Glucose metabolisms in kidney

• Project/Area Number: 18K19556
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• 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(Kenkyū-buntansha): 笹子 敬洋 東京大学, 医学部附属病院, 助教 (20550429) ; 中村 元信 東京大学, 医学部附属病院, 助教 (40459524)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 糖尿病 / 腎臓 / 糖新生 / インスリン抵抗性

Outline of Final Research Achievements

We found that proximal tubules (PT)-specific IRS 1/2 double-knockout mice exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of FoxO1. In contrast, glucose deacetylated PGC1α, a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively.

Academic Significance and Societal Importance of the Research Achievements

本研究は、長年解明されていない“腎臓における糖新生の調節機構とその破綻の分子メカニズム”を解明しようとするものであり、極めて独創性・新規性が高く、また、肥満・2型糖尿病患者が直面している病態を解明しようとしている点で社会的意義も大きい。本研究は、腎臓の糖代謝調節機構の解明を通してその生理的/病態生理的役割を解明し、腎臓生理の根本原理に迫る斬新なプロジェクトであり、糖尿病や腎不全の予防・進行抑制さらに治療につながる卓越した成果が期待できる。

Research Products

• [Journal Article] Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism. (2019)
  • Author(s): Sasako T, Ohsugi M, Kubota N, Itoh S, Okazaki Y, Terai A, Kubota T, Yamashita S, Nakatsukasa K, Kamura T, Iwayama K, Tokuyama K, Kiyonari H, Furuta Y, Shibahara J, Fukayama M, Enooku K, Okushin K, Tsutsumi T, Tateishi R, Tobe K, Asahara H, Koike K, Kadowaki T, Ueki K.
  • Journal Title: Nat. Commun. Volume: 10
  • Peer Reviewed / Open Access
• [Journal Article] Effect of home enteral nutrition after pancreaticoduodenectomy. (2019)
  • Author(s): Ito D, Arita J, Yamamoto M, Akamatsu N, Kaneko J, Ijichi H, Kubota N, Sakamoto Y, Kokudo N, Hasegawa K.
  • Journal Title: Nutrition Volume: 60 Pages: 206-211
  • Peer Reviewed
• [Journal Article] NAPE-PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in an in vitro model of intestinal epithelial cells. (2019)
  • Author(s): Igarashi M, Watanabe K, Tsuduki T, Kimura I, Kubota N.
  • Journal Title: FASEB Journal Volume: 33 Pages: 3167-3179
  • Peer Reviewed
• [Journal Article] Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease. (2019)
  • Author(s): Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T, Mano A, Yamada K, Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T.
  • Journal Title: Mol. Neurodegener. Volume: 14
  • Peer Reviewed / Open Access
• [Journal Article] Innate Lymphoid Cells in the Induction of Obesity. (2019)
  • Author(s): Sasaki T, Moro K, Kubota T, Kubota N, Kato T, Ohno H, Nakae S, Saito H, Koyasu S.
  • Journal Title: Cell Rep. Volume: 28 Pages: 202-217
  • Peer Reviewed
• [Journal Article] Late-Evening Carbohydrate and Branched-Chain Amino Acid Snacks Improve the Nutritional Status of Patients Undergoing Hepatectomy Based on Bioelectrical Impedance Analysis of Body Composition. (2019)
  • Author(s): Kobayashi K, Kaneko J, Yamaguchi T, Kawaguchi Y, Arita J, Akamatsu N, Ishizawa T, Sekine R, Ijichi H, Kubota N, Fukatsu K, Kokudo N, Hasegawa K.
  • Journal Title: Gastrointest. Tumors Volume: 6 Pages: 81-91
• [Journal Article] NAPE-PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in an in vitro model of intestinal epithelial cells (2019)
  • Author(s): Miki Igarashi、Kazuhide Watanabe、Tsuyoshi Tsuduki、Ikuo Kimura、Naoto Kubota
  • Journal Title: The FASEB Journal Volume: 33 Issue: 3 Pages: 3167-3179
  • DOI: 10.1096/fj.201801408r
  • Peer Reviewed
• [Journal Article] The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis. (2018)
