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Functional Improvement in -Islet Cells and Hepatocytes with Decreasing Deuterium from Low Carbohydrate Intake in a Type-II Diabetic
Abstract
A 59-year-old patient with a 18-year history of type-II diabetes is presented who showed dramatic improvements to glucose tolerance tests and increased fasting hepatic glucose production with systemic deuterium depletion. Deuterium, which is well known to decrease the efficiency of the ATP syntheses nanomotors, is likely the mechanism leading to the systemic changes to both insulin and hepatic glucose production in the pancreas and liver, respectively. Systemic deuterium depletion occurs with consumption of low carbohydrate (keto) diets and deuterium depleted water.
... More recently, the rates of remission from deuterium depletion have been studied in the lung [19], rare childhood [20], renal cell [21], and colorectal [22] cancers. Furthermore, the effect of deuterium levels on depression [23], diabetes mellitus [24,25], and heart rate [3] has also been studied. Deuterium is also known to stabilize viral proteins and RNA to enhance their thermostability [26]. ...
... These exercise heart rates were obtained from volunteer 1's hiking and climbing log books. The dates where type II diabetes was diagnosed, the keto cycling diet was initiated, c-peptide improvement occurred, and 66 DDW was added to the diet are indicated [25]. Again, prior to age 53, the predominant energy source was carbohydrates (CHO), and after age 53, the predominant source was changed to fats via the keto cycling diet. ...
... Deuterium has been linked to many medical disorders, including lung [19], rare childhood [20], renal cell [21], colorectal cancers [22], depression [23], diabetes mellitus [24,25], and heart failure [3]. This is due to deuterium slowing the rate of ATP production, shifting the cellular energy production towards the acidic, anaerobic glycolysis pathway. ...
Heart failure results from the loss of structural integrity of the heart and/or a decrease in the rate of maximal ATP production. In cases of relatively preserved structural integrity, a decrease in ATP production in the mitochondria leads to a decrease in the cardiac stroke volume, thereby increasing the heart rate required to maintain the cardiac output. For many years, the exact location of this defect in the metabolic energy cycle remained elusive. Evidence is presented here to show that it is not a single metabolic substrate involved but rather the heavy isotope of hydrogen 2H, deuterium, that is jamming the ATP nanomotors slowing the rate of ATP production. During the digestion of a meal, the cardiac heart rate is shown to be very sensitive to the level of deuterium contained in the fatty acids recently consumed. During strenuous exercise in the fasting state, the enzyme adipose triglyceride lipase (ATGL) is found to mobilize the highest deuterium triglycerides more rapidly than the healthier lower deuterium triglycerides, converting the adipose tissue into a deuterium-depleted energy pool. This is believed to contribute to the low resting heart rates frequently observed in athletes. In vulnerable individuals, i.e., those weakened by disease(s) or space explorers in a weightless environment, the decreased ability to perform strenuous exercise leads to higher deuterium levels in their adipose tissue compromising their ATP production. In these individuals, maintaining healthy deuterium levels is best achieved by an increased intake of lower deuterium-containing foods.
... 6 More recently, the metabolic effects of deuterium depletion have been studied in lung 7 , rare childhood 8 , renal cell 9 , colorectal cancers 10 and diabetes mellitus. [11][12] In this report, the effect of deuteration on cardiac heart rate is presented. It will be shown that deuterium depletion via a keto diet significantly decreased both the resting and exercise heart rates in a volunteer. ...
... In a recent study into the effect of deuterium depletion by a low carbohydrate intake and deuterium depleted water, a significant decrease in resting heart rate was observed with decreasing systemic deuterium. 12 The resting heart rate was found to drop by 20 bpm with a keto cycling diet with an additional 4 bpm drop after the initiation of deuterium depleted water intake four years later. This patient later volunteered as the first of six volunteers to look into the effect of various foods on the resting and exercise heart rates. ...
... [1][2][3] As a result, six volunteers agreed to make in-home recordings of their resting heart rates just before rising from bed to be compared to the dinner eaten the prior evening. Volunteer 1, a scientist, is the volunteer already discussed above and a 60-year-old male athletic individual who has had type-II diabetes mellitus since the age of 41. 12 Volunteer 2 is a 55yo female electrophysiologist technician who has had a history of Systemic Lupus Erythematosus (SLE) for 30 years. Volunteer 3, an engineer, was a 70yo less athletic male but very healthy with no underlying medical conditions. ...
