Food intake targeting and improving acidity in diabetes and cancer

Energy (ATP) is essentially required to keep activity of our body, for example, the brain consumes a lot of ATP required for the Na+,K+-ATPase (pump) to maintain the low intracellular Na+ concentration essentially important for generation of the action potential for keeping neuronal activity. Under the normal condition, protons (H+) are produced as by-products of ATP generation. Various types of proton-excluding transporters exclude the produced protons to the interstitial fluid to keep the normal intracellular pH (Figure 1). The excluded protons move into the blood vessel via the interstitial space (Figure 1). Under the normal condition, the pH of arterial blood and interstitial fluid is not changed mainly via excretion of the produced protons into urine and partly via the lung as CO2 (Figure 1). Even if protons are transported into blood vessels, the pH of arterial blood is strictly controlled within the range of 7.35–7.45 by strong pH buffering factors such as hemoglobin (Hb) and albumin (Figure 2) (Aoi, Zou, Xiao, & Marunaka, 2020; Marunaka, 2018). In contrast, the interstitial fluid has only relatively weak pH buffers such bicarbonate and phosphate (Figure 2), therefore the interstitial fluid pH is variable depending on the metabolic condition (i.e., the amounts of produced protons) (Figure 2). Compared with normal conditions, much more protons are produced via glycolysis in cancer (Warburg effect) and diabetes (Figure 3A) (Bhattacharya, Omar, Feroz, & Soong, 2016; Chen, Liu, Li, & Chen, 2018; Gillies, Pilot, Marunaka, & Fais, 2019; Liberti & Locasale, 2016; Lu, 2019; Pillai et al., 2019; Potter, Newport, & Morten, 2016). The large amount of produced protons are excluded to the interstitial fluid to keep the normal intracellular pH by highly expressed acid transporters such as monocarboxylate transporter, H+-ATPase (pump), and Na+/H+ exchanger (Figure 1): most parts of the protons move into blood vessels, but some parts of the protons remain in the interstitial fluid (Figure 3A). Even in the case that a large amount of protons move into blood vessels, the pH of arterial blood is strictly controlled within the range of 7.35–7.45 by strong pH buffering factors such as hemoglobin (Hb) and albumin (Figure 2) (Aoi et al., 2020; Marunaka, 2018). 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. However, if the interstitial fluid would have strong pH buffers such as Hb and albumin, the collection of the metabolites produced in metabolic tissues into the capillary blood vessels driven by oncotic osmotic pressures does not function, resulting in death. This means that the absence of strong pH buffers in the interstitial fluid are essential events for maintenance of our life. Thus, occurrence of the local acidity around cells in diabetes and cancer is not avoided in usual cases. As mentioned above, cancer cells with no mitochondrial function express highly acid-excluding transporters, causing extremely high acidity in the interstitial fluid (Figure 3) (Gillies et al., 2019; Pillai et al., 2019; Puppulin et al., 2018). In contrast, normal cells express much less acid-excluding transporters compared with cancer cells (Gillies et al., 2019; Pillai et al., 2019): this means that normal cells has much weak ability defensing acidic environments, resulting in being easily destroyed by acidic environments. Thus, cancer cells destroy normal cells by acidifying the extracellular environments around normal cells, then produce the growing-up space for cancer cells themselves. The acidity would also diminish the activity and expression of cell adhesion factor, enabling for cancer cells to detach themselves from the primary lesion and cause metastases (Gillies et al., 2019; Pillai et al., 2019; Sumarokova et al., 2018). Some foods, so-called "alkalizing foods," have strong ability to elevate the lowered pH of body fluids observed in cancer and diabetes. The word of "alkalizing foods" is very popularly disseminated; however, the alkalizing mechanism is not so well understood. Representative "alkalizing foods" are weak organic acids containing carboxyl groups (the lower part of Figure 3B) (Aoi et al., 2020; Marunaka, 2018). Weak organic acids containing carboxyl groups are really acids at the oral intake (the lower part of Figure 3B), however only the carboxyl group but not the proton (H+) is absorbed via the intestine and the colon (the lower part of Figure 3B). The absorbed part of carboxyl group is an important factor chelating protons (H+) produced inside of the body (the upper part of Figure 3B). Acidity of the interstitial fluid around cells observed in diabetes (Aoi et al., 2013; Hosogi et al., 2018; Marunaka, Yoshimoto, Aoi, Hosogi, & Ikegaya, 2014) produces insulin resistance (Hayata, Miyazaki, Niisato, Yokoyama, & Marunaka, 2014). The improvement of acidity of the interstitial fluid (elevation of pH) increases insulin sensitivity (improvement of insulin resistance) (Aoi et al., 2013; Hosogi et al., 2018). Thus, the intake of alkalizing foods would elevate the lowed interstitial fluid pH in diabetes and cancer, resulting in improvement of insulin resistance and prevention of cancer cell growth and metastasis (Aoi et al., 2020; Marunaka, 2018). This work was supported by a grant-in-aid from Japan Society of the Promotion of Science (18H03182 to Y.M.).