Rate Of Lactate Formation Research Articles

The Influence of Pedaling Frequency on Blood Lactate Accumulation in Cycling Sprints.

Anaerobic performance diagnostics in athletes relies on accurate measurements of blood lactate concentration and the calculation of blood lactate accumulation resulting from glycolytic processes. In this study, we investigated the impact of pedaling frequency on blood lactate accumulation during 10-second maximal isokinetic cycling sprints. Thirteen trained males completed five 10-second maximal isokinetic cycling sprints on a bicycle ergometer at different pedaling frequencies (90 rpm, 110 rpm, 130 rpm, 150 rpm, 170 rpm) with continuous power and frequency measurement. Capillary blood samples were taken pre-exercise and up to 30 minutes post-exercise to determine the maximum blood lactate concentration.Blood lactate accumulation was calculated as the difference between maximal post-exercise and pre-start blood lactate concentration. Repeated measurement ANOVA with Bonferroni-adjusted post hoc t-tests revealed significant progressive increases in maximal blood lactate concentration and accumulation with higher pedaling frequencies (p<0.001; η2+>+0.782).The findings demonstrate a significant influence of pedaling frequency on lactate accumulation, emphasizing its relevance in anaerobic diagnostics. Optimal assessment of maximal lactate formation rate is suggested to require a pedaling frequency of at least 130 rpm or higher, while determining metabolic thresholds using the maximal lactate formation rate may benefit from a slightly lower pedaling frequency.

Lamax: determining the optimal test duration for maximal lactate formation rate during all-out sprint cycle ergometry.

This study aimed to ascertain the optimal test duration to elicit the highest maximal lactate formation rate ( Lamax), whilst exploring the underpinning energetics, and identifying the optimal blood lactate sampling period. Fifteen trained to well-trained males (age 27 ± 6years; peak power: 1134 ± 174W) participated in a randomised cross-over design completing three all-out sprint cycling tests of differing test durations (10, 15, and 30s). Peak and mean power output (W and W.kg-1), oxygen uptake, and blood lactate concentrations were measured. Lamax and energetic contributions (phosphagen, glycolytic, and oxidative) were determined using these parameters. The shortest test duration of 10s elicited a significantly (p = 0.003; p < 0.001) higher Lamax (0.86 ± 0.17mmol.L-1.s-1; 95% CI 0.802-0.974) compared with both 15s (0.68 ± 0.18mmol.L-1.s-1; 95% CI 0.596-0.794) and 30s (0.45 ± 0.07mmol.L-1.s-1; 95% CI 0.410-0.487). Differences in Lamax were associated with large effect sizes (d = 1.07, d = 3.15). We observed 81% of the PCr and 53% of the glycolytic work completed over the 30s sprint duration was attained after 10s. BLamaxpost were achieved at 5 ± 2min (ttest 10s), 6 ± 2min (ttest 15s), and 7 ± 2min (ttest 30s), respectively. Our findings demonstrated a 10s test duration elicited the highest Lamax. Furthermore, the 10s test duration mitigated the influence of the oxidative metabolism during all-out cycling. The optimal sample time to determine peak blood lactate concentration following 10s was 5 ± 2min.

Development of a low pollution medium for the cultivation of lactic acid bacteria

Protein rich culture media are employed in the production of lactic acid bacteria (LAB); however, production costs are high. In this work media formulation and evaluation for LAB production were conducted considering physiological properties of lactic acid bacteria. Consumption efficiency (E), yield production (Y) and specific substrate consumption rate (qS) values as response variables were used. Four culture media were used: (1) Man Rogosa Sharp (MRS); (2) cabbage liquor (MC); (3) a new balanced culture medium (MX); and (4) MX supplemented with cabbage liquor (MXC). The culture media were evaluated using two strains: Lactobacillus acidophilus ATCC 4356 and Lactiplantibacillus plantarum ATCC 10241. The EGLU for L. plantarum was 100 % in the three media and YX/S value was 0.02 ± 0.003 in MRS and MX, while YLAC/S was 0.57 ± 0.03 in MRS and 0.51 ± 0.02 in MX. In MXC, the value obtained for YX/S was 0.07 ± 0.002 while YLAC/S was 0.47 ± 0.04. Specific glucose consumption and lactate formation rates for L. plantarum in MRS and MX media did not show significant differences. These results suggest that MX and MXC can be used for efficient production of the LAB at low cost.