Mitochondrial cardiac ATP production efficiency in beef hearts has been known to decrease with increasing systemic deuterium 2H levels since the 1980’s. Recently ketogenic diets which are known to decrease deuterium levels in humans were found to decrease both the resting and exercise heart rates in a volunteer. Furthermore, resting heart rates were found to systematically vary with the deuterium content from the previous meal consumed by six volunteers. A cardiac model is proposed showing extreme sensitivity of heart rate on the deuterium loading of the ATP synthase nanomotors. A predicted increase in heart rate by 28% is expected with a 5% decrease in ATP production. This finding strongly suggests that high deuterium levels in the fatty acids contribute to the diastolic dysfunction in heart failure not already attributed to direct structural damage, i.e., heart failure with preserved ejection fraction.
... The case presented here shows a correlation between the aortic ejection velocity and the aortic pressure gradients with the deuterium level in the food consumed prior to each procedure. The echocardiograms were obtained from a very athletic man who hikes between 800 and 1200 km yearly [9][10]. This man does have well controlled type-II diabetes and also maintains detailed food logs which made this case possible [9]. ...
... It is also recommended to avoid highly processed foods since these often have high deuterium levels [8]. Deuterium depleted water is also helpful but still remains relatively expensive [10]. ...
The deuterium concentration in the fattyacids of food consumed was recently shownto impact the maximal rate of ATP production effecting the resting heart rates in six volunteers. One of these volunteers had three echocardiocardiograms to evaluate an intermittent systolic ejection murmur that first appeared after adopting a ketogenic diet and this murmur became more pronounced following a low deuterium cold water sea food diet. The echocardiograms revealed that the aortic ejectionvelocity and aortic pressuregradients systematically increasewith decreasing deuteriumlevels in the diet. These findings reveal that the meals consumed do have a significant impact on the parameters determined from echocardiography likely due to changes in the ventricular contractility. The aorticpressure gradients extrapolate to zero as the deuterium content approaches 155.9 ppm.
An emerging hallmark of cancer is metabolic reprogramming, which presents opportunities for cancer diagnosis and treatment based on metabolism. We performed a comprehensive metabolic network analysis of major renal cell carcinoma (RCC) subtypes including clear cell, papillary and chromophobe by integrating transcriptomic data with the human genome-scale metabolic model to understand the coordination of metabolic pathways in cancer cells. We identified metabolic alterations of each subtype with respect to tumor-adjacent normal samples and compared them to understand the differences between subtypes. We found that genes of amino acid metabolism and redox homeostasis are significantly altered in RCC subtypes. Chromophobe showed metabolic divergence compared to other subtypes with upregulation of genes involved in glutamine anaplerosis and aspartate biosynthesis. A difference in transcriptional regulation involving HIF1A is observed between subtypes. We identified E2F1 and FOXM1 as other major transcriptional activators of metabolic genes in RCC. Further, the co-expression pattern of metabolic genes in each patient showed the variations in metabolism within RCC subtypes. We also found that co-expression modules of each subtype have tumor stage-specific behavior, which may have clinical implications.
The effects of deuterium depletion on the human organism have been, except for the antitumor action, seldom investigated by now and the available data are scarce. In oncological patients who also suffered from diabetes and were treated with deuterium-depleted water (DDW), an improvement of glucose metabolism was observed, and rat studies also proved the efficacy of DDW to reduce blood sugar level. In the present work, 30 volunteers with pre- or manifest diabetes were enrolled to a clinical study. The patients received 1.5 L of water with reduced deuterium content (104 ppm instead of 145 ppm, equivalent 12 mmol/L in human) daily for 90 days. The effects on fasting glucose and insulin level, on peripheral glucose disposal, and other metabolic parameters were investigated. Fasting insulin and glucose decreased, and insulin reaction on glucose load improved, in 15 subjects, while in the other 15 the changes were opposite. Peripheral glucose disposal was improved in 11 of the subjects. In the majority of the subjects, substantial increase of serum high-density lipoprotein (HDL) cholesterol and significant decrease of serum Na⁺ concentration were also seen—the latter possibly due to activation of a Na⁺/H⁺ antiporter by the decreased intracellular deuterium level. The results support the possible beneficial role of DDW in disorders of glucose metabolism but leave questions open, requiring further studies.
