Deuterium (D), a naturally occurring stable isotope of hydrogen, is present in natural surface waters mainly in the form of HDO at a concentration of approximately 16.8 mmol/L. The two isotopes, hydrogen (1H) and deuterium (2H) have the largest mass difference among stable isotopes of the same element, resulting in significant differences of chemical and physical properties [1–3.].
The effect of D at an elevated concentration in biological systems has been investigated thoroughly [4–5], but these studies ignored the significance of natural D-concentration.
In nature, the deuterium-to-hydrogen ratio (D/H ratio) is about 1:6600; this means that the natural concentration of D is about 150 ppm (0.015 atom %) [2]. A worldwide survey of hydrogen isotopes in precipitation revealed [6–7], that the D content covers a range of 120 ppm and 160 ppm depending mainly on the site of sampling and there are several indications that D/H ratio is not constant in living organisms either [8].
Deuterium in human plasma is abundant with concentrations reaching 12–14 mmol/L, in comparison with the 2.24–2.74 mmol/L concentration of calcium, 0.75–1.2 mmol/L concentration of magnesium, 5.0–5.1 mmol/L value of potassium and 3.3–6.1 mmol/L circulating concentration of glucose.
The impact of reduced D-concentration on living organisms first was published in 1993 [9]. Since then, numerous experimental and clinical observations suggest that deuterium depletion has an anti-mitotic effect in various tumor cells [9–10]. This effect is possibly due to the alteration of H+-ATPase and Na+/H+ antiport system, in part [9]. Other studies have shown that deuterium-depleted water (DDW) induced apoptosis in cancer cells, both in vitro and in vivo [10–12]. The inhibitory effect of DDW on the expression of proto-oncogenes such as c-Myc, Ha-ras and p53 has been also documented [13]. Complete or partial tumor regression has been established in mice xenografts with MDA-MB-231, MCF-7 human breast adenocarcinoma cell lines, and PC-3 human prostate tumor cells. When laboratory animals were exposed to chemical carcinogenesis by 7,12-dimethylbenzanthracene (DMBA), cytoplasmic myelocytomatosis oncogenes, c-Myc, Ha-ras, and p53 were up-regulated, while DDW, applied as drinking water, suppressed the expression of these oncogenes. DDW significantly inhibited proliferation of A549 human lung carcinoma cells in vitro, and H460 lung tumor xenografts in laboratory mice showed a 30% growth regression. The anti-cancer effect of deuterium depletion has already been confirmed in a double-blind, randomized, 4-month-long, phase 2 clinical trial on prostate cancer, and the extended follow-up suggests that DDW delays the progression of the disease [14]. Retrospective clinical studies confirmed the anticancer effect of DDW as the consumption of DDW resulted a severalfold increase in the median survival time (MST) of patients with prostate, breast, lung, and pancreatic cancer [14–17].
At submolecular level, it is shown that all extramitochondrial NADPH synthesis pathways are targeted by DDW. Deuterium-depleted water may be included as non-toxic anticancer treatment modality for prevention and treatment. The terminal complex of mitochondrial electron transport chain (ETC) reducing molecular oxygen to deuterium-depleted metabolic water; this affects gluconeogenesis as well as fatty acid oxidation. NADPH’s deuterium labeling depends on carbon-specific positional glucose deuterium enrichment, as well as deuterium enrichment of the cytoplasmic and mitochondrial water pools within cells. [18, 19].
It’s a very important fact also, that switching from a ketogenic to high-sugar diet interferes with the deuterium-depleting action of mitochondria serving as a potential oncogenic initiator [18].
Several lines of evidences suggest that D2O inhibits insulin release from pancreatic islets by stabilizing the microtubular system of the β-cells or by inhibiting oxidative phosphorylation [20–22]. However, the intracellular H+-concentration has a critical role in glucose-induced time-dependent potentiation of insulin release in pancreatic cells, too [23]. The decrease of the intracellular pH leads to the translocation of glucose transporters (GLUT-4 and GLUT-1) to the sarcoplasma in the canine heart [24]. Based on these findings and the results confirming the key role of naturally occurring D in cell cycle regulation, it was logical to assume that deuterium depletion could interfere with glucose metabolism as well. It was supported with the findings that during the experimental and clinical studies to verify the anticancer effect of deuterium depletion, it was observed that in patients with both cancer and diabetes mellitus (DM), application of DDW lowered the blood sugar level [25, 26].
Ingestion of 1.5 L DDW (104 ppm D) per day for 90 days was mostly beneficial by altering some parameters related to metabolic syndrome in patients with prediabetes or manifest diabetes mellitus. D content of the body had an impact on the physiological regulation in insulin-resistant patients. The fact that DDW simultaneously influenced insulin-, HDL- and glucose levels suggests that the concentration of D within the organism may have an important role in harmonizing metabolic syndrome. In summary, the results support the beneficial role of DDW in disorders of glucose metabolism [25]. A phase 2 clinical study enrolling 30 volunteers with decreased glucose tolerance underwent 90 days long DDW-treatment and physiological parameters characteristic to insulin resistance were evaluated to investigate the impact of DDW on these parameters [26]. Evaluating the serum insulin concentration in the entire cohort relative to the values at 0-minute during the intravenous glucose tolerance test (IVGTT), we found that serum insulin concentration decreased in 15 volunteers and a positive correlation was verified in the decrease of the serum glucose levels. Using the hyperinsulinemic-euglycemic clamp technique, glucose uptake increased in 36% of the subjects (11 patients), suggesting that deuterium depletion may reduce insulin resistance.
This study aimed to evaluate the effect of DDW on the whole-body glucose homeostasis in streptozotocin (STZ)-induced diabetic rat model and elucidate the possible underlying mechanism, as well. Here we show that DDW alone did not alter the glucose uptake of diabetic rats, however, DDW dose-dependently potentiates the effect of insulin administered in suboptimal dose, on glucose homeostasis. This effect, at least in part, may be attributed to the increased GLUT-4 protein translocation from the cytosol to the membrane of skeletal muscle cells.