scholarly journals The involvement of pyruvate cycling in the metabolism of aspartate and glycerate by the perfused rat kidney

1986 ◽  
Vol 237 (3) ◽  
pp. 691-698 ◽  
Author(s):  
R C Scaduto ◽  
E J Davis
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Rat Kidney ◽  
Lactate Production ◽  
Glucose Production ◽  
Kidney Cortex ◽  
Acid Oxidation ◽  
Minor Effect ◽  
Major Pathway ◽  
Pyruvate Cycling ◽  
Reducing Potential

The metabolism of glycerate and aspartate was investigated in perfused rat kidneys. The major pathway active for aspartate metabolism and NH3 production was found to include transamination, and not the purine nucleotide cycle. Pyruvate cycling was identified as a means by which reducing potential is generated in the cytosol for glucose and lactate production from these substrates. Inhibition of mitochondrial pyruvate transport caused an inhibition of glucose production, accumulation of lactate and pyruvate in the perfusate, and a decrease in the [lactate]/[pyruvate] ratio in kidneys perfused with aspartate. These data indicate a role of mitochondrial pyruvate transport in the provision of cytosolic reducing potential. With either aspartate or glycerate, 3-mercaptopicolinic acid (3-MPA) suppressed glucose synthesis and caused accumulation of malate plus fumarate within the kidney. Glucose production from glycerate was much less sensitive to the presence of 3-MPA than was glucose production from aspartate, illustrating a phosphoenolpyruvate carboxykinase (PEPCK)-independent pathway for the cycling of pyruvate. In aspartate-perfused kidneys, the presence of 3-MPA, at concentrations that completely blocked glucose accumulation in the perfusate, did not affect the rate of NH3 production and had only a minor effect on the rate of aspartate uptake. These data allow for an estimation of the rate of pyruvate formation from aspartate of about 1 mumol/min per kidney under conditions of complete PEPCK inhibition. Thus a PEPCK-independent pathway is operative for amino acid oxidation and pyruvate formation in perfused kidneys. The NADP-linked, but not the NAD-linked, ‘malic’ enzyme activity of the kidney cortex was found to be sufficient to catalyse this estimated rate of pyruvate formation.

scholarly journals The impact of obesity, sex, and diet on hepatic glucose production in cats

2009 ◽  
Vol 296 (4) ◽  
pp. R936-R943 ◽  
Author(s):  
Saskia Kley ◽  
Margarethe Hoenig ◽  
John Glushka ◽  
Eunsook S. Jin ◽  
Shawn C. Burgess ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Citrate Synthase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Metabolism ◽  
Peripheral Insulin Resistance ◽  
Pyruvate Cycling ◽  
Hepatic Glucose ◽  
The Impact

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using 2H2O, [U-13C3]propionate, and [3,4-13C2]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin ( P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats ( P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP ( P < 0.003). Female obese cats had ∼1.5 times higher fluxes through phosphoenolpyruvate carboxykinase ( P < 0.02) and citrate synthase ( P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold ( P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals

2012 ◽  
Vol 303 (3) ◽  
pp. R340-R352 ◽  
Author(s):  
Cory D. Champagne ◽  
Dorian S. Houser ◽  
Melinda A. Fowler ◽  
Daniel P. Costa ◽  
Daniel E. Crocker
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Production ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Endogenous Glucose Production ◽  
Large Contribution ◽  
Protein Loss ◽  
Elephant Seals ◽  
Pyruvate Cycling ◽  
Northern Elephant Seals

Animals that endure prolonged periods of food deprivation preserve vital organ function by sparing protein from catabolism. Much of this protein sparing is achieved by reducing metabolic rate and suppressing gluconeogenesis while fasting. Northern elephant seals ( Mirounga angustirostris) endure prolonged fasts of up to 3 mo at multiple life stages. During these fasts, elephant seals maintain high levels of activity and energy expenditure associated with breeding, reproduction, lactation, and development while maintaining rates of glucose production typical of a postabsorptive mammal. Therefore, we investigated how fasting elephant seals meet the requirements of glucose-dependent tissues while suppressing protein catabolism by measuring the contribution of glycogenolysis, glycerol, and phosphoenolpyruvate (PEP) to endogenous glucose production (EGP) during their natural 2-mo postweaning fast. Additionally, pathway flux rates associated with the tricarboxylic acid (TCA) cycle were measured specifically, flux through phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate cycling. The rate of glucose production decreased during the fast (F1,13= 5.7, P = 0.04) but remained similar to that of postabsorptive mammals. The fractional contributions of glycogen, glycerol, and PEP did not change with fasting; PEP was the primary gluconeogenic precursor and accounted for ∼95% of EGP. This large contribution of PEP to glucose production occurred without substantial protein loss. Fluxes through the TCA cycle, PEPCK, and pyruvate cycling were higher than reported in other species and were the most energetically costly component of hepatic carbohydrate metabolism. The active pyruvate recycling fluxes detected in elephant seals may serve to rectify gluconeogeneic PEP production during restricted anaplerotic inflow in these fasting-adapted animals.