Accumulating evidence suggests that metabolic reprogramming has a critical role in carcinogenesis and tumor progression. The usefulness of formalin-fixed paraffin-embedded (FFPE) tissue material for metabolomics analysis as compared with fresh frozen tissue material remains unclear. LC/MS-MS–based metabolomics analysis was performed on 11 pairs of matched tumor and normal tissues in both FFPE and fresh frozen tissue materials from patients with colorectal carcinoma. Permutation t test was applied to identify metabolites with differential abundance between tumor and normal tissues. A total of 200 metabolites were detected in the FFPE samples and 536 in the fresh frozen samples. The preservation of metabolites in FFPE samples was diverse according to classes and chemical characteristics, ranging from 78% (energy) to 0% (peptides). Compared with the normal tissues, 34 (17%) and 174 (32%) metabolites were either accumulated or depleted in the tumor tissues derived from FFPE and fresh frozen samples, respectively. Among them, 15 metabolites were common in both FFPE and fresh frozen samples. Notably, branched chain amino acids were highly accumulated in tumor tissues. Using KEGG pathway analyses, glyoxylate and dicarboxylate metabolism, arginine and proline, glycerophospholipid, and glycine, serine, and threonine metabolism pathways distinguishing tumor from normal tissues were found in both FFPE and fresh frozen samples. This study demonstrates that informative data of metabolic profiles can be retrieved from FFPE tissue materials.
Implications
Our findings suggest potential value of metabolic profiling using FFPE tumor tissues and may help to shape future translational studies through developing treatment strategies targeting metabolites.
In this study, we present the potential application of deuterium-depleted water (DDW) for the prevention and adjuvant treatment of obesity in rats. We tested the hypothesis that DDW can alleviate diet-induced obesity (DIO) and its associated metabolic impairments. Rats fed a high-fat diet had an increased body weight index (BWI), glucose concentration, and level of certain proinflammatory cytokines; decreased levels of insulin in the serum; decreased tryptophan and serotonin in the brain, and a decreased concentration of some heavy metals in the liver. Drinking DDW at a concentration of 10 ppm deuterium/protium (D/H) ad libitum for 3 weeks restored the BWI, glucose (serum), tryptophan (brain), and serotonin (brain) levels and concentration of Zn in the liver in the DIO animals to those of the controls. The levels of proinflammatory cytokines (IL-1β, IL-6, IFNγ) and anti-inflammatory TNFα were decreased in DIO rats, while anti-inflammatory cytokine (IL-4, IL-10) levels remained at the control levels, which is indicative of a pathophysiological syndrome. In contrast, in groups of rats treated with DDW, a significant increase in anti-inflammatory (IL-4, IL-10) and proinflammatory cytokines (IFNγ) was observed. This finding indicates a reduction in systemic inflammation in obese animals treated with DDW. Similarly, the high-fat diet caused an increased level of oxidative stress products, which was accompanied by decreased activity of both superoxide dismutase and catalase, whereas the administration of DDW decreased the level of oxidative stress and enhanced antioxidant enzyme activities.
We present a novel approach to a personalized therapeutic concept for solid tumors. We illustrate this on a rare childhood tumor for which only a generalized treatment concept exists using carbonic anhydrase IX and aquaporin 1 inhibitors. The use of microcalorimetry as a refined in vitro method for evaluation of drug susceptibility in organotypic slice culture has not previously been established. Rapid microcalorimetric drug response assessment can refine a general treatment concept when it is applied in cases in which tumors do not respond to conventional chemo-radiation treatment. For solid tumors, which do not respond to classical treatment, and especially for rare tumors without an established protocol rapid microcalorimetric drug response testing presents an elegant novel approach to test alternative therapeutic approaches. While improved treatment concepts have led to improved outcome over the past decades, the prognosis of high risk disease is still poor and rethinking of clinical trial design is necessary. A small patient population combined with the necessity to assess experimental therapies for rare solid tumors rather at the time of diagnosis than in relapsed or refractory patients provides great challenges. The possibility to rapidly compare established protocols with innovative therapeutics presents an elegant novel approach to refine and personalize treatment.