Dietary Fiber Increases Oxidative Metabolism in Colonocytes but Not in Distal Small Intestinal Enterocytes Isolated from Rats

Colonocyte and distal small intestinal enterocyte metabolism was studied in rats fed either an elemental diet or an elemental diet supplemented with 30% mixed dietary fiber for 14 d. Cells were incubated in RPMI 1640 culture media containing 14C-labeled glutamine (1 mmol/L), glucose (11 mmol/L), and short-chain fatty acids: acetate, propionate and butyrate (5 mmol/L). Substrate oxidation and product formation were measured. Colonocytes from the fiber-fed group had 22–51% higher oxidation rates than the elementalfed group for all substrates tested. The group consuming the fiber diet had 28% less glutamate formation from glutamine by isolated colonocytes than the group consuming the elemental diet. Enterocyte acetate oxidation and lactate formation rates were lower (60 and 30%) in the fiber-fed animals vs. the elemental-fed group. Including short-chain fatty acids and ketone bodies in incubation media differentially affected acetate, glutamine and glucose metabolism in isolated intestinal cells, depending on segment and diet. Short-chain fatty acid and glucose oxidation rates were higher for colonocytes than enterocytes and glutamate formation was greater in enterocytes than colonocytes. Fiber consumption increased this segmental disparity. This study demonstrates that dietary fiber consumption increases substrate oxidation by isolated colonocytes but not distal small intestinal enterocytes.

Lactate Thresholds and the Simulation of Human Energy Metabolism: Contributions by the Cologne Sports Medicine Group in the 1970s and 1980s.

Today, researchers, practitioners, and physicians measure the concentration of lactate during a graded exercise test to determine thresholds related to the maximal lactate steady state (maxLass) as a sensitive measure of endurance capacity. In the 1970s and 1980s, a group of Cologne-based researchers around Wildor Hollmann, Alois Mader, and Hermann Heck developed the methodology for systematic lactate testing and introduced a 4 mmol.L−1 lactate threshold. Later, they also developed the concept of the maxLass, and Mader designed a sophisticated mathematical model of human energy metabolism during exercise. Mader`s model simulates metabolic responses to exercise based on individual variables such as maximum oxygen uptake (O2max) and the maximal rate of lactate formation (νLa.max). Mader’s model predicts that the νLa.max reduces the power at the anaerobic threshold and endurance performance but that a high νLa.max is required for events with high power outputs in elite athletes. Mader’s model also assumed before the millennium that the rate of fat oxidation is explained by the difference between glycolytic pyruvate synthesis and the actual rate of pyruvate oxidation which is consistent with current opinion. Mader’s model also simulated the O2max slow component in the mid-1980s. Unfortunately, several landmark studies by the Cologne group were only published in German, and as a result, contributions by the Cologne group are under-appreciated in the English-speaking world. This narrative review aims to introduce key contributions of the Cologne group to human metabolism research especially for readers who do not speak German.

Comparison of maximum lactate formation rates in ergometer sprint and maximum strength loads

Comparison of maximum lactate formation rates in ergometer sprint and maximum strength loads

Assessing the transport rate of hyperpolarized pyruvate and lactate from the intra- to the extracellular space.

