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Insulin receptors are located at the plasma membrane of the insulin-targeted cells such as myocytes, adipocytes, etc., and insulin binds to the extracellular site of its receptor facing the interstitial fluid. Thus, changes in interstitial fluid microenvironments, specially pH, affect the insulin-binding affinity to its receptor. The most well-known clinical condition regarding pH is systemic acidosis (arterial blood pH\u2009&amp;lt;\u20097.35) frequently observed in severe T2DM associated with insulin resistance. Because the insulin-binding site of its receptor faces the interstitial fluid, we should recognize the interstitial fluid pH value, one of the most important factors influencing the insulin-binding affinity. It is notable that the interstitial fluid pH is unstable compared with the arterial blood pH even under conditions that the arterial blood pH stays within the normal range, 7.35\u20137.45. This review article introduces molecular mechanisms on unstable interstitial fluid pH value influencing the insulin action via changes in insulin-binding affinity and ameliorating actions of weak organic acids on insulin resistance via their characteristics as bases after absorption into the body even with sour taste at the tongue.<\/jats:p>","DOI":"10.1042\/bst20200667","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T13:14:18Z","timestamp":1616764458000},"page":"715-726","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Roles of interstitial fluid pH and weak organic acids in development and amelioration of insulin resistance"],"prefix":"10.1042","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3846-0937","authenticated-orcid":false,"given":"Yoshinori","family":"Marunaka","sequence":"first","affiliation":[{"name":"Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto 604-8472, Japan"},{"name":"Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto 602-8566, Japan"},{"name":"Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu 525-8577, Japan"},{"name":"International Research Center for Food Nutrition and Safety, College of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"2021111916100159100_BST-2020-0667CC1","volume-title":"StatPearls","year":"2020"},{"key":"2021111916100159100_BST-2020-0667CC2","doi-asserted-by":"publisher","first-page":"596197","DOI":"10.3389\/fonc.2020.596197","article-title":"Metabolic constants and plasticity of cancer cells in a limiting glucose and glutamine microenvironment-A pyruvate perspective","volume":"10","year":"2020","journal-title":"Front. 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