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.

scholarly journals Phosphorylation state of cytosolic and mitochondrial adenine nucleotides and of pyruvate dehydrogenase in isolated rat liver cells

1976 ◽  
Vol 156 (1) ◽  
pp. 91-102 ◽  
Author(s):  
E A Siess ◽  
O H Wieland
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Adenine Nucleotides ◽  
Active Form ◽  
Inverse Correlation ◽  
Liver Cells ◽  
Diabetic Rats ◽  
Pyruvate Dehydrogenase Kinase ◽  
Intact Cells ◽  
Phosphorylation State

1. Cytosolic and mitochondrial ATP and ADP concentrations of liver cells isolated from normal fed, starved and diabetic rats were determined. 2. The cytosolic ATP/ADP ratio was 6,9 and 10 in normal fed, starved and diabetic rats respectively. 3. The mitochondrial ATP/ADP ratio was 2 in normal and diabetic rats and 1.6 in starved rats. 4. Adenosine increased the cytosolic and lowered the mitochondrial ATP/ADP ratio, whereas atractyloside had the opposite effect. 5. Incubation of the hepatocytes with fructose, glycerol or sorbitol led to a fall in the ATP/ADP ratio in both the cytosolic and the mitochondrial compartment. 6. The interrelationship between the mitochondrial ATP/ADP ratio and the phosphorylation state of pyruvate dehydrogenase in intact cells was studied. 7. In hepatocytes isolated from fed rats an inverse correlation between the mitochondrial ATP/ADP ratio and the active form of pyruvate dehydrogenase (pyruvate dehydrogenase a) was demonstrable on loading with fructose, glycerol or sorbitol. 8. No such correlation was obtained with pyruvate or dihydroxyacetone. For pyruvate, this can be explained by inhibition of pyruvate dehydrogenase kinase. 9. Liver cells isolated from fed animals displayed pyruvate dehydrogenase a activity twice that found in vivo. Physiological values were obtained when the hepatocytes were incubated with albumin-oleate, which also yielded the highest mitochondrial ATP/ADP ratio.

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 Regulation of pyruvate dehydrogenase kinase activity from pig kidney cortex

1992 ◽  
Vol 288 (2) ◽  
pp. 369-373 ◽  
Author(s):  
T Pawelczyk ◽  
M S Olson
Keyword(s):  
Ionic Strength ◽  
Pyruvate Dehydrogenase ◽  
Kinase Activity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Kidney Cortex ◽  
Small Range ◽  
High Concentration ◽  
Optimum Activity ◽  
Pig Kidney

The activity of pyruvate dehydrogenase (PDH) kinase in the purified PDH complex from pig kidney is sensitive to changes in ionic strength. The enzyme has optimum activity within a small range of ionic strength (0.03-0.05 M). An increase in ionic strength from 0.04 M to 0.2 M lowers the activity of PDH kinase by 32% and decreases the Km for ATP from 25 microM to 10 microM. At constant ionic strength (0.15 M) the enzyme has optimum activity over a broad pH range (7.2-8.0). The PDH kinase is stimulated 2.2-fold by 20 mM-K+, whereas Na+ even at high concentration (80 mM) has no effect on the enzyme activity. The stimulation of PDH kinase by K+ is not dependent on pH and ionic strength. PDH kinase is inhibited by HPO4(2-) in the presence of K+, whereas HPO4(2-) has no effect on the activity of this enzyme in the absence of K+. HPO4(2-) at concentrations of 2 and 10 mM inhibits PDH kinase by 28% and 55% respectively. The magnitude of this inhibition is not dependent on the ATP/ADP ratio. Inhibition by HPO4(2-) in the concentration range 0-10 mM is non-competitive with respect to ATP, and becomes mixed-type at concentrations over 10 mM. The Ki for HPO4(2-) is 10 mM. When HPO4(2-) is replaced by SO4(2-), the same effects on the activity of PDH kinase are observed. PDH kinase is also inhibited by Cl-. In the presence of 80 mM-Cl- the PDH kinase is inhibited by 40%. The inhibition by Cl- is not dependent on K+. In conclusion, we postulate that changes in phosphate concentrations may play a significant role in the regulation of PDH kinase activity in vivo.

