Prevention of diabetes mellitus and Alzheimer dementia via improvement of low interstitial pH by food constituent

• Project/Area Number: 18H03182
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Ritsumeikan University
• Principal Investigator: 丸中 良典 立命館大学, 総合科学技術研究機構, 教授 (00127036)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Granted (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 糖尿病 / 間質液 / pH / 食品 / インスリン抵抗性 / アルツハイマー型認知症

Outline of Annual Research Achievements

糖尿病患者でのアルツハイマー型認知症発症リスクが高いことが知られているが、その原因は不明である。我々は糖尿病で間質液pHが低下し、この間質液pH低下がインスリン抵抗性発症の成因であることを発見し、間質液pH低下によりアルツハイマー型認知症の原因物質と考えられているアミロイドベータ生成が促進され、一方アミロイドベータ分解が低下し、その結果アミロイドベータ蓄積が促進される可能性を見出した。 しかしながらこれらの分子機構は未だ明らかとはなっていない。本研究アミロイドベータ、以下の研究仮説を立て、この研究仮説を正しいことを証明する。

研究仮説：以下の大きく分けて２つの研究仮説を立てた。A) 糖尿病での脳を含む間質液pH低下によりアミロイドベータ生成酵素であるβ ・γセクレターゼの活性および発現量の増大が起こり、一方でアミロイドベータ分解酵素であるネプリライシンの活性および発現量が低下し、その結果糖尿病での脳における線維化アミロイドベータ蓄積が増大する 。　B) ウメ食品を代表とした弱酸カルボン酸含有食品摂取で間質液pHが正常に保持されることにより、血糖値上昇・インスリン抵抗性発症・アミロイドベータ蓄積の予防をもたらすことが可能となる。

研究目的：1)上記仮説A)およびB)を動物およびヒトにおいて証明する。　2)間質液pHを正常に制御し得る食品選定の選定を行なう。

Current Status of Research Progress

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

Reason

糖尿病での脳を含む間質液pH低下によりアミロイドベータ生成酵素であるβ ・γセクレターゼの活性および発現量の増大が起こり得ること、一方でアミロイドベータ分解酵素であるネプリライシンの活性および発現量が低下し得ること、これらの結果、糖尿病での脳における線維化アミロイドベータ蓄積が増大する可能性を見出した。
ウメ食品を代表とした弱酸カルボン酸含有食品摂取で間質液pHが正常に保持されることを見出した。その結果、血糖値上昇を抑制し得ること、インスリン抵抗性の発症も抑制されうること、またアミロイドベータ蓄積の予防をもたら得ることも明らかとなった。

以上の結果より、ウメ関連食品での間質液pH低下改善をもたらす食品の選定に目処がたち、またその食品摂取にて血糖値改善をもたらし得る可能性も見出したことによる。これらの結果を実際の食生活の中に取り入れる試みも行う。

Strategy for Future Research Activity

ウメ関連食品での間質液pH低下改善をもたらす食品の選定に目処がたち、このことを確固たることにするための実験を実施する。
またその食品摂取にて血糖値改善をもたらし得ることを確固たることにするための実験を実施する。

