病治療が血管合併症を抑制する分子機構の検討 (2016)
  • Author(s): 窪田直人、窪田哲也、門脇孝
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 京都
  • Invited
• [Presentation] Elucidation of the molecular mechanism of “selective insulin resistance” in the liver (2016)
  • Author(s): 窪田直人、窪田哲也、門脇孝
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Invited
• [Presentation] 「糖尿病治療が血管合併症を抑制する分子機構の検討」～大規模臨床試験をふまえて～ (2016)
  • Author(s): 窪田直人
  • Organizer: 日本血管生物医学会秋期特別シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] 肝臓の「選択的インスリン抵抗性」には正常なIRS-1の発現とIRS-2の発現低下が重要である (2016)
  • Author(s): 窪田直人、窪田哲也、井上真理子、高本偉碩、山内敏正、植木浩二郎、門脇孝
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京
• [Presentation] 肝臓における「選択的インスリン抵抗性」の分子機構の解明」 (2015)
  • Author(s): 窪田直人、窪田哲也、井上真理子、高本偉碩、山内敏正、植木浩二郎、門脇孝
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-27
• [Presentation] 「糖尿病合併症の成因Up to Date その発症機序の解明に迫る 血管内皮細胞をターゲットとした糖尿病合併症へのアプローチ」 (2015)
  • Author(s): 窪田直人、窪田哲也、門脇 孝
  • Organizer: 第30回日本糖尿病合併症学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] Clarification of molecular mechanisms of type 2 diabetes using genetic engineering techniques in mice. (2015)
  • Author(s): Naoto Kubota
  • Organizer: 7th AASD Scientific Meeting and Annual Scientific Meeting of the Hong Kong Society of Endocrinology, Metabolism and Reproduction
  • Place of Presentation: Hong Kong, China
  • Year and Date: 2015-11-21
  • Int'l Joint Research / Invited
• [Presentation] 2型糖尿病の病態と薬物治療 (2015)
  • Author(s): 窪田直人
  • Organizer: 第15回日本糖尿病情報学会年次学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-29
  • Invited
• [Presentation] 2型糖尿病における肝臓の糖・脂質代謝調節破綻の分子機構」 (2015)
  • Author(s): 窪田直人、窪田哲也、井上真理子、高本偉碩、山内敏正、植木浩二郎、門脇孝
  • Organizer: 第112回日本内科学会総会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10
• [Book] Diabetes Strategy (2016)
  • Author(s): 窪田直人
  • Total Pages: 2
  • Publisher: 先端医学社
• [Book] 【薬物療法アップデート】糖吸収・排泄調節系 α－グルコシダーゼ阻害薬・SGLT2阻害薬。最新醫學別冊 診断と治療のABC 糖尿病 (2016)
  • Author(s): 窪田直人、門脇孝
  • Total Pages: 7
  • Publisher: 最新医学社
• [Book] Medical Science Digest (2016)
  • Author(s): 窪田直人、門脇孝
  • Total Pages: 4
  • Publisher: ニュー・サイエンス社