scholarly journals 3-Mercaptopicolinic acid, an inhibitor of gluconeogenesis

1974 ◽  
Vol 138 (3) ◽  
pp. 387-394 ◽  
Author(s):  
N. W. DiTullio ◽  
C. E. Berkoff ◽  
B. Blank ◽  
V. Kostos ◽  
E. J. Stack ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Diabetic Rats ◽  
Kidney Cortex ◽  
Hepatic Glycogen ◽  
Hypoglycaemic Effect ◽  
Rat Kidney Cortex ◽  
Urea Production ◽  
Rat Livers

1. 3-Mercaptopicolinic acid (SK&F 34288) inhibited gluconeogenesis in vitro, with lactate as substrate, in rat kidney-cortex and liver slices. 2. In perfused rat livers, gluconeogenesis was inhibited when lactate, pyruvate or alanine served as substrate, but not with fructose, suggesting pyruvate carboxylase or phosphoenolpyruvate carboxylase as the site of inhibition. No significant effects were evident in O2 consumption, hepatic glycogen, urea production, or [lactate]/[pyruvate] ratios. 3. A hypoglycaemic effect was evident in vivo in starved and alloxan-diabetic rats, starved guinea pigs and starved mice, but not in 4h-post-absorptive rats. 4. In the starved rat the hypoglycaemia was accompanied by an increase in blood lactate. 5. A trace dose of [14C]lactate in vivo was initially oxidized to a lesser extent in inhibitor-treated rats, but during 90min the total CO2 evolved was slightly greater. The total amount of the tracer oxidized was not significantly different from that in the controls.

scholarly journals The effects of various anions and cations on the regulation of pyruvate dehydrogenase complex activity from pig kidney cortex

1988 ◽  
Vol 253 (3) ◽  
pp. 819-825 ◽  
Author(s):  
T Pawelczyk ◽  
R A Easom ◽  
M S Olson
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Maximal Activity ◽  
Hill Coefficient ◽  
Kidney Cortex ◽  
Complex Activity ◽  
Pig Kidney ◽  
Constant Strength ◽  
Dehydrogenase Complex

The activity of pyruvate dehydrogenase complex (PDC) purified from pig kidney cortex was found to be affected by various uni- and bi-valent ions. At a constant strength of 0.13 M at pH 7.8, K+, Na+, Cl-, HCO3- and HPO4(2-) had significant effects on the activity of PDC: Na+, K+ and HPO4(2-) stimulated, but HCO3- and Cl- inhibited. The stimulatory effect of Na+ was mediated by a change in the Vmax. of PDC only, whereas K+ produced an increase in Vmax. and a change in the Hill coefficient (h). The extent of stimulation produced by HPO4(2-)4 on the activity of PDC was dependent on the concentrations of K+ and Na+. Both cations at concentrations higher than 40 mM partially prevented the effect of HPO4(2-)4. Cl- and HCO3- anions decreased the Vmax. of the enzyme and increased the S0.5 for pyruvate. The effects of Na+, K+, Cl-, HPO4(2-) and HCO3- on the activity of PDC were additive. In the presence of 80 mM-K+, 20 mM-Na+, 10 mM-HPO4(2-), 20 mM-Cl- and 20 mM-HCO3- the activity of PDC was increased by 30%, the S0.5 for pyruvate was increased from 75 to 158 microM and h was decreased from 1.3 to 1.1. Under these conditions and at 1.0 mM-pyruvate, the activity of PDC was 80% of the maximal activity achieved in the presence of these ions and 4.5 mM-pyruvate. The present study suggests that PDC may operate under non-saturating concentrations for substrate in vivo.

scholarly journals Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise

1976 ◽  
Vol 158 (2) ◽  
pp. 203-210 ◽  
Author(s):  
S A Hagg ◽  
S I Taylor ◽  
N B Ruberman
Keyword(s):  
Skeletal Muscle ◽  
Dehydrogenase Activity ◽  
Pyruvate Dehydrogenase ◽  
Preceding Paper ◽  
Diabetic Rats ◽  
Pyruvate Dehydrogenase Kinase ◽  
Lactate Oxidation ◽  
Pyruvate Oxidation ◽  
Measured Activity ◽  
Exercise Induced