The use of [1-(13) C]pyruvate hyperpolarized by means of dynamic nuclear polarization provides a direct way to track the metabolic transformations of this metabolite in vivo and in cell cultures. The identification of the intra- and extracellular contributions to the (13) C NMR resonances is not straightforward. In order to obtain information about the rate of pyruvate and lactate transport through the cellular membrane, we set up a method that relies on the sudden 'quenching' of the extracellular metabolites' signal. The paramagnetic Gd-tetraazacyclododecane triacetic acid (Gd-DO3A) complex was used to dramatically decrease the longitudinal relaxation time constants of the (13) C-carboxylate resonances of both pyruvate and lactate. When Gd-DO3A was added to an MCF-7 cellular culture, which had previously received a dose of hyperpolarized [1-(13) C]pyruvate, the contributions of the extracellular pyruvate and lactate signals were deleted. From the analysis of the decay curves of the (13) C-carboxylate resonances of pyruvate and lactate it was possible to extract information about the exchange rate of the two metabolites across the cellular membrane. In particular, it was found that, in the reported experimental conditions, the lactate transport from the intra- to the extracellular space is not much lower than the rate of lactate formation. The method reported herein is non-destructive and it could be translated to in vivo studies. It opens a route for the use of hyperpolarized pyruvate to assess altered activity of carboxylate transporter proteins that may occur in pathological conditions. Copyright © 2016 John Wiley & Sons, Ltd.

Discussion: "The kinetics of blood lactate in boys during and following a single and repeated all-out sprints of cycling are different than in men" - Do children indeed release and remove lactate faster than adults?

Discussion: "The kinetics of blood lactate in boys during and following a single and repeated all-out sprints of cycling are different than in men" - Do children indeed release and remove lactate faster than adults?

1,2-Diazole and 2,2,2-Trifluoroethanol and Their Regulatory Effects on Ethanol and Lactic Acid Formation in the Living Culture of Rhizopus oryzae

In heterofermentation of Rhizopus oryzae, ethanol is the major byproduct which reduces the production of a desired product, an optically pure L-lactic acid. To improve lactic acid production, regulating the alcohol fermentative pathway to limit ethanol production has been done by various techniques. In vitro study on alcohol dehydrogenase (ADH) inhibition in several organisms showed that 1,2-diazole and 2,2,2-trifluoroethanol were competitively bound at the active sites that eventually limited ethanol production. In this study, 1,2-diazole and 2,2,2-trifluoroethanol were present during fermentation of R. oryzae. It was found that both 1,2-diazole and 2,2,2-trifluoroethanol not only strongly affected ethanol formation but they also indirectly regulated lactate production as observed by the decreasing affinity for glucose flux toward lactate and ethanol production. The increase in both ethanol and lactate formation rates revealed 1,2-diazole and 2,2,2-trifluoroethanol not only regulated the reversible redox reaction by ADH, but they also caused the dynamic change in the conversion of all metabolites in the living R. oryzae in order to maintain the balanced flux for cellular growth and maintenance.

Effect of Oxygen Concentration on Viability and Metabolism in a Fluidized-Bed Bioartificial Liver Using 31P and 13C NMR Spectroscopy

Many oxygen mass-transfer modeling studies have been performed for various bioartificial liver (BAL) encapsulation types; yet, to our knowledge, there is no experimental study that directly and noninvasively measures viability and metabolism as a function of time and oxygen concentration. We report the effect of oxygen concentration on viability and metabolism in a fluidized-bed NMR-compatible BAL using in vivo ³¹P and ¹³C NMR spectroscopy, respectively, by monitoring nucleotide triphosphate (NTP) and ¹³C-labeled nutrient metabolites, respectively. Fluidized-bed bioreactors eliminate the potential channeling that occurs with packed-bed bioreactors and serve as an ideal experimental model for homogeneous oxygen distribution. Hepatocytes were electrostatically encapsulated in alginate (avg. diameter, 500 μm; 3.5×10⁷ cells/mL) and perfused at 3 mL/min in a 9-cm (inner diameter) cylindrical glass NMR tube. Four oxygen treatments were tested and validated by an in-line oxygen electrode: (1) 95:5 oxygen:carbon dioxide (carbogen), (2) 75:20:5 nitrogen:oxygen:carbon dioxide, (3) 60:35:5 nitrogen:oxygen:carbon dioxide, and (4) 45:50:5 nitrogen:oxygen:carbon dioxide. With 20% oxygen, β-NTP steadily decreased until it was no longer detected at 11 h. The 35%, 50%, and 95% oxygen treatments resulted in steady β-NTP levels throughout the 28-h experimental period. For the 50% and 95% oxygen treatment, a ¹³C NMR time course (∼5 h) revealed 2-¹³C-glycine and 2-¹³C-glucose to be incorporated into [2-¹³C-glycyl]glutathione (GSH) and 2-¹³C-lactate, respectively, with 95% having a lower rate of lactate formation. ³¹P and ¹³C NMR spectroscopy is a noninvasive method for determining viability and metabolic rates. Modifying tissue-engineered devices to be NMR compatible is a relatively easy and inexpensive process depending on the bioreactor shape.

