新規なインスリン抵抗性増悪因子XORの生理的・病態生理的役割の解明

2020 Fiscal Year Research-status Report

• Project/Area Number: 20K11654
• Research Institution: Juntendo University
• Principal Investigator: 佐藤 博亮 順天堂大学, 医学部, 先任准教授 (20323595)
• Co-Investigator(Kenkyū-buntansha): 森谷 千尋 順天堂大学, 医学部, 助教 (90645037)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: インスリン抵抗性 / 糖尿病 / XOR

Outline of Annual Research Achievements

2型糖尿病の病態においてインスリン抵抗性の発症機序を解明することは糖尿病治療戦略において重要な課題である。高尿酸血症とインスリン抵抗性や肥満との間に正の相関を示すことが多くの観察研究で報告されているが、因果関係は不明である。
本研究では尿酸の産生に重要な酵素であるXORに着目し，XOR阻害薬フェブキソスタットを用いてXORがインスリン抵抗性に及ぼす影響を検討した。
6週齢、雄、Wistarラットを高脂肪餌群と高脂肪餌+フェブキソスタット群の2群に分け、4週間飼育し、インスリン感受性を正常血糖・高インスリンクランプ検査にて評価した。
フェブキソスタット投与群は、全身のインスリン感受性を示すglucose infusion rateが有意に増加しインスリン抵抗性の改善を認めた。末梢組織でのインスリン感受性を示すinsulin stimulated glucose disposal rateは有意な増加を認めたが、肝臓でのインスリン感受性を示すclamp hepatic glucose outputは有意な変化を認めなかった。
以上より、フェブキソスタットは末梢組織でのインスリン抵抗性を改善することが示唆された。さらにクランプ検査の結果と一致して、フェブキソスタット投与群は、クランプ検査後の骨格筋においてAktやAMPKのリン酸化を有意に増加したが，肝臓のAktやAMPKのリン酸化は有意な変化を認められなかった。
以上の結果より、フェブキソスタットは骨格筋においてインスリン抵抗性改善作用を示すことが明らかになった。すなわち、XORは尿酸産生に関与するばかりではなく、骨格筋でのインスリン抵抗性の病態にも深く関与している可能性が示唆された。

Current Status of Research Progress

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

Reason

XOR阻害薬であるフェブキソスタットは、骨格筋でのインスリン抵抗性を改善することを明らかにすることができ、XORは尿酸産生に関与するばかりではなく、骨格筋でのインスリン抵抗性の病態にも深く関与している可能性を示すことができた。

