Roles of interstitial fluid pH in diabetes mellitus: Glycolysis and mitochondrial function

Figure 2 Production of H⁺, and H⁺ transporting systems in peripheral tissues (A) and the lung (B). A: In cells of peripheral tissues, H⁺ is produced from organic acids generated as metabolites via glycolysis such as lactic acid. H⁺ is directly extruded via Na⁺/H⁺ exchanger (NHE), H⁺-ATPase and H⁺-coupled monocarboxylate (MC) transporter (MCT) from intracellular to extracellular (interstitial) spaces, and moves into blood, and binds to albumin. Further, a part of H⁺ produced from metabolites is converted to CO₂ and H₂O consuming HCO₃^-via carbonic anhydrase (CA)-mediated facilitation process. To supply HCO₃^- consumed for conversion of H⁺ to CO₂ and H₂O in cells, Na⁺-driven Cl^-/HCO₃^- exchanger (NDCBE) and Na⁺-HCO₃^- cotransporter (NBC) participate in uptake of HCO₃^- into intracellular from extracellular (interstitial) spaces. CO₂ moves into red blood cell (RBC, erythrocyte) in blood via permeation across the plasma membrane of RBC due to high CO₂ permeability of the plasma membrane, and is converted to H⁺ and HCO₃^- consuming H₂O via CA-mediated facilitation process. H⁺ produced from CO₂ and H₂O via CA-mediated facilitation process in RBC binds to hemoglobin. HCO₃^- produced from CO₂ and H₂O via CA-mediated facilitation process in RBC is extruded from intracellular to extracellular (interstitial) spaces via exchange of Cl^- existing in the extracellular space by anion exchanger (AE): this exchanging step of HCO₃^- extrusion and Cl^- uptake is so called as Cl^- shift; B: In the lung, the reversible process occurs due to low CO₂ circumstances.