Roles of interstitial fluid pH and weak organic acids in development and amelioration of insulin resistance

Type 2 diabetes mellitus (T2DM) is one of the most common lifestyle-related diseases (metabolic disorders) due to hyperphagia and/or hypokinesia. Hyperglycemia is the most well-known symptom occurring in T2DM patients. Insulin resistance is also one of the most important symptoms, however, it is still unclear how insulin resistance develops in T2DM. Detailed understanding of the pathogenesis primarily causing insulin resistance is essential for developing new therapies for T2DM. 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 < 7.35) 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, 7.35–7.45. 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.

Why probiotics yogurt is beneficial to HIV/AIDS patients?

AIDS patients often display symptom of diarrhea, an indication of hydrogen bonding mediated by viral proteins with amino acids capable of secondary chemical bonding. With hydrogen bonding to protons, local strong acids such as HCl could build up, giving rise to proton stress which may damage cells or trigger tumorigenesis. Weak organic acids counteract strong acids and attenuate proton stress. The integration of antiviral medicine with probiotics could yield favorable outcomes to AIDS patients and meanwhile reduce cancer incidences.

Is Weak Acid Beneficial for Addressing Checkpoint Inhibitor–Triggered Cancer Hyper Progression in Anti-PD1/PD-L1 Immunotherapies?

Numerous cases of checkpoint inhibitor–triggered cancer hyperprogression have been documented. A previous hypothesis attributes cancer onset to the local buildup of hydrogen chloride, jointly mediated by hydrogen bond donors and acceptors and basic amino acids. The anti-PD1/PD-L1 immunotherapies may have caused a surge of protons or chloride ions for the effective treatment of neoplasm, thus giving rise to the local formation of hydrogen chloride and subsequently cancer hyperprogression in some susceptible individuals. It was postulated that the local strength of acidity is critical for tumor growth and metastasis, as the intake of weak organic acids reduces cancer risks. The anti-PD1/PD-L1 immunotherapies can be integrated with weak organic acids to reduce adverse reactions and generate better anticancer outcomes.

Effect of Organic Acids on the Electrochemical Migration of Tin in Thin Electrolyte Layer

Background and Objective: The effects of representative solder flux residue weak organic acids on electrochemical migration (ECM) of tin in thin electrolyte layer were studied using a technique based on the coupling of in situ electrochemical measurements and optical observations, as well as ex situ characterizations. Methods and Results: The results showed that the increasing amount of weak organic acid decreased the probability of ECM and dendrites formed were mainly composed of metallic tin. Tin ions reacted with organic compound ions from hydrolysis of weak organic acids to form complexes with electronegativity, which retarded the transfer of tin ions. Some complexes can be oxidized to the insoluble tin oxides on the anode surface and blocked the dissolution of anode during tin ECM. Conclusion: The growth rate of tin dendrite was found to be limited by the dissociation of complexes. Mechanisms involved were proposed to explain the role of weak organic acid in the tin ECM.

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

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.