Changes in mRNAs for enzymes of glutamine metabolism in kidney and liver during ammonium chloride acidosis

1994 ◽  
Vol 267 (3) ◽  
pp. F400-F406 ◽  
Author(s):  
A. C. Schoolwerth ◽  
P. A. deBoer ◽  
A. F. Moorman ◽  
W. H. Lamers
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Rat Kidney ◽  
Glutamine Metabolism ◽  
Kidney Cortex ◽  
Mrna Levels ◽  
Rat Kidney Cortex ◽  
Physiological Conditions ◽  
Glutamine Synthase ◽  
Sustained Increase

Changes in protein and mRNAs for enzymes of glutamine metabolism were determined in rat kidney cortex at different times after induction of NH4Cl acidosis. After NH4Cl, phosphoenolpyruvate carboxykinase (PEPCK) mRNA increased 16-fold by 10 h (P < 0.05) and then returned to control levels by 30 h. In situ hybridization (ISH) showed that PEPCK mRNA was confined to medullary rays; after NH4Cl, expression of PEPCK expanded throughout the cortex, reaching a maximal intensity at 10 h. Phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GDH) mRNAs increased 8- and 2.6-fold, respectively (both P < 0.05), by 10 h before decreasing; the increased expression was confirmed by ISH. Immunohistochemistry showed that increased PEPCK, PDG, and GDH protein occurred at variable times after the rise in mRNAs. The increase was confined to proximal tubules and was sustained, a finding noted also by Western blot analysis. In contrast, glutamine synthase protein and mRNA, confined to deep cortex and outer medullar, did not change after NH4Cl. These studies reveal striking changes in PEPCK and PDG mRNAs in rat renal cortex during acidosis. The ISH pattern suggested that increased amounts of PEPCK were synthesized in recruited cells which contained little enzyme under physiological conditions. mRNA levels for PEPCK, PDG, and GDH peaked at 10 h before returning to control levels. Despite the decrease in mRNAs, a sustained increase in proteins was noted.

scholarly journals Proteomic profiling and pathway analysis of the response of rat renal proximal convoluted tubules to metabolic acidosis

2013 ◽  
Vol 305 (5) ◽  
pp. F628-F640 ◽  
Author(s):  
Kevin L. Schauer ◽  
Dana M. Freund ◽  
Jessica E. Prenni ◽  
Norman P. Curthoys
Keyword(s):  
Metabolic Acidosis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Pathological Condition ◽  
Rat Kidney ◽  
Proximal Convoluted Tubule ◽  
Kidney Cortex ◽  
Combined Processes ◽  
Proteomic Profiling ◽  
Rat Kidney Cortex ◽  
Cytosolic Proteins

Metabolic acidosis is a relatively common pathological condition that is defined as a decrease in blood pH and bicarbonate concentration. The renal proximal convoluted tubule responds to this condition by increasing the extraction of plasma glutamine and activating ammoniagenesis and gluconeogenesis. The combined processes increase the excretion of acid and produce bicarbonate ions that are added to the blood to partially restore acid-base homeostasis. Only a few cytosolic proteins, such as phosphoenolpyruvate carboxykinase, have been determined to play a role in the renal response to metabolic acidosis. Therefore, further analysis was performed to better characterize the response of the cytosolic proteome. Proximal convoluted tubule cells were isolated from rat kidney cortex at various times after onset of acidosis and fractionated to separate the soluble cytosolic proteins from the remainder of the cellular components. The cytosolic proteins were analyzed using two-dimensional liquid chromatography and tandem mass spectrometry (MS/MS). Spectral counting along with average MS/MS total ion current were used to quantify temporal changes in relative protein abundance. In all, 461 proteins were confidently identified, of which 24 exhibited statistically significant changes in abundance. To validate these techniques, several of the observed abundance changes were confirmed by Western blotting. Data from the cytosolic fractions were then combined with previous proteomic data, and pathway analyses were performed to identify the primary pathways that are activated or inhibited in the proximal convoluted tubule during the onset of metabolic acidosis.

Renal glucose production and uptake in separate sites, and its significance

1962 ◽  
Vol 203 (3) ◽  
pp. 572-576 ◽  
Author(s):  
William P. McCann
Keyword(s):  
Glucose Metabolism ◽  
Rat Kidney ◽  
Glucose Production ◽  
Metabolic Energy ◽  
Kidney Cortex ◽  
Rat Kidney Cortex ◽  
Nephron Segments ◽  
Collecting Ducts ◽  
Cortical Slices

Slices of rat kidney cortex, medulla, and papilla were incubated in serum under O2-CO2 mixtures, and their glucose exchanges measured. Cortical slices released more glucose than can be explained by glycogen or other tissue glucose forms, or slice swelling. Medullary and papillary slices, however, rapidly took up glucose, even when NaCl and/or urea were added to the serum to mimic probable in vivo conditions for these tissues. Renal glucose metabolism is discussed on the basis of these and other observations, leading to the following premises: a) glucose is formed in and released from proximal convolutions, while it is less certain that this occurs in distal convolutions; b) loops and collecting ducts, if not other nephron segments, may rely heavily on glucose for metabolic energy; and c) there are circumstantial relations between net renal glucose metabolism and diuresis.