Abstract 3215: Metabolic alterations of cancer cell as potential anti-cancer target

Abstract In cancer cells, energy generating pathways are markedly altered like many other processes. Warburg described this effect as increase the rate of glycolysis in the expense of oxidative phosphorylation. Dysfunctional Mitochondria, not Oxygen insufficiency, cause cancer cells to produce inordinate amounts of Lactic acid. The fact that most cancers have poor vascular systems has led to assume that such cells are deprived of a normal supply of oxygen, and thus it was forced to switch for anaerobic glycolysis. Recently many experiments illustrated that, cancer cells keep using anaerobic glycolysis even under conditions where Oxygen is plentiful, resulting in high rates of lactate formation. This indicates; cancer cell switches to anaerobic glycolysis because it's in need for Lactic acid. In comparison to Morula's cell has higher concentration of Lactic acid, than other fully differentiated adult cells, at the same time it has less concentration than cancer cells. This means that Lactic acid is associated with poor differentiation and high proliferation of cells in both cancer and health situations. But after the cell has been specialized and became fully differentiated, Lactic acid starts losing this property. In this context, Lactic acid playing a pivotal role in cell transformation and p53 de-activation, at the same time it's interfere with signaling pathway to activate or enhance the activity of ERK 1/2, result in cell proliferation. Since there is direct link between p53 and COX by showing p53 induction correlated with an up regulation of COXI subunit expression at the mRNA level. So loss of p53 resulted in decreased COXII protein expression with concomitant decreases in COX enzyme activity, and thus halts Mitochondrial oxidative phosphorylation, at the same time force cells to become entirely dependent on glycolysis to meet energy demands. In response, cells start importing more Glucose into the Cytosol by increase the activity of GLUT, which it's under the control of Atypical PKC isozymes, these isozymes control insulin-stimulated glucose transport by promoting the translocation of glucose transporters to the plasma membrane. PKC isozymes are involved in a wide array of diverse cellular functions. Most isozymes (PKC-beta) are involved in proliferation, and differentiation, whereas (PKC-epsilon) is anti-apoptotic. PKC results in activation of Ras, this in turn results in activation of ERK 1/2, and PI3K. PI3K responsible for activation of MDM2, which results in inhibition p53 activity. And thus, over activation of PKC by Lactic acid results in halting p53, and enhancing the activity of Ras. So obviously Lactic acid has binding site in PKC's domain to activate it. But the difference in its activation in cancer and normal ES cells is that in ES cells is controlled by the amount of Lactic acid produced. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3215. doi:1538-7445.AM2012-3215

High post-mortem temperature combined with rapid glycolysis induces phosphorylase denaturation and produces pale and exudative characteristics in broiler Pectoralis major muscles

This study investigated the effect of early post-mortem temperature on broiler protein characteristics and meat quality. Muscles were kept at different temperatures (0, 20 and 40 °C) until 4 h post-mortem and then stored at 4 °C. Rapid degradation of ATP and glycogen, thus inducing a high rate of lactate formation and pH drop, were found in the 40 °C group during incubation. When extracting proteins, a lower protein content of the sarcoplasmic fraction and a higher protein content of the myofibrillar fraction were found in the 40 °C group at 24 h post-mortem; SDS-PAGE and western-blotting results revealed that phosphorylase was associated with the myofibrillar fraction. Furthermore, the 40 °C group had paler surfaces, higher drip loss and lower processing properties. These data suggest that elevated temperature during early post-mortem period, resulting in rapid glycolysis, induced phosphorylase denaturation and association with myofibrillar proteins thus generating pale and exudative characteristics.