Research Products

• [Int'l Joint Research] Jiangsu University/University of Macau/Zhejiang University(中国)
• [Int'l Joint Research] National Institute of Health/Universita Politecnica delle Marche/University of Naples Federico II(イタリア)
• [Int'l Joint Research] H. Lee Moffitt Cancer Center Res Inst/Medical College of Wisconsin/University of Massachusetts(米国)
• [Int'l Joint Research] University of New South Wales(オーストラリア)
• [Int'l Joint Research] Bulgarian Academy of Sciences(ブルガリア)
• [Int'l Joint Research]
• [Int'l Joint Research] Jiangsu University/University of Macau(中国)
• [Int'l Joint Research] National Institute of Health/Regina Elena Cancer Institute(イタリア)
• [Int'l Joint Research] H. Lee Moffitt Cancer Center & Res Inst(米国)
• [Int'l Joint Research] Academy of Sciences of Uzbekistan(ウズベキスタン)
• [Journal Article] Enhancement of ciliary beat amplitude by carbocisteine in ciliated human nasal epithelial cells (2020)
  • Author(s): Inui Taka‐aki、Yasuda Makoto、Hirano Shigeru、Ikeuchi Yukiko、Kogiso Haruka、Inui Toshio、Marunaka Yoshinori、Nakahari Takashi
  • Journal Title: Laryngoscope Volume: -
  • DOI: 10.1002/lary.28185
  • Peer Reviewed
• [Journal Article] Standard medical nutrition therapy of 25kcal/kg ideal bodyweight/day often does not reach even resting energy expenditure for patients with type 2 diabetes (2020)
  • Author(s): Fukuda T, Tanaka M, Yamazaki M, MARUNAKA Y, Fukui M
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Pages: 626-632
  • DOI: 10.1111/jdi.13167
  • Peer Reviewed / Open Access
• [Journal Article] ANO9 Regulated Cell Cycle in Human Esophageal Squamous Cell Carcinoma. (2020)
  • Author(s): Katsurahara K, Shiozaki A, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, Marunaka Y, Otsuji E.
  • Journal Title: Annals of Surgical Oncology Volume: ー
  • DOI: 10.1245/s10434-020-08368-y
  • Peer Reviewed
• [Journal Article] Refining transfer set in calibration transfer of near infrared spectra by backward refinement of samples (2020)
  • Author(s): Zheng K, Feng T, Zhang W, Huang X, Li Z, Zhang D, Shi J, MARUNAKA Y, Zou X
  • Journal Title: Analytical Methods Volume: 12 Pages: 1495-1503
  • DOI: 10.1039/d0ay00085j
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Body fluid pH balance in metabolic health and possible benefits of dietary alkaline foods (2020)
  • Author(s): Aoi W, Zou X, Xiao J, MARUNAKA Y
  • Journal Title: eFood Volume: 1 Pages: 12-23
  • DOI: 10.2991/efood.k.190924.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The algal polysaccharide ulvan suppresses growth of hepatoma cells (2020)
  • Author(s): Zhao C, Lin G, Wu D, Liu D, You L, Hogger P, Simal-Gandara J, Wang M, da Costa JGM, MARUNAKA Y, Daglia M, Khan H, Filosa R, Wang S, Xiao J
  • Journal Title: Food Frontiers Volume: 1 Pages: 83-101
  • DOI: 10.1002/fft2.13
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Food intake targeting and improving acidity in diabetes and cancer (2020)
  • Author(s): MARUNAKA Y, Niisato N, Zou X, Xiao J, Nakahari T
  • Journal Title: Food Frontiers Volume: 1 Pages: 9-12
  • DOI: 10.1002/fft2.5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Airway ciliary beating affected by the Pcp4 dose-dependent [Ca2+]i in Down syndrome mice, Ts1Rhr (2020)
  • Author(s): Kogiso H, Raveau M, Yamakawa K, Saito D, Ikeuchi Y, Okazaki T, Asano S, Inui T, MARUNAKA Y, Nakahari T
  • Journal Title: Int J Mol Sci Volume: 21 Pages: 1947-1947
  • DOI: 10.3390/ijms21061947
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Food Frontiers: An academically sponsored new journal (2020)
  • Author(s): L Wang, J Simal‐Gandara, M Du, B Lu, JL Quiles, ZY Chen, B Hennig, M Wang, H Xiao, J Arcot, T Yue, B Zheng, X Zou, Y MAMRUNAKA, et al.
  • Journal Title: Food Frontiers Volume: 1 Pages: 3-5