A case report is presented in which a type-II diabetic patient significantly improved his dysfunctional β -islet cells using a combination of a strenuous exercise program, cyclical ketogenic diet, and oral GABA/probiotic supplementation. The patient was diagnosed with type-II diabetes at the age of 41 which then progressed through a typical series of treatment changes over 14 years. Treatment periods consisted of metformin therapy alone for 4 years followed by a metformin/glyburide combination therapy for 6 years, and eventually an insulin/metformin combination therapy for 4 years. One year after the initiation of insulin, the patient increased the level of strenuous physical activity (hiking and weight lifting) and adopted a ketogenic diet. Oral GABA and probiotic supplementation were also initiated at the age of 52.7. By the age of 55, the patient no longer required any insulin and is currently being managed with metformin alone. C-peptide values indicate a functional improvement of the β -islet cells during the time of insulin/GABA/probiotic treatment.
Currently, the only widely available metabolic imaging technique in the clinic is positron emission tomography (PET) detection of the radioactive glucose analog 2-¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸FDG). However, ¹⁸FDG-PET does not inform on metabolism downstream of glucose uptake and often provides ambiguous results in organs with intrinsic high glucose uptake, such as the brain. Deuterium metabolic imaging (DMI) is a novel, noninvasive approach that combines deuterium magnetic resonance spectroscopic imaging with oral intake or intravenous infusion of nonradioactive ²H-labeled substrates to generate three-dimensional metabolic maps. DMI can reveal glucose metabolism beyond mere uptake and can be used with other ²H-labeled substrates as well. We demonstrate DMI by mapping metabolism in the brain and liver of animal models and human subjects using [6,6′-²H2]glucose or [²H3]acetate. In a rat glioma model, DMI revealed pronounced metabolic differences between normal brain and tumor tissue, with high-contrast metabolic maps depicting the Warburg effect. We observed similar metabolic patterns and image contrast in two patients with a high-grade brain tumor after oral intake of ²H-labeled glucose. Further, DMI used in rat and human livers showed [6,6′-²H2]glucose stored as labeled glycogen. DMI is a versatile, robust, and easy-to-implement technique that requires minimal modifications to existing clinical magnetic resonance imaging scanners. DMI has great potential to become a widespread method for metabolic imaging in both (pre)clinical research and the clinic.
The paper presents the results of the study on the influence of water with a reduced deuterium content and the meat semi-prepared foods produced with its addition on the indicators of the laboratory animals with the model of alloxan diabetes. The effect of low concentrations of deuterium on the body weight dynamics was shown as well as the manifestation of glucosuria and ketonuria, and clinico-biological indicators of the animal's blood. The experiment was carried out during 42 days on male rats of Wistar stock, which were divided into 4 groups - 2 experimental, control (n=10) and intact (n=6), and consisted of three stages: adaptational, the stage of modeling of alloxan diabetes (a single intraperitoneal injection of alloxan monohydrate - 12 mg/100 g body weight) and dietic therapeutic. The animals of the experimental groups consumed water with a reduced deuterium content and standard vivarium diet or the meat minced semi-prepared products produced with its addition and cooked to culinary readiness. The control group consumed tap water and standard vivarium diet. In animals of the 1st group, which consumed the meat product, glucosuria persisted up to the 28th day (the 11th day after administration of alloxan), ketonuria up to the34th day (the 17th day after modeling). In rats of the 2nd group, which consumed water with the decreased deuterium content, glucose in urea was not detected already on the 7th day after administration of alloxan, ketones on the 17th day after modeling of the disease, respectively. In animals of the control group, glucosuria and ketonuria persisted up to the end of the experiment. As a result of the investigations, the positive effect of water with a reduced deuterium content and the meat food produced with its use was established. It was manifested in a decrease of glucose level in the urea of the animals from the experimental groups compared to the control group on the 5th day of disease modeling and normalization on the 17th day of modeling. This experimentally demonstrated the possibility to use deuterium-depleted water in a meat product composition intended for nutrition of people with an impairment of carbohydrate metabolism for correction of metabolic processes.
