The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

Abstract

Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH under metabolic disorder conditions becomes lower than the normal level. Insulin resistance is one of the most important key factors in pathogenesis of diabetes mellitus, nevertheless the molecular mechanism of insulin resistance occurrence is still unclear. Our studies indicate that lowered interstitial fluid pH occurs in diabetes mellitus, causing insulin resistance via reduction of the binding affinity of insulin to its receptor. Therefore, the key point for improvement of insulin resistance occurring in diabetes mellitus is development of methods or techniques elevating the lowered interstitial fluid pH. Intake of weak organic acids is found to improve the insulin resistance by elevating the lowered interstitial fluid pH in diabetes mellitus. One of the molecular mechanisms of the pH elevation is that: (1) the carboxyl group (R-COO−) but not H+ composing weak organic acids in foods is absorbed into the body, and (2) the absorbed the carboxyl group (R-COO−) behaves as a pH buffer material, elevating the interstitial fluid pH. On the other hand, high salt intake has been suggested to cause diabetes mellitus; however, the molecular mechanism is unclear. A possible mechanism of high salt intake-caused diabetes mellitus is proposed from a viewpoint of regulation of the interstitial fluid pH: high salt intake lowers the interstitial fluid pH via high production of H+ associated with ATP synthesis required for the Na+,K+-ATPase to extrude the high leveled intracellular Na+ caused by high salt intake. This review article introduces the molecular mechanism causing the lowered interstitial fluid pH and insulin resistance in diabetes mellitus, the improvement of insulin resistance via intake of weak organic acid-containing foods, and a proposal mechanism of high salt intake-caused diabetes mellitus.

Food intake targeting and improving acidity in diabetes and cancer

“…In contrast, the local acidity around cells (interstitial fluids) less than pH of 7.0 (in some case, pH becomes ∼6.2; Puppulin et al., 2018) occurs in cases of cancers and diabetes. The difference of pH control in body fluids depends on the presence of pH buffer factors, since the interstitial fluid has no strong pH buffers such as Hb and albumin (Figure 2) (Aoi et al., 2020; Marunaka, 2018). The absence of strong pH buffers such as Hb and albumin in the interstitial fluid different from blood is a weak point regarding pH control.…”

Body Fluid pH Balance in Metabolic Health and Possible Benefits of Dietary Alkaline Foods

“…Fluid pH in the interstitial space of metabolic tissues is easily reduced due to lower pH-buffering capacity than cytosol and blood circulation (Figures 1 and 2). The production of lactic acid is accelerated by elevating glycolytic metabolism in both myocytes and adipocytes [1] (Figure 1). In hepatocytes, the production of ketone bodies, beta-hydroxybutyric and acetoacetic acids, is accelerated by excess fatty acid metabolism [11,55].…”

“…β-Hydroxybutyric acid (β-hydroxybutyrate − /H + ) is a major ketone body and a metabolite of fatty acid in the liver. β-Hydroxybutyric acid exists in its ionized forms, β-hydroxybutyrate anion (β-hydroxybutyrate − ) and protons, reducing the intracellular fluid pH [1,11,12].…”

“…To maintain the intracellular pH in most living cells at alkaline levels as mentioned above, the acid produced in the intracellular space is extruded into the interstitial fluid (the extracellular fluid) [1,9]. Growing concepts suggest that the acidity of the interstitial fluid is one of the most serious pathogenesis causing various diseases including diabetes mellitus, tumor metastasis, and so on [1,9] (see the detail in Section 4).…”

“…Dietary intervention is a crucial lifestyle change required to maintain the acid-base balance in the body fluid [1][2][3]. Several food factors have potential roles in improvement of the buffering capacity and proton transport systems in the cells of metabolic tissues; thus, these factors may be useful in preventing metabolic dysfunction [1,2,4,5]. This review focuses on the significance of regulation of intracellular and extracellular fluid pH and the possible benefits of dietary foods associated with the prevention of disease development and improving physical fitness level.…”