Insulin Action in Hyperthyroidism: A Focus on Muscle and Adipose Tissue

Hyperthyroidism leads to an enhanced demand for glucose, which is primarily provided by increased rates of hepatic glucose production due to increased gluconeogenesis (in the fasting state) and increased Cori cycle activity (in the late postprandial and fasting state). Adipose tissue lipolysis is increased in the fasting state, resulting in increased production of glycerol and nonesterified fatty acids. Under these conditions, increased glycerol generated by lipolysis and increased amino acids generated by proteolysis are used as substrates for gluconeogenesis. Increased nonesterified fatty acid levels are necessary to stimulate gluconeogenesis and provide substrate for oxidation in other tissues (such as muscle). In the postprandial period, insulin-stimulated glucose uptake by the skeletal muscle has been found to be normal or increased, mainly due to increased blood flow. Under hyperthyroid conditions, insulin-stimulated rates of glycogen synthesis in skeletal muscle are decreased, whereas there is a preferential increase in the rates of lactate formation vs. glucose oxidation leading to increased Cori cycle activity. In hyperthyroidism, the Cori cycle could be considered as a large substrate cycle; by maintaining a high flux through it, a dynamic buffer of glucose and lactate is provided, which can be used by other tissues as required. Moreover, lipolysis is rapidly suppressed to normal after the meal to facilitate the disposal of glucose by the insulin-resistant muscle. This ensures the preferential use of glucose when available and helps to preserve fat stores.

In Situ Modulation of Oxidative Stress: A Novel and Efficient Strategy to Kill Cancer Cells

Cancer cells show an up-regulation of glycolysis, they readily take up vitamin C, and they appear more susceptible to an oxidative stress than the surrounding normal cells. Here we compare, analyse and discuss these particular hallmarks by performing experiments in murine hepatomas (TLT cells) and freshly isolated mouse hepatocytes. The results show that rates of lactate formation are higher in TLT cells as compared to mouse hepatocytes, but their ATP content represents less than 25% of that in normal cells. The uptake of vitamin C is more important in hepatoma cells as compared to normal hepatocytes. This uptake mainly occurs through GLUT1 transporters. Hepatoma cells have less than 10% of antioxidant enzyme activities as compared to normal hepatocytes. This decrease includes not only the major antioxidant enzymes, namely catalase, superoxide dismutase and glutathione peroxidase, but also the GSH content. Moreover, catalase is almost not expressed in hepatoma cells as shown by western blot analysis. We explored therefore a selective exposure of cancer cells to an oxidative stress induced by pro-oxidant mixtures containing pharmacological doses of vitamin C and a redox active compound such as menadione (vitamin K(3)). Indeed, the combination of vitamin C (which accumulates in hepatoma cells) and a quinone undergoing a redox cycling (vitamin K(3)) leads to an oxidative stress that kills cancer cells in a selective manner. This differential sensitivity between cancer cells and normal cells may have important clinical applications, as it has been observed with other pro-oxidants like Arsenic trioxide, isothiocyanates, Adaphostin.

