{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T03:59:14Z","timestamp":1770782354230,"version":"3.50.0"},"reference-count":123,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,30]],"date-time":"2023-04-30T00:00:00Z","timestamp":1682812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society of the Promotion of Science","doi-asserted-by":"publisher","award":["JP18H03182"],"award-info":[{"award-number":["JP18H03182"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society of the Promotion of Science","doi-asserted-by":"publisher","award":["JP21H03368"],"award-info":[{"award-number":["JP21H03368"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Insulin resistance is one of the etiologies of type 2 diabetes mellitus (T2DM) and has been suggested to contribute to the development of Alzheimer\u2019s disease by promoting amyloid-\u03b2 accumulation. Various causes of insulin resistance have been suggested; however, mechanisms of insulin resistance development remain to be elucidated in many respects. Elucidating the mechanisms underlying the development of insulin resistance is one of the key factors in developing methods to prevent the onset of T2DM and Alzheimer\u2019s disease. It has been suggested that the body pH environment plays an important role in the control of cellular functions by regulating the action of hormones including insulin and the activity of enzymes and neurons, thereby maintaining homeostatic conditions of the body. This review introduces: (1) Mitochondrial dysfunction through oxidative stress caused by obesity-induced inflammation. (2) Decreased pH of interstitial fluid due to mitochondrial dysfunction. (3) Development of insulin resistance due to diminution of insulin affinity to its receptor caused by the lowered interstitial fluid pH. (4) Accelerated accumulation of amyloid-\u03b2 due to elevated activities of \u03b2- and \u03b3-secretases caused by the lowered interstitial fluid pH. (5) Diet therapies for improving insulin resistance with weak organic acids that act as bases in the body to raise the pH of lowered interstitial fluid and food factors that promote absorption of weak organic acids in the gut.<\/jats:p>","DOI":"10.3390\/biom13050779","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:54:46Z","timestamp":1682949286000},"page":"779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Mechanisms of Obesity-Induced Development of Insulin Resistance and Promotion of Amyloid-\u03b2 Accumulation: Dietary Therapy Using Weak Organic Acids via Improvement of Lowered Interstitial Fluid pH"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3846-0937","authenticated-orcid":false,"given":"Yoshinori","family":"Marunaka","sequence":"first","affiliation":[{"name":"Medical Research Institute, Kyoto Industrial Health Association, Kyoto 604-8472, Japan"},{"name":"Research Organization of Science and Technology, Ritsumeikan University, Kusatsu 525-8577, Japan"},{"name":"Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41586-019-1797-8","article-title":"The integrative biology of type 2 diabetes","volume":"576","author":"Roden","year":"2019","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1111\/jdi.13614","article-title":"Role of skeletal muscle lipids in the pathogenesis of insulin resistance of obesity and type\u20092 diabetes","volume":"12","author":"Gilbert","year":"2021","journal-title":"J. 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