Lung cancer causes more deaths in men and women than any other cancer related disease. Currently, few effective strategies exist to predict how patients will respond to treatment. We evaluated the serum metabolomic profiles of 25 lung cancer patients undergoing chemotherapy ± radiation to evaluate the feasibility of metabolites as temporal biomarkers of clinical outcomes. Serial serum specimens collected prospectively from lung cancer patients were analyzed using both nuclear magnetic resonance (¹H-NMR) spectroscopy and gas chromatography mass spectrometry (GC–MS). Multivariate statistical analysis consisted of unsupervised principal component analysis or orthogonal partial least squares discriminant analysis with significance assessed using a cross-validated ANOVA. The metabolite profiles were reflective of the temporal distinction between patient samples before during and after receiving therapy (¹H-NMR, p < 0.001: and GC–MS p < 0.01). Disease progression and survival were strongly correlative with the GC–MS metabolite data whereas stage and cancer type were associated with ¹H-NMR data. Metabolites such as hydroxylamine, tridecan-1-ol, octadecan-1-ol, were indicative of survival (GC–MS p < 0.05) and metabolites such as tagatose, hydroxylamine, glucopyranose, and threonine that were reflective of progression (GC–MS p < 0.05). Metabolite profiles have the potential to act as prognostic markers of clinical outcomes for lung cancer patients. Serial ¹H-NMR measurements appear to detect metabolites diagnostic of tumor pathology, while GC–MS provided data better related to prognostic clinical outcomes, possibility due to physiochemical bias related to specific biochemical pathways. These results warrant further study in a larger cohort and with various treatment options.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-016-0961-5) contains supplementary material, which is available to authorized users.
The naturally occurring isotope of hydrogen (1H), deuterium (2H), could have an important biological role. Deuterium depleted water delays tumor progression in mice, dogs, cats and humans. Hydratase enzymes of the tricarboxylic acid (TCA) cycle control cell growth and deplete deuterium from redox cofactors, fatty acids and DNA, which undergo hydride ion and hydrogen atom transfer reactions. A model is proposed that emphasizes the terminal complex of mitochondrial electron transport chain reducing molecular oxygen to deuterium depleted water (DDW); this affects gluconeogenesis as well as fatty acid oxidation. In the former, the DDW is thought to diminish the deuteration of sugar-phosphates in the DNA backbone, helping to preserve stability of hydrogen bond networks, possibly protecting against aneuploidy and resisting strand breaks, occurring upon exposure to radiation and certain anticancer chemotherapeutics. DDW is proposed here to link cancer prevention and treatment using natural ketogenic diets, low deuterium drinking water, as well as DDW production as the mitochondrial downstream mechanism of targeted anti-cancer drugs such as Avastin and Glivec. The role of 2H in biology is a potential missing link to the elusive cancer puzzle seemingly correlated with cancer epidemiology in western populations as a result of excessive 2H loading from processed carbohydrate intake in place of natural fat consumption.
DOI: 10.1016/j.mehy.2015.11.016
http://www.sciencedirect.com/science/article/pii/S0306987715004399
Short Title: Deuterium Oncoisotope Disequilibrium Theory of Cancer - Oncoisotope Depletion as an Adjuvant Treatment in Cancer
Background: Deuterium, a stable isotope of hydrogen, binds to oxygen to form D2O. D2O exist in the environment at 1/6700 of H2O (150 ppm) and is expected to have some biological effects. Several lines of evidences suggest that D2O inhibits insulin release from pancreatic islets. Very little or no data is available on the action of lowering D2O content of the cellular environment. Some experimental and clinical observations suggest that depletion of D2O has anti-mitotic effect in various tumor cells. Some clinical observations also suggest that depletion D2O has anti-mitotic effect in various tumor cells. Some clinical observation also suggest that depletion D2O interfere with glucose metabolism diabetic patients.
Objective: In our experiments we wanted to test the effect of removal of D2O on the glucose metabolism in sreptozotocin (STZ)-induced diabetic rat model.