scholarly journals Induction of rat kidney gluconeogenesis during acute liver intoxication by carbon tetrachloride

1978 ◽  
Vol 174 (2) ◽  
pp. 461-467 ◽  
Author(s):  
M J Faus ◽  
J A Lupiáñez ◽  
A Vargas ◽  
F Sánchez-Medina
Keyword(s):  
Carbon Tetrachloride ◽  
Phosphoenolpyruvate Carboxykinase ◽  
De Novo ◽  
Rat Kidney ◽  
Glucose Production ◽  
Lactate Dehydrogenase Activity ◽  
Previously Treated ◽  
Cortical Slices ◽  
Liver Intoxication

1. Glucose production from L-lactate was completely inhibited 24h after carbon tetrachloride treatment in liver from 48h-starved rats. The activities of phosphoenolpyruvate carboxykinase, fructose diphosphatase and glucose 6-phosphatase were decreased by this treatment in fed and starved rats, whereas lactate dehydrogenase activity was only decreased in fed animals. 2. The production of glucose by renal cortical slices from fed rats previously treated with carbon tetrachloride was enhanced when L-lactate, pyruvate and glutamine but not fructose were used as glucose precursors. Renal phosphoenolpyruvate carboxykinase activity was increased in this condition. 3. This increase was counteracted by cycloheximide or actinomycin D, suggesting that the effect was due to the synthesis de novo of the enzyme. 4. The pattern of hepatic gluconeogenic metabolites in treated animals was characterized by an increase in lactate, pyruvate, malate and citrate as well as a decrease in glucose 6-phosphate, suggesting an impairment of liver gluconeogenesis in vivo. 5. In contrast, the profile of renal metabolites suggested that gluconeogenesis was operative in the treated rats, as indicated by the marked increase in the content of phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate and glucose 6-phosphate. 6. It is postulated that renal gluconeogenesis could contribute to the maintenance of glycaemia in carbon tetrachloride-treated rats.

scholarly journals Inhibition of lactate glucogneogenesis in rat kidney by dichloroacetate

1978 ◽  
Vol 170 (3) ◽  
pp. 551-560 ◽  
Author(s):  
J H Lacey ◽  
P J Randle
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Rat Kidney ◽  
Active Form ◽  
Glucose Production ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Pyruvate Dehydrogenase Kinase ◽  
No Oxidation ◽  
Kidney Cortex

1. Sodium dichloroacetate (1mM) inhibited glucose production from L-lactate in kidney-cortex slices from fed, starved or alloxan-diabetic rates. In general gluconeogenesis from other substrates was no inhibited. 2. Sodium dichloracetate inhibited glucose production from L-lactate but no from pyruvate in perfused isolated kidneys from normal or alloxan-diabetic rats. 3. Sodium dichloroacetate is an inhibitor of the pyruvate dehydrogenase kinase reaction and it effected conversion of pyruvate dehydrogenase into its its active (dephosphorylated) form in kidney in vivo. In general, pyruvate dehydrogenase was mainly in the active form in kidneys perfused or incubated with L-lactate and the inhibitory effect of dichloroacetate on glucose production was not dependent on activation of pyruvate dehydrogenase. 4. Balance data from kidney slices showed that dichloroacetate inhibits lactate uptake, glucose and pyruvate production from lactate, but no oxidation of lactate. 5. The mechanism of this effect of dichloroactetate on glucose production from lactate has not been fully defined, but evidence suggests that it may involve a fall in tissue pyruvate concentration and inhibition of pyruvate carboxylation.

DDT-Induced Stimulation of Key Gluconeogenic Enzymes In Rat Kidney Cortex

1972 ◽  
Vol 50 (2) ◽  
pp. 225-229 ◽  
Author(s):  
S. Kacew ◽  
R. L. Singhal ◽  
G. M. Ling
Keyword(s):  
Pyruvate Carboxylase ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Rat Kidney ◽  
Kidney Cortex ◽  
Glucocorticoid Hormones ◽  
Rat Kidney Cortex ◽  
Gluconeogenic Enzymes ◽  
Maximal Stimulation ◽  
Adrenalectomized Rats ◽  
Stimulation Of

Administration of technical DDT or o,p′-DDT produced marked increases in pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase, and glueose-6-phospfaatase activities in rat kidney cortex. Significant increases in these key gluconeogenic enzymes occurred at 2–3 days and maximal stimulation was seen 5–7 days after the beginning of o,p′-DDT treatment. This DDT isomer, when given to adrenalectomized rats, produced increases in renal enzymes similar to those observed in intact animals. Furthermore, since administration of triamcinolone to o,p′-DDT-treated rats failed to potentiate the action of this insecticide on various enzymes, evidence indicates that the stimulation of kidney cortex gluconeogenesis by DDT is not mediated through a release of glucocorticoid hormones from the adrenal cortex.

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