Trajectories of liver histology on drug intervention in NAFLD associated with diabetes

• Project/Area Number: 23K08004
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kanazawa University
• Principal Investigator: 竹下 有美枝 金沢大学, 医学系, 准教授 (40507042)
• Project Period (FY): 2023-04-01 – 2027-03-31
• Project Status: Granted (Fiscal Year 2024)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2026: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2025: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2024: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 代謝機能不全に関連した脂肪性肝疾患 / 2型糖尿病 / 非アルコ－ル性脂肪性肝疾患 / 非アルコール性脂肪性肝疾患

Outline of Research at the Start

NAFLD（非アルコ－ル性脂肪性肝疾患）を伴う糖尿病患者の病態や臨床経過は十分に明らかにされておらず適切な薬物療法も確立されていない。本研究ではNAFLDを伴う糖尿病患者に絞り、薬物療法前後の161名の連続肝生検組織による肝臓病理と発現遺伝子、および人工膵臓を用いた臓器特異的なインスリン感受性などの代謝マーカ－との関連を解析する。NAFLDを伴う糖尿病に対する適切な薬物療法を提案するとともに、薬物療法が及ぼすNAFLD病理と細胞内分子への作用点を明らかにし、NAFLDの進展阻止にむけた基盤となる研究を行う。

Outline of Annual Research Achievements

MASLDは糖尿病、脂質異常症、高血圧、肥満症などを合併するだけでなく、MASHを経て肝硬変、肝がんに至る。NAFLDを伴う糖尿病患者の治療では、糖尿病の治療に加えて、肝臓そのもの、特に肝線維化阻止に対する適切な治療法が模索されている。
MASLD伴う2型糖尿病患者40例を対象に、48週間のSGLT-2阻害薬とスルホニル尿素（SU）薬は、ともにHbA1cを同等に有意に低下させたが、SGLT2阻害薬群でのみ、肝酵素・体重・肝臓病理スコアが有意に低下した。48週間のSGLT-2阻害薬介入による肝線維化の改善率は60％であり、既報のMASLDに対する介入研究に比し高い線維化改善率を示した。
薬剤介入による肝臓発現遺伝子の変化数は、SGLT2阻害薬群では663遺伝子、SU群はわずか51遺伝子であった。発現量の異なる遺伝子のパスウェイ解析を行ったところ、SGLT2阻害薬群で、脂肪酸分解とアミノ酸分解、TCA回路とペルオキシソームの活性化、糖新生に関わる肝発現遺伝子が亢進し、炎症や線維化形成に関連する遺伝子は減弱した。
シングルセルRNA-seq遺伝子用いた遺伝子セットエンリッチメント解析を行ったところ、SGLT2阻害薬群は、ペルオキシソームが豊富でMASLDの主要標的領域であるゾーン3肝細胞の肝類洞内皮細胞の発現を上昇させた。さらに、MASLD発症に必須の役割を果たすγδT細胞、炎症性マクロファージ、星状細胞、形質細胞の発現を低下させた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

MASLDを伴う2型糖尿病患者の連続肝生検組織を用いて、薬剤介入によるMASLDの病理所見と肝臓の発現遺伝子の変化を明らかにした。糖尿病治療薬介入の相違によるMASLDの肝臓発現遺伝子の変化を経時的に解析することによって、学術的な問いである糖尿病とMASLDを改善する適切な薬物療法についてさらに研究遂行していく。

Strategy for Future Research Activity

糖尿病治療薬がNAFLDの病理を改善する作用点について、病理と発現遺伝子の解析に引き続き、血清と肝臓のメタボロ－ム解析を行い、糖尿病を背景とするMASLDの進展阻止に資する基盤研究を行う。