Methods: Diabetes was induced by a single ip. injection of 60mg/kg body weight of STZ. After 2 weeks, animals were randomly distributed into several groups to test the effect of D2O (25-150 ppm) on glucose metabolism in diabetic animals with or without 2x1 U/day insulin treatment. The following parameters were tested: serum glucose, -fructose amine, -HbAIC, -creatinine, -TBARS and -insulin; urine glucose, -creatinine and -protein. At the end of the experiments, 8 weeks of treatment, membrane associated GLUT-4 content was estimated by western-blot technique from m. soleus.
Results: Our results indicate that STZ treatment significantly increased serum glucose, fructose amine, HbAIC and TBARS concentration. Depletion of D2O did not influence any of the measured parameters in animals not received insulin. However the measured parameters were significantly lower in those animals received lower D2O containing drinking water and insulin treatment. The membrane associated GLUT-4 was significantly higher in these animals also.
Conclusion: These data suggest that D2O depletion enhance insulin effect on GLUT-4 translocation and potentiate glucose uptake in diabetic animals. The major characteristic feature of metabolic syndrome is the decreased insulin sensitivity. Insulin resistance/hyper-insulinemia is strongly associated with hyperlipidemia and hypertension, two major risk factors of coronary heart disease. Based on our experimental data, deuterium depleted water could be used to treat patients with MS by increasing the insulin sensitivity. The mode of action of D2O depletion is not fully understood and needs further experiments to elucidate this question.
Sleep restriction results in decreased insulin sensitivity and glucose tolerance in healthy subjects. We hypothesized that sleep duration is also a determinant of insulin sensitivity in patients with type 1 diabetes.
We studied seven patients (three men, four women) with type 1 diabetes: mean age 44 +/- 7 years, BMI 23.5 +/- 0.9 kg/m(2), and A1C 7.6 +/- 0.3%. They were studied once after a night of normal sleep duration and once after a night of only 4 h of sleep. Sleep characteristics were assessed by polysomnography. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies with an infusion of [6,6-(2)H(2)]glucose. RESULTS Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (469 +/- 8.5 vs. 222 +/- 7.1 min, P = 0.02). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids (NEFAs), or endogenous glucose production. Endogenous glucose production during the hyperinsulinemic clamp was not altered during the night of sleep restriction compared with the night of unrestricted sleep (6.2 +/- 0.8 vs. 6.9 +/- 0.6 micromol x kg lean body mass(-1) x min(-1), NS). In contrast, sleep restriction decreased the glucose disposal rate during the clamp (25.5 +/- 2.6 vs. 22.0 +/- 2.1 micromol x kg lean body mass(-1) x min(-1), P = 0.04), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by approximately 21% (P = 0.04). Sleep restriction did not alter plasma NEFA levels during the clamp (143 +/- 29 vs. 133 +/- 29 micromol/l, NS).
Partial sleep deprivation during a single night induces peripheral insulin resistance in these seven patients with type 1 diabetes. Therefore, sleep duration is a determinant of insulin sensitivity in patients with type 1 diabetes.
A systematic study was done examining the steady state kinetics of F1-catalyzed nucleotide hydrolysis in the presence of various activating divalent metal cations. Values of Km and kcat were obtained from Lineweaver-Burk plots, and kcat/Km values were calculated. With some exceptions, kcat/Km was shown to be independent of the metal present for F1-catalyzed ATP hydrolysis, independent of the nucleotide hydrolyzed with magnesium as the metal cation present, and independent of temperature with most activating metal cations. An average value for kcat/Km of 2.62 X 10(5) M-1 S-1 is calculated as the lower limit to the second order rate constant for binding substrate to enzyme. Changes in steady state kinetic parameters with temperature were also studied. The Ki value for ADP inhibition of F1-catalyzed ATP hydrolysis with magnesium as divalent cation present was found to be temperature-independent. Plots of log kcat versus 1/T showed either abrupt breaks or straight line dependencies depending on the metal ion present. These results may indicate that different rate-limiting steps in the reaction sequence can be operative at different temperatures depending on the divalent cation present.