1. The interconversion of pyruvate dehydrogenase between its inactive phosphorylated and active dephosphorylated forms was studied in skeletal muscle. 2. Exercise, induced by electrical stimulation of the sciatic nerve (5/s), increased the measured activity of (active) pyruvate dehydrogenase threefold in intact anaesthetized rated within 2 min. No further increase was seen after 15 min of stimulation. 3. In the perfused rat hindquarter, (active) pyruvate dehydrogenase activity was decreased by 50% in muscle of starved and diabetic rats. Exercise produced a twofold increase in its activity in all groups; however, the relative differences between fed, starved and diabetic groups persisted. 4. Perfusion of muslce with acetoacetate (2 mM) decreased (active) pyruvate dehydrogenase activity by 50% at rest but not during exercise. 5. Whole-tissue concentrations of pyruvate and citrate, inhibitors of (active) pyruvate dehydrogenase kinase and (inactive) pyruvate dehydrogenase phosphate phosphatase respectively, were not altered by excerise. A decrease in the ATP/ADP ratio was observed, but did not appear to be sufficient to account for the increase in (active) pyruvate dehydrogenase activity. 6. The results suggest that interconversion of the phosphorylated and dephosphorylated forms of pyruvate dehydrogenase plays a major role in the regulation of pyruvate oxidation by eomparison of enzyme activity with measurements of lactate oxidation in the perfused hindquarter [see the preceding paper, Berger et al. (1976)] suggest that pyruvate oxidation is also modulated by the concentrations of substrates, cofactors and inhibitors of (active) pyruvate dehydrogenase activity.

scholarly journals Studies of the long-term regulation of hepatic pyruvate dehydrogenase kinase

1998 ◽  
Vol 329 (1) ◽  
pp. 89-94 ◽  
Author(s):  
C. Mary SUGDEN ◽  
G. D. Lee FRYER ◽  
A. Karen ORFALI ◽  
A. David PRIESTMAN ◽  
Elaine DONALD ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Pyruvate Dehydrogenase ◽  
Unsaturated Fatty Acids ◽  
Fold Increase ◽  
Membrane Lipid ◽  
Dietary Lipid ◽  
Pyruvate Dehydrogenase Kinase ◽  
Plasma Insulin Concentration

The administration of a low-carbohydrate/high-saturated-fat (LC/HF) diet for 28 days or starvation for 48 h both increased pyruvate dehydrogenase kinase (PDHK) activity in extracts of rat hepatic mitochondria, by approx. 2.1-fold and 3.5-fold respectively. ELISAs of extracts of hepatic mitochondria, conducted over a range of pyruvate dehydrogenase (PDH) activities, revealed that mitochondrial immunoreactive PDHKII (the major PDHK isoform in rat liver) was significantly increased by approx. 1.4-fold after 28 days of LC/HF feeding and by approx. 2-fold after 48 h of starvation. The effect of LC/HF feeding to increase hepatic PDHK activity was retained through hepatocyte preparation, but was decreased on 21 h culture with insulin (100μ-i.u./ml). A sustained (24 h) 2-4-fold elevation in plasma insulin concentration in vivo (achieved by insulin infusion via an osmotic pump) suppressed the effect of LC/HF feeding so that hepatic PDHK activities did not differ significantly from those of (insulin-infused) control rats. The increase in hepatic PDHK activity evoked by 28 days of LC/HF feeding was prevented and reversed (within 24 h) by the replacement of 7% of the dietary lipid with long-chain ω-3 fatty acids. Analysis of hepatic membrane lipid revealed a 1.9-fold increase in the ratio of total polyunsaturated ω-3 fatty acids to total mono-unsaturated fatty acids. The results indicate that the increased hepatic PDHK activities observed in livers of LC/HF-fed or 48 h-starved rats are associated with long-term actions to increase hepatic PDHKII concentrations. The long-term regulation of hepatic PDHK by LC/HF feeding might be achieved through an impaired action of insulin to suppress PDHK activity. In addition, the fatty acid composition of the diet, rather than the fat content, is a key influence.