Research Products

• [Journal Article] Cysteine redoxome landscape in mouse brown adipose tissue under acute cold exposure (2025)
  • Author(s): Oo Hein Ko、Galicia-Medina Cynthia M.、Nishiuchi Takumi、Tanida Ryota、Goto Hisanori、Nakano Yujiro、Takeshita Yumie、Saito Yoshiro、Takayama Hiroaki、Takamura Toshinari
  • Journal Title: iScience Volume: 28 Issue: 3 Pages: 112051-112051
  • DOI: 10.1016/j.isci.2025.112051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sex Differences in the Relationship Between Nutrient Intake and Mortality Results of the Shika Cohort Study (2025)
  • Author(s): Hayashi K, Nakamura M, Tsujiguchi H, Hara A, Suzuki K, Miyagi S, Takazawa C, Zhao J, Camara J, Marama T, Asai A, Katano K, Kasahara T, Sato K, Ogawa A, Fukushima S, Shibata A, Suzuki F, Shimizu Y, Kambayashi Y, Kannon T, Takeshita Y, Tsuboi H, Tajima A, Konoshita T, Takamura T, Nakamura H
  • Journal Title: Nutrients Volume: 17 Issue: 5 Pages: 755-755
  • DOI: 10.3390/nu17050755
  • Peer Reviewed / Open Access
• [Journal Article] Hepatokine leukocyte cell-derived chemotaxin 2 as a biomarker of insulin resistance, liver enzymes, and metabolic dysfunction-associated steatotic liver disease in the general population (2025)
  • Author(s): Suzuki K, Tsujiguchi H, Hara A, Takeshita Y, Goto H, Nakano Y, Yamamoto R, Takayama H, Tajima A, Yamashita T, Honda M, Nakamura H, Takamura T
  • Journal Title: J Diabetes Investig Volume: 16 Issue: 2 Pages: 298-298
  • DOI: 10.1111/jdi.14351
  • Peer Reviewed / Open Access
• [Journal Article] Metastatic Pheochromocytoma/Paraganglioma Overproducing Multiple Catecholamines (2024)
  • Author(s): Yoshioka Keiko、Nakano Yujiro、Horichi Moeka、Aono Daisuke、Takeshita Yumie、Takamura Toshinari
  • Journal Title: JCEM Case Reports Volume: 3 Issue: 1
  • DOI: 10.1210/jcemcr/luae241
  • Peer Reviewed / Open Access
• [Journal Article] Primary Unilateral Adrenal Anaplastic Large Cell Lymphoma: Remission by Chemotherapy (2024)
  • Author(s): Goto D, Takeshita Y, Nagai K, Goto H, Nakano Y, Takamura T.
  • Journal Title: JCEM Case Rep. Volume: 2 Issue: 12
  • DOI: 10.1210/jcemcr/luae229
  • Peer Reviewed / Open Access
• [Journal Article] Oxytocin Receptor Polymorphism Is Associated With Sleep Apnea Symptoms (2024)
  • Author(s): Goto Hisanori、Yamamoto Yasuhiko、Tsujiguchi Hiromasa、Sato Takehiro、Yamamoto Reina、Takeshita Yumie、Nakano Yujiro、Kannon Takayuki、Hosomichi Kazuyoshi、Suzuki Keita、Nakamura Masaharu、Kambayashi Yasuhiro、Karashima Shigehiro
  • Journal Title: Journal of the Endocrine Society Volume: 9 Issue: 1 Pages: 198-198
  • DOI: 10.1210/jendso/bvae198
  • Peer Reviewed / Open Access
• [Journal Article] A Supramolecular Biosensor for Rapid and High-Throughput Quantification of a Disease-Associated Niacin Metabolite (2024)