The role of tyrosine in the catalytic mechanism of nucleoside triphosphate hydrolysis by beef heart mitochondrial ATPase is explored. We compare the rates of the ATPase reaction by both nitrated and native F1 at both pH 8 and pH 6. The pH-activity profile of nitrated F1 is compared to the pH-activity profile of the unmodified enzyme. These data indicate that the phenolic group of an active-site tyrosine must be protonated during the hydrolysis reaction. Deuterium oxide is used in the reaction buffer to explore the role of protons in the ATPase reaction. Kinetic constants of the nucleoside triphosphates are obtained at various levels of D2O using both the nitrated and native forms of F1. Several nucleoside diphosphates are used as inhibitors of F1-catalyzed ITP hydrolysis. Dissociation constants of these inhibitors are obtained at both low and high concentrations of D2O for both the nitrated and native F1. We explore the possibility that a tyrosine and an arginine lie in close proximity in the F1 active site by studying the effects of sequential modification of arginine and tyrosine. These results are interpreted in terms of possible ATP hydrolysis mechanisms. Two possible roles for tyrosine in the hydrolysis of nucleoside triphosphates by F1 are suggested.
Assessment of heart rate has been used for millennia as a marker of health. Several studies have indicated that low resting heart rate (RHR) is associated with health and longevity, and conversely, a high resting heart to be associated with disease and adverse events. Longitudinal studies have shown a clear association between increase in heart rate over time and adverse events. RHR is a fundamental clinical characteristic and several trials have assessed the effectiveness of heart rate lowering medication, for instance beta-blockers and selective sinus node inhibition. Advances in technology have provided new insights into genetic factors related to RHR as well as insights into whether elevated RHR is a risk factor or risk marker. Recent animal research has suggested that heart rate lowering with sinus node inhibition is associated with increased lifespan. Furthermore, genome-wide association studies in the general population using Mendelian randomization have demonstrated a causal link between heart rate at rest and longevity. Furthermore, the development in personal digital devices such as mobile phones, fitness trackers and eHealth applications has made heart rate information and knowledge in this field as important as ever for the public as well as the clinicians. It should therefore be expected that clinicians and health care providers will be met by relevant questions and need of advice regarding heart rate information from patients and the public. The present review provides an overview of the current knowledge in the field of heart rate and health.
Recent reports identified activation of the GABA signaling pathway as a means to induce transdifferentiation of pancreatic α cells into β cells. These reports followed several previous studies that found that α cells were particularly well suited to conversion into β cells in mice, but only after nearly complete β cell loss or forced overexpression of key transcriptional regulators. The possibility of increasing β cell number via reprograming of α cells with a small molecule is enticing, as this could be a potential new pharmacologic therapy for diabetes. Here, we employed rigorous genetic lineage tracing of α cells, using Glucagon-CreERT2;Rosa-LSL-eYFP mice, to evaluate if activation of GABA signaling caused α-to-β cell reprogramming. In contrast to previous reports, we found that even after long-term treatment of mice with artesunate or GABA, neither α-to-β cell transdifferentiation nor insulin secretion were stimulated, putting into question whether these agents represent a viable path to a novel diabetes therapy.
https://academic.oup.com/neuro-oncology/article/3057929/What-to-eat-or-what-not-to-eat-that-is-still-the
Magyarul (in Hungarian):
https://drive.google.com/open?id=0B_IX9UXcs7UYcG5iM3FwcEhBeTQ
Free PubMed copy - United States National Library of Medicine (NLM):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464377/
At ~1 deuterium/6600 protons natural abundance the ATP synthase protein nanomotor may break down in every few seconds without effective deuterium depleting biochemical processes through glycolysis and the TCA cycle. This talk explains how deuterons damage mitochondrial ATP synthase nano-mechanics by severely compromising proton on-off loading onto the Asp61 C-protein residue of the FO rapidly (9000/min) rotating nano-motor subunit. This is based on the ~1500 proton/second transfer velocity of the rotating protein. Alike, there are deuterium-induced isotope effects caused by its low dissociation constant from asparagine and its high mass to co-regulate the TCA cycle by malate dehydrogenase during oxaloacetate formation. This is because in malate dehydrogenase there are also Asp168 