  • Author(s): Kobayashi M, Ohsugi M, Sasako T, Awazawa M, Umehara T, Iwane A, Kobayashi N, Okazaki Y, Kubota N, Suzuki R, Waki H, Horiuchi K, Hamakubo T, Kodama T, Aoe S, Tobe K, Kadowaki T, Ueki K
  • Journal Title: Mol. Cell Biol. Volume: 38 Issue: 16 Pages: 81-91
  • DOI: 10.1128/mcb.00116-18
  • Peer Reviewed / Open Access
• [Journal Article] The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity (2018)
  • Author(s): Yanagida Keisuke、Igarashi Hidemitsu、Yasuda Daisuke、Kobayashi Daiki、Ohto-Nakanishi Takayo、Akahoshi Noriyuki、Sekiba Atsushi、Toyoda Tsudoi、Ishijima Tomoko、Nakai Yuji、Shojima Nobuhiro、Kubota Naoto、Abe Keiko、Kadowaki Takashi、Ishii Satoshi、Shimizu Takao
  • Journal Title: JCI Insight Volume: 3 Issue: 24 Pages: 397293-397293
  • DOI: 10.1172/jci.insight.97293
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity (2018)
  • Author(s): Kubota Tetsuya、Inoue Mariko、Kubota Naoto、Takamoto Iseki、Mineyama Tomoka、Iwayama Kaito、Tokuyama Kumpei、Moroi Masao、Ueki Kohjiro、Yamauchi Toshimasa、Kadowaki Takashi
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4863-4863
  • DOI: 10.1038/s41467-018-07358-9
  • NAID: 120007133395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 「糖尿病とNASH/NAFLD：分子メカニズムと最新の治療」「肥満に伴う選択的インスリン抵抗性の分子機構―肝臓のmetabolic zonation―」 (2019)
  • Author(s): 窪田直人
  • Organizer: 第62回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 「Role of chronic inflammation in diabetes (慢性炎症と糖尿病:血糖調節の破綻と合併症におけるその意義)」「肥満に伴うM2a-subtypeマクロファージ活性化障害の分子機構」 (2019)
  • Author(s): 窪田 哲也, 窪田 直人, 門脇 孝
  • Organizer: 第62回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] メタボリックシンドロームとしての脂肪肝「メタボリックシンドロームにおける肝臓の選択的インスリン抵抗性」 (2019)
  • Author(s): 窪田 直人, 窪田 哲也, 門脇 孝
  • Organizer: 第105回日本消化器病学会総会
  • Invited
• [Presentation] マクロファージにおけるIrs2はIL-4によるM2a-subtype活性化を減弱し、インスリン抵抗性を惹起する (2019)
  • Author(s): 窪田 哲也、窪田 直人、井上 真理子、林 高則、相原 允一、高本 偉碵、植木 浩二郎、山内 敏正、門脇 孝
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 血管内皮細胞のIrs2の役割の解明 (2019)
  • Author(s): 窪田 哲也, 窪田 直人, 林 高則, 相原 允一, 高本 偉碵, 山内 敏正, 門脇 孝
  • Organizer: 第41回日本高血圧学会総会
• [Presentation] 肥満合併症としての肝疾患-NASHと肝細胞癌をどう捉えるか- 肥満に伴う選択的インスリン抵抗性の分子機構 肝臓のmetabolic zonation (2019)
  • Author(s): 窪田 直人, 窪田 哲也, 山内 敏正, 門脇 孝
  • Organizer: 第39回日本肥満学会総会
  • Invited
• [Presentation] マクロファージIrs2はNCoR1/HDAC3/FoxO1を介してM2a-subtypeマクロファージの活性化を調節する (2019)
  • Author(s): 窪田 哲也, 窪田 直人, 井上 真理子, 林 高則, 相原 允一, 高本 偉碩, 山内 敏正, 植木 浩二郎, 門脇 孝
  • Organizer: 第39回日本肥満学会総会
• [Presentation] 中枢におけるインスリン受容体基質(IRS)1の成長・代謝に関する役割の解明 (2019)
  • Author(s): 林 高則、窪田 直人、窪田 哲也、井上 真理子、相原 允一、高本 偉碩、門脇 孝
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Book] Medical Science Digest (2020)
  • Author(s): 窪田直人
  • Total Pages: 4
  • Publisher: ニュー・サイエンス社
• [Book] 月刊糖尿病ライフさかえ (2019)
  • Author(s): 窪田直人
  • Total Pages: 2
  • Publisher: 公益社団法人日本糖尿病協会
• [Book] 診断と治療 (2019)
  • Author(s): 窪田直人
  • Total Pages: 7
  • Publisher: 医学書出版
• [Book] 月刊糖尿病 (2019)
  • Author(s): 窪田直人
  • Total Pages: 6
  • Publisher: 医学出版
• [Book] 内分泌・糖尿病・代謝内科 (2018)
  • Author(s): 窪田 直人、佐々木 元大、笹子 敬洋、門脇 孝
  • Total Pages: 5
  • Publisher: (有)科学評論社
• [Book] 医と食 (2018)
  • Author(s): 窪田 哲也、窪田 直人、門脇 孝
  • Total Pages: 4
  • Publisher: (公社)生命科学振興会「医と食」編集部
• [Book] 腎と透析 (2018)
  • Author(s): 窪田 直人、門脇 孝
  • Total Pages: 5
  • Publisher: (株)東京医学社
• [Book] 内分泌・糖尿病・代謝内科 (2018)
  • Author(s): 桜井 賛孝、窪田 直人、門脇 孝
  • Total Pages: 5
  • Publisher: (有)科学評論社