  • Author(s): Ueno Masaya、Sugiyama Hiroki、Kurayoshi Kenta、Kobayashi Masahiko、Tadokoro Yuko、Kasahara Atsuko、Shoulkamy Mahmoud I.、Maeda Katsuhiro、Ogoshi Tomoki、Hirao Atsushi
  • Journal Title: Analytical Chemistry Volume: 96 Issue: 36 Pages: 14499-14507
  • DOI: 10.1021/acs.analchem.4c02653
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thyroid Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia: Insights on Successful Noninvasive Imaging (2024)
  • Author(s): Goto H, Tanimura I, Nakano Y, Takeshita Y, Takamura T.
  • Journal Title: JCEM Case Rep. Volume: 2 Issue: 8
  • DOI: 10.1210/jcemcr/luae138
  • Peer Reviewed / Open Access
• [Journal Article] The declining insulinogenic index correlates with inflammation and metabolic dysregulation in non-obese individuals assessed by blood gene expression (2024)
  • Author(s): Nasti Alessandro、Okumura Miki、Takeshita Yumie、Ho Tuyen Thuy Bich、Sakai Yoshio、Sato Taka-Aki、Nomura Chiaki、Goto Hisanori、Nakano Yujiro、Urabe Takeshi、Nakamura Seiji、Tamura Takuro、Matsubara Kenichi、Takamura Toshinari、Kaneko Shuichi
  • Journal Title: Diabetes Research and Clinical Practice Volume: 208 Pages: 111090-111090
  • DOI: 10.1016/j.diabres.2024.111090
  • Peer Reviewed / Open Access
• [Journal Article] Diabetes Accelerates Steatohepatitis in Mice (2024)
  • Author(s): Abuduyimiti Tuerdiguli、Goto Hisanori、Kimura Kumi、Oshima Yu、Tanida Ryota、Kamoshita Kyoko、Leerach Nontaphat、Abuduwaili Halimulati、Oo Hein Ko、Li Qifang、Galicia-Medina Cynthia M.、Takayama Hiroaki、Ishii Kiyo-aki、Nakano Yujiro、Takeshita Yumie、Takamura Toshinari、5others
  • Journal Title: The American Journal of Pathology Volume: 194 Issue: 5 Pages: 693-707
  • DOI: 10.1016/j.ajpath.2024.01.007
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between the changes in hepatokine levels and metabolic effects after laparoscopic sleeve gastrectomy in severely obese patients (2023)
  • Author(s): Umemura Akira、Sasaki Akira、Takamura Toshinari、Takayama Hiroaki、Takeshita Yumie、Toya Yosuke、Kakisaka Keisuke、Hasegawa Yutaka、Ishigaki Yasushi
  • Journal Title: Surgery Today Volume: 未定 Issue: 6 Pages: 581-590
  • DOI: 10.1007/s00595-023-02767-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Study Protocol for the Pleiotropic Effects of Sodium?Glucose Cotransporter?2 Inhibitor on Organ-Specific Sympathetic Nerve Activity and Insulin Sensitivity in Participants with Type?2 Diabetes (2023)
  • Author(s): Takeshita Yumie、Nomura Chiaki、Murai Hisayoshi、Mukai Yusuke、Hirai Tadayuki、Hamaoka Takuto、Tokuno Shota、Tanaka Takeo、Goto Hisanori、Nakano Yujiro、Usui Soichiro、Nakajima Kenichi、Takamura Masayuki、Takamura Toshinari
  • Journal Title: Diabetes Therapy Volume: 15 Issue: 1 Pages: 269-280