  • DOI: 10.1002/fft2.8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 細胞内 Cl-による細胞機能調節と疾患 (2020)
  • Author(s): 丸中良典
  • Journal Title: 腎と透析：特集 Cl-：電解質クイーン Volume: 88 Pages: 419-422
• [Journal Article] Ciliary beating amplitude controlled by intracellular Cl- and a high rate of CO2 production in ciliated human nasal epithelial cells (2019)
  • Author(s): Inui TA, Murakami K, Yasuda M, Hirano S, Ikeuchi Y, Kogiso H, Hosogi S, Inui T, MARUNAKA Y, Nakahari T
  • Journal Title: Pflugers Archiv - European Journal of Physiology Volume: 471 Pages: 1127-1142
  • DOI: 10.1007/s00424-019-02280-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of low temperature on the regulation of cell volume after hypotonic shock in gastric cancer cells. (2019)
  • Author(s): Shiozaki A, Yamazato Y, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Marunaka Y, Otsuji E.
  • Journal Title: Int J Oncol Volume: 55 Pages: 905-914
  • DOI: 10.3892/ijo.2019.4853
  • Peer Reviewed
• [Journal Article] LRRC8A Expression Influences Growth of Esophageal Squamous Cell Carcinoma. (2019)
  • Author(s): Konishi T, Shiozaki A, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, Marunaka Y, Otsuji E.
  • Journal Title: Am J Pathol Volume: 189 Pages: 1973-1985
  • DOI: 10.1016/j.ajpath.2019.06.006
  • Peer Reviewed
• [Journal Article] pH balance and lactic acid increase in the vitreous body of diabetes mellitus patients (2019)
  • Author(s): Mieno H, MARUNAKA Y, Inaba T, Kojima K, Yoneda K, Nagata K, Sotozono C
  • Journal Title: Experimental Eye Research Volume: 188 Pages: 107789-107789
  • DOI: 10.1016/j.exer.2019.107789
  • Peer Reviewed
• [Journal Article] The expression and role of TRPV2 in esophageal squamous cell carcinoma. (2019)
  • Author(s): Kudou M, Shiozaki A, Yamazato Y, Katsurahara K, Kosuga T, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, Marunaka Y, Otsuji E.
  • Journal Title: Scientific Reports Volume: 9 Pages: 16055-16055
  • DOI: 10.1038/s41598-019-52227-0
  • Peer Reviewed / Open Access
• [Journal Article] Cell Volume-Activated and -Correlated Anion Channels in Mammalian Cells: Their Biophysical, Molecular and Pharmacological Properties. (2019)
  • Author(s): Y. Okada, T. Okada, K.S. Numata, M.R. Islam, Y.A. Akatsuka, T. Numata, M. Kubo, T. Shimizu, R.S. Kurbannazarova, Y. Marunaka, and R.Z. Sabirov
  • Journal Title: Pharmacol Rev Volume: 71 Pages: 49-88
  • DOI: 10.1124/pr.118.015917
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting acidity in cancer and diabetes (2019)
  • Author(s): Gillies RJ, Pilot C, MARUNAKA Y, Fais S
  • Journal Title: Biochim Biophys Acta Rev Cancer Volume: 1871 Pages: 273-280
  • DOI: 10.1016/j.bbcan.2019.01.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl-]i in mouse airway cilia (2019)
  • Author(s): Ikeuchi Y, Kogiso H, Hosogi S, Tanaka S, Shimamoto C, Matsumura H, Inui T, MARUNAKA Y, Nakahari T.
  • Journal Title: Pflugers Archiv - European Journal of Physiology Volume: 471 Pages: 365-380
  • DOI: 10.1007/s00424-018-2212-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Causes, consequences, and therapy of tumors acidosis (2019)
  • Author(s): Pillai SR, Damaghi M, Marunaka Y, Spugnini EP, Fais S, Gillies RJ.
  • Journal Title: Cancer Metastasis Rev Volume: 印刷中
  • DOI: 10.1007/s10555-019-09792-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Xenin-25 induces anion secretion by activating non-cholinergic secretomotor neurons in the rat ileum (2019)
  • Author(s): Kuwahara A, Kuwahara Y, Kato I, Kawaguchi K, Harata D, Asano S, Inui T, Marunaka Y.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 印刷中
  • DOI: 10.1152/ajpgi.00333.2018
  • Peer Reviewed
• [Journal Article] Functional analysis and clinical significance of sodium iodide symporter expression in gastric cancer (2019)