Improvement of the energy metabolism of recombinant CHO cells by cell sorting for reduced mitochondrial membrane potential

One of the major problems in process performance of mammalian cell cultures is the production of lactic acid. Cell specific glucose uptake rates usually correlate to glucose concentration and approximately 80% of the metabolised glucose is converted into lactic acid. As the mitochondrial membrane potential was shown to correlate to cell specific glucose uptake rates, we used Rhodamine 123, a lipophilic cationic dye for cell sorting to improve the energy metabolism of existing production cell lines. Two recombinant CHO cell lines with known differences in lactic acid production rate were used to evaluate Rhodamine 123 staining as a descriptor for glucose uptake rates and to determine whether it is possible to isolate subclones with altered metabolic properties. Such subclones would exhibit an improved process performance, and in addition could be used as models for genomic and metabolic studies. From the cell line with high lactate production, a subclone sorted for reduced mitochondrial membrane potential was found to have a lower specific lactate formation rate compared to the parental cell line in batch cultures. In addition, the glucose consumption rate was also reduced, while both the growth rate and the final cell concentration were increased. A subclone sorted for high mitochondrial membrane potential, on the other hand, had a higher glucose consumption rate, a higher lactate production rate and reduced growth. The potential of using flow cytometric cell sorting methods based on physiological activity for cell line optimisation is discussed.

Down-regulation of lactate dehydrogenase-A by siRNAs for reduced lactic acid formation of Chinese hamster ovary cells producing thrombopoietin

Lactate, one of the major waste products in mammalian cell culture, can inhibit cell growth and affect cellular metabolism at high concentrations. To reduce lactate formation, lactate dehydrogenase-A (LDH-A), an enzyme catalyzing the conversion of glucose-derived pyruvate to lactate, was down-regulated by an expression vector of small interfering RNAs (siRNA) in recombinant Chinese hamster ovary (rCHO) cells producing human thrombopoietin (hTPO). Three clones expressing low levels of LDH-A, determined by reverse transcription-PCR and an enzyme activity test, were established in addition to a negative control cell line. LDH-A activities in the three clones were decreased by 75-89%, compared with that of the control CHO cell line, demonstrating that the effect of siRNA is more significant than that of other traditional methods such as homologous recombination (30%) and antisense mRNA (29%). The specific glucose consumption rates of the three clones were reduced to 54-87% when compared to the control cell line. Similarly, the specific lactate production rates were reduced to 45-79% of the control cell line level. In addition, reduction of LDH-A did not impair either cell proliferation or hTPO productivity. Taken together, these results show that the lactate formation rate in rCHO cell culture can be efficiently reduced through the down-regulation of LDH via siRNA.

The effects of peroxovanadate and peroxovanadyl on glucose metabolism in vivo and identification of signal transduction proteins involved in the mechanism of action in isolated soleus muscle

The insulin-like effects of peroxovanate (POV) and peroxovanadyl (PSV) on rates of lactate formation and glycogen synthesis were measured in isolated incubated soleus muscle preparations. In another experiment rats were made insulin deficient by streptozotocin injection and treated with POV and PSV (0.25 mM) administered in the drinking water and in the course of 7 days glycemia were determined. Also, signal transduction proteins ERK 1 and ERK 2 involved in the insulin signaling were measured in soleus muscle of diabetic rats treated with POV and PSV. Peroxides of vanadate and vanadyl significantly stimulated glucose utilization in soleus muscle preparations in vitro. The stimulation of glycogen synthesis and lactate formation by POV and PSV was similar to insulin stimuli. Rats treated with POV or PSV presented reduction of glycemia, food and fluid intake with amelioration of the diabetic state during the short period of treatment (7 days). POV and PSV modulated ERK1/2 phosphorilation and the insulin administration in these rats caused an addictive effect on phosphorilation state of these proteins.

Computational studies of the effects of myocardial blood flow reductions on cardiac metabolism.

BackgroundA computational model of myocardial energy metabolism was used to assess the metabolic responses to normal and reduced myocardial blood flow. The goal was to examine to what extent glycolysis and lactate formation are controlled by the supply of glycolytic substrate and/or the cellular redox (NADH/NAD+) and phosphorylation (ATP/ADP) states.MethodsFlow was reduced over a wide range and for a sufficient duration in order to investigate the sequence of events that occur during the transition to a new metabolic steady state.ResultsSimulation results indicated multiple time-dependent controls over both glycolysis and lactate formation.ConclusionsChanges in phosphorylation state and glucose uptake only significantly affect the initial phase of the glycolytic response to ischemia, while glycogen breakdown exerts control over glycolysis during the entire duration of ischemia. Similarly, changes in the redox state affect the rates of lactate formation and release primarily during the initial transient phase of the response to the reductions in blood flow, while the rate of glycolysis controls the rate of lactate formation throughout the entire period of adaptation.