  • DOI: 10.1007/s13300-023-01497-z
  • Peer Reviewed / Open Access
• [Journal Article] Selenoprotein P deficiency protects against immobilization-induced muscle atrophy by suppressing atrophy-related E3 ubiquitin ligases (2023)
  • Author(s): Abuduwaili Halimulati、Kamoshita Kyoko、Ishii Kiyo-Aki、Takahashi Kenta、Abuduyimiti Tuerdiguli、Qifang Li、Isobe Yuki、Goto Hisanori、Nakano Yujiro、Takeshita Yumie、Takayama Hiroaki、Harada Kenichi、Takamura Toshinari
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism Volume: - Issue: 6 Pages: E542-E552
  • DOI: 10.1152/ajpendo.00270.2022
  • Peer Reviewed / Open Access
• [Journal Article] PAC1 deficiency protects obese male mice from immobilization-induced muscle atrophy by suppressing FoxO-atrogene axis (2023)
  • Author(s): Li Qifang、Ishii Kiyo-aki、Kamoshita Kyoko、Takahashi Kenta、Abuduwaili Halimulati、Takayama Hiroaki、Galicia-Medina Cynthia M、Tanida Ryota、Oo Hein Ko、Gafiyatullina Guzel、Yao Xingyu、Abuduyimiti Tuerdiguli、Hamazaki Jun、Harada Kenichi、Murata Shigeo、Takamura Toshinari
  • Journal Title: Endocrinology Volume: - Issue: 6 Pages: 164-165
  • DOI: 10.1210/endocr/bqad065
  • Peer Reviewed / Open Access
• [Journal Article] Nutrigenetic Interaction Between Apolipoprotein C3 Polymorphism and Fat Intake in People with Nonalcoholic Fatty Liver Disease (2023)
  • Author(s): Yamamoto Reina、Takeshita Yumie、Tsujiguchi Hiromasa、Kannon Takayuki、Sato Takehiro、Hosomichi Kazuyoshi、Suzuki Keita、Kita Yuki、Tanaka Takeo、Goto Hisanori、Nakano Yujiro、Yamashita Tatsuya、Kaneko Shuichi、Tajima Atsushi、Nakamura Hiroyuki、Takamura Toshinari
  • Journal Title: Current Developments in Nutrition Volume: 7 Issue: 4 Pages: 100051-100051
  • DOI: 10.1016/j.cdnut.2023.100051
  • Peer Reviewed / Open Access
• [Journal Article] Trajectories of Liver Fibrosis and Gene Expression Profiles in Nonalcoholic Fatty Liver Disease Associated With Diabetes (2023)
  • Author(s): Sako Saori、Takeshita Yumie、Takayama Hiroaki、Goto Hisanori、Nakano Yujiro、Ando Hitoshi、Tsujiguchi Hiromasa、Yamashita Tatsuya、Arai Kuniaki、Kaneko Shuichi、Nakamura Hiroyuki、Harada Kenichi、Honda Masao、Takamura Toshinari
  • Journal Title: Diabetes Volume: 72 Issue: 9 Pages: 1297-1306
  • DOI: 10.2337/db22-0933
  • Peer Reviewed / Open Access
• [Presentation] Impact of low-calorie diets and bariatric surgery on organ-specific insulin sensitivity in the liver and skeletal muscle (2024)
  • Author(s): M. Mori, Y. Takeshita, D. Matsubara, S Tokuno, H. Goto, M. Okumura, Y. Nakano, T. Takamura
  • Organizer: EASD 2024
  • Int'l Joint Research
• [Presentation] Metabolic characteristics associated with the bariatric surgery-mediated improvement of liver pathology in Japanese participants with morbid obesity (2024)