Strategy for Future Research Activity

XOR阻害薬であるフェブキソスタットの骨格筋でのインスリン抵抗性改善作用をin vitroで検討し、その作用機序を明らかにする。

Research Products

• [Journal Article] A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin (2021)
  • Author(s): Yamasaki、Tamura Y、Kaga H、Sato M、Kiya M、Kadowaki S、Suzuki R、Furukawa Y、Sugimoto D、Funayama T、Someya Y、Kakehi S、Nojiri S、Satoh H、Kawamori R、Watada H
  • Journal Title: Diabetes, Obesity and Metabolism Volume: 23 Pages: 1092～1100
  • DOI: 10.1111/dom.14312
  • Peer Reviewed / Open Access
• [Journal Article] Effect of thyroxine treatment on pregnancy outcomes in infertile Japanese women with TSH levels between 2.5 μIU/mL and the upper reference limit: a retrospective study (2021)
  • Author(s): Tsunemi A、Uchida T、Kuroda K、Ikemoto Y、Ochiai A、Goto H、Sugiyama R、Satoh Hi、Itakura A、Watada Hi
  • Journal Title: Endocrine Journal Volume: 68 Pages: 171～177
  • DOI: 10.1507/endocrj.EJ20-0380
  • Peer Reviewed
• [Journal Article] Prevalence and Features of Impaired Glucose Tolerance in Young Underweight Japanese Women (2021)
  • Author(s): Sato M、Tamura Y、Nakagata T、Someya Y、Kaga H、Yamasaki N、Kiya M、Kadowaki S、Sugimoto D、Satoh H、Kawamori R、Watada H
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 106 Pages: e2053～e2062
  • DOI: 10.1210/clinem/dgab052
  • Peer Reviewed
• [Journal Article] Influence of Short-Term Dietary and Therapeutic Iodine Restriction on the Therapeutic Effects of Radioactive Iodine Therapy in Patients with Graves' Disease (2021)
  • Author(s): Nishio R、Uchida T、Suzuki L、Onose Hi、Goto H、Yamada E、Satoh H、Watada H
  • Journal Title: Thyroid Volume: 31 Pages: 439～445
  • DOI: 10.1089/thy.2020.0126
• [Journal Article] Adipose Insulin Resistance and Decreased Adiponectin Are Correlated With Metabolic Abnormalities in Nonobese Men (2021)
  • Author(s): Kiya M、Tamura Y、Takeno K、Someya Y、Kakehi S、Sato M、Yamasaki N、Kadowaki S、Suzuki R、Furukawa Y、Sugimoto D、Kaga H、Funayama T、Nishitani-Y M、Shimada K、Daida H、Aoki S、Satoh H、Kawamori R、Watada H
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 106 Pages: e2228～e2238
  • DOI: 10.1210/clinem/dgab037
  • Peer Reviewed
• [Journal Article] Fast walking is a preventive factor against new-onset diabetes mellitus in a large cohort from a Japanese general population (2021)
  • Author(s): Iwasaki M、Kudo A、Asahi K、Machii N、Iseki K、Satoh H、Moriyama T、Yamagata K、Tsuruya K、Fujimoto S、Narita I、Konta T、Kondo M、Shibagaki Y、Kasahara M、Watanabe T、Shimabukuro M
  • Journal Title: Scientific Reports Volume: 11 Pages: 716
  • DOI: 10.1038/s41598-020-80572-y
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between risk of hyper- low-density lipoprotein cholesterolemia and evacuation after the Great East Japan Earthquake (2021)
  • Author(s): Satoh H, Okazaki K, Ohira T, Sakai A, Hosoya M, Yasumura S, Kawasaki Y, Hashimmoto K, Ohtsuru A, Takahashi A, Watanabe K, Shimabukuro M, Kazama JJ, Hashimoto S, Kobashi G, Ohira H, Ohto H, Kamiya K
  • Journal Title: Journal of Epidemiology Volume: － Pages: －
  • DOI: 10.2188/jea.JE20200267
  • Peer Reviewed
• [Journal Article] Influence of post-disaster evacuation on incidence of hyperuricemia in residents of Fukushima Prefecture: the Fukushima Health Management Survey (2020)
  • Author(s): Hashimoto S, Nagai M, Ohira T, Fukuma S, Hosoya M, Yasumura S, Satoh H, Suzuki H, Sakai A, Ohtsuru A, Kawasaki Y, Takahashi A, Okazaki K, Kobashi G, Kamiya K, Yamashita S, Fukuhara SI, Ohto H