  • Author(s): Shiozaki Atsushi、Ariyoshi Yosuke、Iitaka Daisuke、Kosuga Toshiyuki、Shimizu Hiroki、Kudou Michihiro、Konishi Tomoki、Shoda Katsutoshi、Arita Tomohiro、Konishi Hirotaka、Komatsu Shuhei、Kubota Takeshi、Fujiwara Hitoshi、Okamoto Kazuma、Kishimoto Mitsuo、Konishi Eiichi、Marunaka Yoshinori、Ichikawa Daisuke、Otsuji Eigo
  • Journal Title: Gastric Cancer. Volume: 22 Pages: 473-485
  • DOI: 10.1007/s10120-018-0874-2
  • NAID: 40021884050
  • Peer Reviewed
• [Journal Article] The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH (2018)
  • Author(s): MARUNAKA Y
  • Journal Title: Int J Mol Sci Volume: 19 Pages: 3244-3244
  • DOI: 10.3390/ijms19103244
  • Peer Reviewed / Open Access
• [Journal Article] Daidzein-Stimulated Increase in the Ciliary Beating Amplitude via an [Cl?]i Decrease in Ciliated Human Nasal Epithelial Cells (2018)
  • Author(s): Inui Taka-aki、Yasuda Makoto、Hirano Shigeru、Ikeuchi Yukiko、Kogiso Haruka、Inui Toshio、Marunaka Yoshinori、Nakahari Takashi
  • Journal Title: Int J Mol Sci Volume: 19 Pages: 3754-3754
  • DOI: 10.3390/ijms19123754
  • Peer Reviewed / Open Access
• [Journal Article] Improvement of Diabetes Mellitus Symptoms by Intake of Ninjin'yoeito (2018)
  • Author(s): Hosogi S, Ohsawa M, Kato I, Kuwahara A, Inui T, Inui A,MARUNAKA Y
  • Journal Title: Front Nutr Volume: 5 Pages: 112-112
  • DOI: 10.3389/fnut.2018.00112
  • Peer Reviewed / Open Access
• [Journal Article] Spontaneous oscillation of the ciliary beat frequency regulated by release of Ca2+ from intracellular stores in mouse nasal epithelia (2018)
  • Author(s): Kuremoto Toshihiro、Kogiso Haruka、Yasuda Makoto、Inui Taka-aki、Murakami Kentaro、Hirano Shigeru、Ikeuchi Yukiko、Hosogi Shigekuni、Inui Toshio、Marunaka Yoshinori、Nakahari Takashi
  • Journal Title: Biochem Biophys Res Commun Volume: 507 Pages: 211-216
  • DOI: 10.1016/j.bbrc.2018.11.010
  • Peer Reviewed / Open Access
• [Journal Article] Bioconjugation strategy for cell surface labelling with gold nanostructures designed for highly localized pH measurement. (2018)
  • Author(s): Leonardo Puppulin, Shigekuni Hosogi, Hongxin Sun, Kazuhiko Matsuo, Toshio Inui, Yasuaki Kumamoto, Toshinobu Suzaki, Hideo Tanaka and Yoshinori Marunaka
  • Journal Title: Nature Commun Volume: 9 Pages: 1-13
  • DOI: 10.1038/s41467-018-07726-5
  • NAID: 120006549200
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Building-up the primary culture system for ependymal ciliary cells from newborn mice (2020)
  • Author(s): Namoto Y, Ishii Y, Okazaki T, Asano S, MARUNAKA Y, Nakahari T
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Activation of airway ciliary beating by an [Ca2+]i increased via nifedipine-sensitive Ca2+ channels stimulated by amboxol (2020)
  • Author(s): Saito D, Kawaguchi K, Asano S, MARUNAKA Y, Nakahari T
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Secretory reflex pathway of short chain fatty acids in the rat distal colon (2020)
  • Author(s): Harata D, Asano S, Kuwahara A, Kuwahara Y, Kato I, Inui T, MARUNAKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Surface enhanced Raman spectroscopy probe for nanometer-scale measurement of pH and hydrogen peroxides on the outer membrane of cells (2020)
  • Author(s): Puppulin L, Hosogi S, Tanaka H, Kumamoto Y, Ashihara E, MARUANKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
  • Invited
• [Presentation] Non-invasive sample measurement derived from live tissue by Raman spectroscopic microscopy (2020)
  • Author(s): Akaji S, MARUNAKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
  • Invited
• [Presentation] Regulation of body fluid and electrolytes: Physiological significance of interstitial fluid (2020)
  • Author(s): MARUANKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
  • Invited
• [Presentation] Improving action of Ninji’yoeito on the syndrome of diabetes mellitus (2019)