  • Author(s): D. Matsubara, Y. Takeshita, Y. Nakano, M. Okumura, M. Mori, S. Tokuno, H. Goto, T. Takamura
  • Organizer: EASD 2024
  • Int'l Joint Research
• [Presentation] Transient elevation of minerals and bone resorption during 48-week treatment with an SGLT2 inhibitor tofogliflozin in people with type 2 diabetes (2024)
  • Author(s): S. Tokuno, Y. Takeshita, M. Okumura, H. Goto, Y. Nakano, T. Takamura
  • Organizer: EASD 2024
  • Int'l Joint Research
• [Presentation] 新規NAFLD疾患感受性遺伝子オキシトシン受容体の病態での意義 (2024)
  • Author(s): 後藤 久典,山本 靖彦,辻口 博聖,竹下 有美枝,中野 雄二郎,中村 裕之,篁 俊成
  • Organizer: 第97回日本内分泌学会学術総会
• [Presentation] アルギニン負荷に対するインスリン‐ グルカゴン応答ネットワーク (2024)
  • Author(s): 海古井由佳、田中 健雄、後藤 久典、奥村 美輝、中野雄二郎、竹下有美枝、篁 俊成
  • Organizer: 第34回臨床内分泌代謝Update
• [Presentation] 高用量デキサメタゾン投与で抑制されず，海綿静脈洞サンプリングより診断したクッシング病の一例 (2024)
  • Author(s): 小林 愛佳，東 夏成，奥村 美輝，後藤 久典，中野雄二郎，池田 博子，竹下有美枝，篁 俊成
  • Organizer: 第23回日本内分泌学会北陸支部学術集会
• [Presentation] Effects of Tofogliflozin and Glimepiride in Liver Histology on Nonalcoholic Fatty Liver Disease with Type 2 Diabetes. (2023)
  • Author(s): Yumie Takeshita, Masao Honda, Yuki Kita, Shuichi Kaneko, Toshinari Takamura.
  • Organizer: APASL Taiwan 2023
  • Int'l Joint Research
• [Presentation] Effects of sodium-glucose cotransporter 2 inhibitor versus sulfonylurea on nonalcoholic fatty liver disease and diabetes (2023)
  • Author(s): Yumie Takeshita, Masao Honda, Shuichi Kaneko, Toshinari Takamura.
  • Organizer: EASL SLD SUMMIT 2023
  • Int'l Joint Research
• [Book] SGLT2阻害薬と肝臓保護 (2024)
  • Author(s): 竹下 有美枝,篁 俊成
  • Total Pages: 61
  • Publisher: 医学のあゆみ
• [Book] 糖尿病：疾患概要と治療の基本方針 健康寿命を考えた日常頻用薬の選び方・使い方 (2024)
  • Author(s): 竹下有美枝
  • Total Pages: 412
  • Publisher: 診断と治療社
  • ISBN: 9784787826510
• [Book] スルホニル尿素薬による低血糖のリスクを減らすためには？健康寿命を考えた日常頻用薬の選び方・使い方 (2024)
  • Author(s): 奥村美輝 竹下有美枝
  • Total Pages: 412
  • Publisher: 診断と治療社
  • ISBN: 9784787826510
• [Book] グリニド薬が有効と考えられる患者像は？健康寿命を考えた日常頻用薬の選び方・使い方 (2024)
  • Author(s): 小西正剛 竹下有美枝 篁俊成
  • Total Pages: 412
  • Publisher: 診断と治療社
  • ISBN: 9784787826510
• [Book] GLP-1受容体作動薬が効果的な病態は？健康寿命を考えた日常頻用薬の選び方・使い方 (2024)
  • Author(s): 竹下有美枝
  • Total Pages: 65
  • Publisher: 診断と治療社
  • ISBN: 9784787826510
• [Book] αグルコシダ－ゼ阻害薬が有効と考えられる患者像は？健康寿命を考えた日常頻用薬の選び方・使い方 (2024)
  • Author(s): 小西正剛 竹下有美枝 篁俊成
  • Total Pages: 412
  • Publisher: 診断と治療社
  • ISBN: 9784787826510
• [Book] 糖尿病及びその合併症の病態解明と治療アルゴリズムに資する臨床研究 (2024)
  • Author(s): 竹下有美枝
  • Total Pages: 45
  • Publisher: 金沢大学十全医学会
• [Book] NAFLD/NASH合併糖尿病に対する非臨床・臨床のエビデンス GLP-1受容体作動薬・GIP/GLP-1受容体作動薬 (2024)
  • Author(s): 竹下有美枝 篁俊成
  • Total Pages: 4
  • Publisher: 医学の歩み
• [Book] SGLT2阻害薬とNAFLD (2023)
  • Author(s): 竹下有美枝
  • Total Pages: 4
  • Publisher: Medical View Point