and several arginine residues that participate in proton binding, stabilization and transfer reactions. The inherent complexities of glycolysis and the TCA cycle is explained by their primary role in deuterium depletion, as well as multiple exchanges with metabolic water in the cytoplasm coming from the mitochondrial matrix. In simple terms glycolysis acts as a metabolic “dryer” to rip off all extracellular and extramitochondrial deuterium and hydrogen atoms from glucose, while the TCA cycle acts as a metabolic “washer” by adding hydrogen atoms back from low deuterium metabolic matrix water to specific carbons to be oxidized in the TCA cycle. Therefore, natural ketogenic substrate oxidation via deuterium depleted matrix water production becomes a critical resource for mitochondrial health. On the other hand, the Warburg effect and serine oxidation with glycine cleavage (SOGC) are deuterium loading alternative energy producing pathways and are the result of excessive deuteronation of the mitochondrial matrix and intermembrane space. In conclusion, excessive deuterium loading is involved in isotopic breakdowns of ATP synthase, malate dehydrogenase and thus TCA cycle nanomechanics, which require mitochondrial repairs with important adaptive changes in cellular metabolism. These may produce the Warburg effect for lactate efflux due to insufficient pyruvic acid oxidation, even in the presence of oxygen at intolerable deuterium levels in diseased mammalian cells. The talk offers mechanisms how deuterium becomes an oncoisotope and how global warming, for example, may be a contributor to increased cancer incidence worldwide due to limited deuterium fractionation during water cycling in Nature. Talk: https://youtu.be/6P8gqB4zLGQ
The intestinal hormone glucagon-like peptide-1 (GLP-1) has been shown to promote an increase in pancreatic β-cell mass via proliferation of islet cells and differentiation of non-insulin-secreting cells. In this study, we have characterized some of the events that lead to the differentiation of pancreatic ductal cells in response to treatment with human GLP-1. Rat pancreatic ductal (ARIP) cells were cultured in the presence of GLP-1 and analyzed for cell counting, cell cycle distribution, expression of cyclin-dependent-kinase (Cdk) inhibitors, transcription of β-cell-specific genes, loss of ductal-like phenotype and acquisition of β-cell-like gene expression profile. Exposure of ARIP cells to 10 nM GLP-1 induced a significant reduction in the cell replication rate and a significant decrease in the percentage of cells in S phase of the cell cycle. This was associated with an increase in the number of cells in G0-G1 phase and a reduction of cells in G2-M phase. Western blot analysis for the Cdk inhibitors, kinase inhibitor protein 1 (p27 Kip1 ) and Cdk-interacting protein 1 (p21 Cip1 ), demonstrated a significant increase in p27 Kip1 and p21 Cip1 levels within the first 24 h from the beginning of GLP-1 treatment. As cells slowed down their proliferation rate, GLP-1 also induced a time-dependent expression of various β-cell-specific mRNAs. The glucose transporter GLUT-2 was the first of those factors to be expressed (24 h treatment), followed by insulin (44 h) and finally by the enzyme glucokinase (56 h). In addition, immunocytochemistry analysis showed that GLP-1 induced a time-dependent down-regulation of the ductal marker cytokeratin-20 (CK-20) and a time-dependent induction of insulin expression. Finally, GLP-1 promoted a glucose-dependent secretion of insulin, as demonstrated by HPLC and RIA analyses of the cell culture medium. The present study has demonstrated that GLP-1 induces a cell cycle re-distribution with a decrease in cell proliferation rate prior to promoting the differentiation of cells towards an endocrine-like phenotype.
A study was done examining the steady-state kinetics of F1-catalyzed ATP and ITP hydrolyses in the presence or absence of D2O as a function of temperature. The steady-state kinetic parameters kcat and kcat/Km were obtained. For ATP hydrolysis, kcat/Km was independent of temperature in the presence or absence of D2O, while kcat/Km for ITP hydrolysis increased in both cases. The relative magnitudes of change of kcat and kcat/Km in the presence and absence of D2O over the temperature range studied were much different for the cases of ATP and ITP hydrolysis. A normal isotope effect was observed in plots of kcat H2O/kcat D2O versus temperature for ATP hydrolysis, which increased then leveled off as temperature increased. An inverse isotope effect at low temperatures changed to a normal isotope effect and increased dramatically as temperature increased during ITP hydrolysis. The results are discussed in terms of the nature and location of the rate-limiting steps in the reaction mechanisms.
Bio-electrical Impedance Analysis
- D Pieribone
D. Pieribone, "Bio-electrical Impedance
Analysis," TheBody, 1998.
https://www.thebody.com/article/bioelectrical-impedance-analysis.