Differential effects of vanadium, tungsten and molybdenum on inhibition of glucose formation in renal tubules and hepatocytes of control and diabetic rabbits: beneficial action of melatonin and N-acetylcysteine.

Effect of vanadyl acetylacetonate (VAc), tungstate and molybdate on gluconeogenesis has been studied in isolated hepatocytes and kidney-cortex tubules. In renal tubules of control and alloxan-diabetic animals, the rank order of the metal-compounds-induced (i) inhibition of glucose formation from alanine+glycerol+octanoate or aspartate+glycerol+octanoate, (ii) decrease in the mitochondrial membrane potential (delta psim), (iii) increase in the hydroxyl free radicals (HFR) generation and (iv) decline in glucose-6-phosphatase activity was the following: VAc > tungstate > molybdate. Moreover, in contrast to VAc, both tungstate and molybdate at 100 microM concentration did not practically decrease glucose production in hepatocytes isolated from diabetic rabbits, and significantly increased the rate of lactate formation in renal tubules. N-acetylcysteine at 2 mM concentration partially attenuated vanadium-induced alterations in glucose formation, delta psim and the cellular glutathione redox state, whereas 0.1 mM melatonin did not abolish vanadium-induced changes in gluconeogenesis despite attenuation of vanadium effects on HFR formation and delta psim decline. However, similarly to control rabbits, following 6 days of intraperitoneal administration of both VAc (1.275 mg V/kg body weight daily) and melatonin (1 mg/kg body weight daily) to alloxan-diabetic animals, vanadium-induced elevated serum creatinine and urea levels were decreased, indicating the beneficial effect of melatonin on diabetes- and vanadium-induced nephrotoxicity in rabbits. As serum glucose levels were also significantly diminished by vanadium+melatonin treatment of diabetic animals, the combination therapy of vanadium compounds and melatonin needs a careful evaluation.

Inhibition of gluconeogenesis by vanadium and metformin in kidney-cortex tubules isolated from control and diabetic rabbits

Effect of vanadyl acetylacetonate (VAc) and metformin on gluconeogenesis has been studied in isolated hepatocytes and kidney-cortex tubules of rabbit. Glucose formation from alanine+glycerol+octanoate, pyruvate or dihydroxyacetone was inhibited by 50–80% by 100 μM VAc or 500 μM metformin in renal tubules of control and alloxan-diabetic animals, while the inhibitory action of these compounds in hepatocytes was less pronounced (by about 20–30%). In contrast to VAc, metformin increased the rate of lactate formation by about 2-fold in renal tubules incubated with alanine+glycerol+octanoate. In view of VAc-induced changes in intracellular gluconeogenic intermediates and gluconeogenic enzyme activities, it is likely that this compound may decrease fluxes through pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. In contrast to VAc, metformin-induced decrease in renal gluconeogenesis may result from a decline of cytosolic oxaloacetate level and consequently PEPCK activity. Following 6 days of VAc administration (1.275 mg V kg −1 body weight daily) the blood glucose level in alloxan-diabetic rabbits was normalised while blood glucose changes in control animals were not observed. On the contrary, in diabetic animals treated for 6 days with metformin (200 mg kg −1 body weight day −1) a high blood glucose level was maintained. Unfortunately, VAc-treated control and diabetic rabbits exhibited elevated serum urea and creatinine levels. In VAc-treated animals vanadium was accumulated in kidney-cortex up to 7.6±0.6 μg V g −1 dry weight. In view of a potential vanadium nephrotoxicity a therapeutic application of vanadium compounds needs a critical re-evaluation.