Phytochemical Screening and Anti-Diabetic Efficacy of O. Sanctum Seed Extract on Streptozotocin Induced Diabetic Rats

2017 ◽  
Vol 54 (3) ◽  
pp. 336
Author(s):  
Kavitha K. ◽  
Ponne S.
Keyword(s):  
Body Weight ◽  
Digestive Enzymes ◽  
Fasting Blood Glucose ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Seed Extract ◽  
Phytochemical Screening ◽  
Weight Changes

The present study was designed to assess the in vitro and in vivo anti-diabetic efficacy of <em>O. sanctum</em> seed and its phytochemical screening. In vitro inhibitory effect on carbohydrate digestive enzymes like α-amylase and α-glucosidase and in vivo parameters such as fasting blood glucose and body weight changes were studied, a potent inhibitory effect was observed on activities of digestive enzymes and a marked decrease in the glucose level in the <em>O. sanctum</em> seed extract treated streptozotocin induced diabetic rats was noted. Further a marked reduction in body weight was also observed.

Regulation of sgk by aldosterone and its effects on the epithelial Na+ channel

2000 ◽  
Vol 278 (4) ◽  
pp. F613-F619 ◽  
Author(s):  
Alexander Shigaev ◽  
Carol Asher ◽  
Hedva Latter ◽  
Haim Garty ◽  
Eitan Reuveny
Keyword(s):  
De Novo ◽  
Rat Kidney ◽  
Kidney Cortex ◽  
Na Channel ◽  
Xenopus Laevis Oocytes ◽  
Fourfold Increase ◽  
Tight Epithelia ◽  
High Level

Aldosterone is the major corticosteroid regulating Na+ absorption in tight epithelia and acts primarily by activating the epithelial Na+ channel (ENaC) through unknown induced proteins. Recently, it has been reported that aldosterone induces the serum- and glucocorticoid-dependent kinase sgk and that coexpressing ENaC with this kinase in Xenopus laevis oocytes increases the amiloride-sensitive Na+current (Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, and Pearce D. Proc Natl Acad Sci USA 96: 2514–2519, 1999). The present study was done to further characterize regulation of sgk by aldosterone in native mammalian epithelia and to examine its effect on ENaC. With both in vivo and in vitro protocols, an almost fivefold increase in the abundance of sgk mRNA has been demonstrated in rat kidney and colon but not in lung. Induction of sgk by aldosterone was detected in kidney cortex and medulla, whereas the papilla expressed a constitutively high level of the kinase. The increase in sgkmRNA was detected as early as 30 min after the hormonal application and was independent of de novo protein synthesis. The observed aldosterone dose-response relationships suggest that the response is mediated, at least in part, by occupancy of the mineralocorticoid receptor. Coexpressing sgk and ENaC in Xenopus oocytes evoked a fourfold increase in the amiloride-blockable Na+ channel activity. A point mutation in the β-subunit known to impair regulation of the channel by Nedd4 (Y618A) had no significant effect on the response to sgk.

scholarly journals α-Glucosidase Inhibitory, Anti-Oxidant, and Anti-Hyperglycemic Effects of Euphorbia nivulia–Ham. in STZ-Induced Diabetic Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582093942
Author(s):  
Muhammad Younus ◽  
Muhammad Mohtasheem ul Hasan ◽  
Khalil Ahmad ◽  
Ali Sharif ◽  
Hafiz Muhammad Asif ◽  
...  
Keyword(s):  
High Performance ◽  
Wistar Rat ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Control Group ◽  
Control Drug ◽  
Antidiabetic Effects

In this study, we aimed to investigate the antidiabetic effects of Euphorbia nivulia (En), native to Cholistan Desert area of Bahawalpur, Pakistan. First, we performed high-performance liquid chromatography analysis and found that this plant contains ferulic acid, gallic acid, quercetin, benzoic acid, polyphenols, and flavonoids. Then, we performed in vitro and in vivo studies to assess its effects on diabetic Wistar rat model. The experiments were performed and compared with control drug glibenclamide. The 70% hydroalcoholic extract of En exhibited 97.8% in vitro α-glucosidase inhibitory effect at a dose of 1.0 mg/mL. We orally administered the extract of En and control drug to the streptozotocin (STZ)-induced diabetic rats and analyzed its antidiabetic effects. We found that the extract of En with a dose of 500 mg/kg/body weight exhibited significant effect to reduce blood glucose in STZ-induced rats as compared with the control group ( P < .001). Our histological data also showed that the extract significantly improved the histopathology of pancreas. Collectively, both in vitro and in vivo studies revealed that En possesses α-glucosidase inhibitory, antioxidant, and anti-hyperglycemic effect in STZ-induced diabetic rats.

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