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Pages: 1025～1032
  • DOI: 10.1007/s10157-020-01924-6
  • Peer Reviewed
• [Journal Article] Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non‐obese men (2020)
  • Author(s): Kaga H, Tamura Y, Takeno K, Kakehi S, Someya Y, Funayama T, Furukawa Y, Suzuki R, Sugimoto D, Kadowaki S, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Giacca A, Sato H, Kawamori R, Watada H
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Pages: 874～877
  • DOI: 10.1111/jdi.13227
  • Peer Reviewed
• [Journal Article] Conversion of pancreatic α cells into insulin-producing cells modulated by β-cell insufficiency and supplemental insulin administration (2020)
  • Author(s): Katahira T, Miyatsuka T, Miura M, Suzuki L, Himuro M, Nishida Y, Satoh H, Watada H
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Pages: 178～183
  • DOI: 10.1016/j.bbrc.2019.10.100
  • Peer Reviewed
• [Journal Article] Influence of post‐disaster evacuation on childhood obesity and hyperlipidemia (2020)
  • Author(s): Kawasaki Y, Nakano H, Hosoya M, Yasumura S, Ohira T, Satoh H, Suzuki H, Sakai A, Ohtsuru A, Takahashi A, Kobashi G, Kamiya K
  • Journal Title: Pediatrics International Volume: 62 Pages: 669～676
  • DOI: 10.1111/ped.14162
  • Peer Reviewed
• [Journal Article] Plasma glucagon levels measured by sandwich ELISA are correlated with impaired glucose tolerance in type 2 diabetes (2020)
  • Author(s): Kobayashi M, Satoh H, Matsuo T, Kusunoki Y, Tokushima M, Watada H, Namba M, Kitamura T
  • Journal Title: Endocrine Journal Volume: 67 Pages: 903～922
  • DOI: 10.1507/endocrj.EJ20-0079
  • Peer Reviewed
• [Journal Article] Lower intake of saturated fatty acids is associated with persistently higher arterial stiffness in patients with type 2 diabetes (2020)
  • Author(s): Mita T, Someya Y, Osonoi Y, Osonoi T, Saito M, Nakayama S, Ishida H, Sato H, Gosho M, Watada H
  • Journal Title: Journal of Diabetes Investigation Volume: 12 Pages: 226～233
  • DOI: 10.1111/jdi.13347
  • Peer Reviewed
• [Journal Article] Ingestion of an exogenous ketone monoester improves the glycemic response during oral glucose tolerance test in individuals with impaired glucose tolerance: A cross‐over randomized trial (2020)
  • Author(s): Nakagata T, Tamura Y, Kaga H, Sato M, Yamasaki N, Someya Y, Kadowaki S, Sugimoto D, Satoh H, Kawamori R, Watada H
  • Journal Title: Journal of Diabetes Investigation Volume: － Pages: －
  • DOI: 10.1111/jdi.13423
  • Peer Reviewed
• [Journal Article] Relationship between the prevalence of polycythemia and factors observed in the mental health and lifestyle survey after the Great East Japan Earthquake (2020)
  • Author(s): Sakai A, Nakano H, Ohira T, Maeda M, Okazaki K, Takahashi A, Kawasaki Y, Satoh H, Ohtsuru A, Shimabukuro M, Kazama J, Hashimoto S, Hosoya M, Yasumura S, Yabe H, Ohto H, Kamiya K
  • Journal Title: Medicine Volume: 99 Pages: e18486～e18486
  • DOI: 10.1097/MD.0000000000018486
  • Peer Reviewed
• [Journal Article] Characteristics associated with elevated 1‐h plasma glucose levels during a 75‐g oral glucose tolerance test in non‐obese Japanese men (2020)
  • Author(s): Sato M, Tamura Y, Someya Y, Takeno K, Kaga H, Kadowaki S, Sugimoto D, Kakehi S, Funayama T, Furukawa Y, Suzuki R, Nakagata T, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Sato H, Kawamori R, Watada H
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Pages: 1520～1523