  • Author(s): MARUNAKA Y
  • Organizer: 62th Annual Meeting of the Japan Diabetes Society
  • Invited
• [Presentation] Improving actions of natural foods and Ninjin’yoeito (a herbal medicine) on diabetes mellitus symptoms via improvement of interstitial fluid pH (2019)
  • Author(s): MARUNAKA Y
  • Organizer: International Conference on Natural Toxicology and Pharmacology
  • Int'l Joint Research / Invited
• [Presentation] Actions of flavonoids and natural compounds on ion environments: Its physiological roles (2019)
  • Author(s): MARUNAKA Y
  • Organizer: International Workshop on Intelligent Detection of Food and Safety
  • Int'l Joint Research / Invited
• [Presentation] Involvement of EP receptors in the regulation of Short circuit current by prostaglandins in A6 cells (2019)
  • Author(s): Sun H, MARUNAKA Y, Asano S
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies.
  • Int'l Joint Research
• [Presentation] Secretory reflex pathway of Xenin-25 in the rat ileum (2019)
  • Author(s): Kuwahara A, Kuwahara Y, Kato I, Inui T, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Secretory reflex pathway of SCFA in the rat distal colon (2019)
  • Author(s): Harata D, Asano S, Kuwahara A, Inui T, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Neurogenic relaxation of Xenin on spontaneous circular muscle contractions in rat distal colon (2019)
  • Author(s): Kuwahara Y, Kato I, Kuwahara A, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Aldosterone action on epithelial Na+ channel trafficking under the insulin-stimulated condition (2019)
  • Author(s): Marunaka R, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Inhibition of the frequency of airway ciliary beating by PDE1 activation in Down syndrome mouse (2019)
  • Author(s): Kogiso H, Ikeuchi Y, Tanaka S, Hosogi S, Shimamoto C, Raveau M, Yamakawa K, Nakahari T, Asano S, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Airway ciliary beating activated by enhanced Ca2+ signal in Hochuekki- to (TJ-41) treated mice (2019)
  • Author(s): Ikeuchi Y, Kogiso H, Tanaka S, Hosogi S, Nakahari T, Asano S, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Highly localized pH sensing on the outer membrane of cells using surface enhanced Raman spectroscopy (2019)
  • Author(s): Puppulin L, Hosogi S, Tanaka H, MARUNAKA Y
  • Organizer: The 9th Congress of Federation of Asian and Oceanian Physiological Societies
  • Int'l Joint Research
• [Presentation] Improvement of blood glucose level in diabetic rats by intake of citrate (2018)
  • Author(s): Hino K. Ebisu G, Hosogi S, MARUNAKA Y
  • Organizer: The 7th Asian Congress of Diabetes: The rise of nutrition and diabetes in Asia
  • Int'l Joint Research
• [Presentation] Epithelial Na+ channel (ENaC) trafficking process between the intracellular space and the apical membrane using mathematical analysis with a four-state model (2018)
  • Author(s): MARUNAKA Y
  • Organizer: The 40th Annual Meeting of The Membrane Society of Japan
  • Invited
• [Presentation] Effects of Ninjin'yoeito on insulin resistance via improvement of the interstitial fluid pH Seminar on Possibility of the Chinese medicine in the super aged society (2018)
  • Author(s): MARUNAKA Y
  • Organizer: The 60th Annual Meeting of Japan Geriatircs Society
  • Invited
• [Presentation] Roles of ion circumstances in bodily and cellular functions: Physiological meanings of interstitial fluid pH and action of food on the interstitial fluid pH (2018)
  • Author(s): MARUNAKA Y
  • Organizer: The 3rd International Symposium on Phytochemicals in Medicine and Food
  • Int'l Joint Research / Invited
• [Book] Encyclopedia of Respiratory Medicine (2020)
  • Author(s): Niisato N, MARUNAKA Y
  • Publisher: Elsevier
  • ISBN: 9780123708793
• [Remarks] 丸中良典 研究室
  • URL: https://marunaka-y.com/