  • DOI: 10.1111/jdi.13245
  • Peer Reviewed
• [Journal Article] Effect of Plasma Exchange in Thyroid Storm With Consideration of Its Distribution Into the Extravascular Space (2020)
  • Author(s): Shinohara M, Uchida T, Funayama T, Watanabe M, Kusaoi M, Yamaji K, Tamura N, Goto H, Sato H, Watada H
  • Journal Title: Journal of the Endocrine Society Volume: 4 Pages: －
  • DOI: 10.1210/jendso/bvaa023
  • Peer Reviewed
• [Journal Article] Effect of real‐life insulin pump with predictive low‐glucose management use for 3 months: Analysis of the patients treated in a Japanese center (2020)
  • Author(s): Tsunemi A, Sato J, Kurita M, Wakabayashi Y, Waseda N, Koshibu M, Shinohara M, Ozaki A, Nakamura H, Hirano N, Ikeda F, Satoh H, Watada H
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Pages: 1564～1569
  • DOI: 10.1111/jdi.13288
  • Peer Reviewed
• [Journal Article] Both higher fitness level and higher current physical activity level may be required for intramyocellular lipid accumulation in non-athlete men (2020)
  • Author(s): Yamasaki N, Tamura Y, Takeno K, Kakehi S, Someya Y, Funayama T, Furukawa Y, Kaga H, Suzuki R, Sugimoto D, Kadowaki S, Sato M, Nakagata T, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Sato H, Kawamori R, Watada H
  • Journal Title: Scientific Reports Volume: 10 Pages: －
  • DOI: 10.1038/s41598-020-61080-5
  • Peer Reviewed
• [Presentation] The 7-Day Diabetes Education Hospitalization Program Improves Quality of Life and Treatment Satisfaction (2020)
  • Author(s): Kurita M, Satoh H, Kadowaki S, Watada H
  • Organizer: 80th American Diabetes Association Scientific Sessions
  • Int'l Joint Research
• [Presentation] The Impact of Visulalizing Macronutrient content via Food-Long App “Calomeal” on glycemic Control and QoL in People with Thpe 2 Diabetes (2020)
  • Author(s): Tsunemi A, Sato J, Enomoto M, Iwagaki Y, Sugimoto S, Someya Y, Kiya M, Matsuhashi E, Wakabayashi Y, Funayama T, Uchida T, Miyatsuka T, Azuma K, Shimizu T, Satoh H, Kanazawa A, Watada H
  • Organizer: 80th American Diabetes Association Scientific Sessions
  • Int'l Joint Research
• [Presentation] Coexistence of Hypoadiponectinemia and Impaired Adipose Tissue Insulin Sensitivity Increases the Risk of Metabolic Abnomality Due to Muscle Insulin Resistance in Nonobese Japanese Men (2020)
  • Author(s): Kiya M, Tamura Y, Takeno K, Someya Y, Kakehi S, Sato M, Yamasaki N, Kadowaki S, Suzuki R, Furukawa Y, Sugimoto D, Kaga H, Funayama T, Satoh H, Kawamori R, Watada H
  • Organizer: 80th American Diabetes Association Scientific Sessions
  • Int'l Joint Research
• [Presentation] 糖尿病教育入院中に血清Cペプチド・インスリン濃度の乖離から発見されたインスリン抗体陽性の2型糖尿病の1例 (2020)
  • Author(s): 金井晶子，佐藤博亮，栗田実佳、吉田千紗，綿田裕孝
  • Organizer: 第662回日本内科学会関東地方会
• [Presentation] 糖尿病教育入院がQOLに及ぼす影響についての検討 (2020)
  • Author(s): 栗田実佳，佐藤博亮，吉田千紗，門脇聡，綿田裕孝
  • Organizer: 第63回日本糖尿病学会年次学術集会
• [Presentation] 食事記録アプリが2型糖尿病患者の食習慣および血糖コントロールに与える影響 (2020)
  • Author(s): 常見亜佐子，佐藤淳子，杉本栄，幸由布子，榎本真理，木屋舞，松橋瑛子，若林侑香，船山崇，内田豊義，宮塚健，東浩介，清水友章，佐藤博亮，金澤昭雄，綿田裕孝
  • Organizer: 第63回日本糖尿病学会年次学術集会
• [Presentation] 非肥満男性の脂肪機能異常（低アディポネクチン血症と脂肪インスリン抵抗性の併存）は，脂肪肝や筋インスリン抵抗性と関連する (2020)
  • Author(s): 木屋舞，田村好史，竹野影海，染谷由希，筧佐織，佐藤元律，山崎望，門脇聡，鈴木瑠璃子，古川康彦，杉本大介，加賀英義，船山崇，佐藤博亮，河盛隆造，綿田裕孝
  • Organizer: 第63回日本糖尿病学会年次学術集会
• [Presentation] 糖尿病教育入院中にKallman症候群の診断に至った糖尿病の1症例 (2020)
  • Author(s): 門脇聡，佐藤博亮，栗田実佳，尾崎敦子，綿田裕孝
  • Organizer: 第30回臨床内分泌代謝Update