scholarly journals Effect of streptozotocin-induced diabetes mellitus on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase

1980 ◽  
Vol 188 (3) ◽  
pp. 601-608 ◽  
Author(s):  
M B Weinberg ◽  
M F Utter
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Pyruvate Dehydrogenase Complex ◽  
Mitochondrial Protein ◽  
Diabetic Rats ◽  
Pulse Labelling ◽  
Enzyme Protein ◽  
Carboxylase Activity ◽  
Streptozotocin Induced Diabetes ◽  
Synthesis And Degradation

Immunochemical techniques were used to study the effect of streptozotocin-induced diabetes on the amounts of pyruvate carboxylase and pyruvate dehydrogenase and on their rates of synthesis and degradation. Livers from diabetic rats had twice the pyruvate carboxylase activity of livers from normal rats when expressed in terms of DNA or body weight. The changes in catalytic activity closely paralleled changes in immunoprecipitable enzyme protein. Relative rates of synthesis determined by pulse-labelling studies showed that the ratio of synthesis of pyruvate carboxylase to that of average mitochondrial protein was increased 2.0-2.5 times in diabetic animals over that of control animals. Other radioisotopic studies indicated that the rate of degradation of this enzyme was not altered significantly in diabetic rats, suggesting that the increase in this enzyme was due to an increased rate of synthesis. Similar experiments with pyruvate dehydrogenase, the first component of the pyruvate dehydrogenase complex, showed that livers from diabetic rats had approximately the same amount of immunoprecipitable enzyme protein as the control animals, but a larger proportion of the enzyme was in its inactive state. The rates of synthesis and degradation of pyruvate dehydrogenase were not affected significantly by diabetes.

scholarly journals Conversion of inactive (phosphorylated) pyruvate dehydrogenase complex into active complex by the phosphate reaction in heart mitochondria is inhibited by alloxan-diabetes or starvation in the rat

1978 ◽  
Vol 173 (2) ◽  
pp. 669-680 ◽  
Author(s):  
N J Hutson ◽  
A L Kerbey ◽  
P J Randle ◽  
P H Sugden
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Rat Heart ◽  
Pyruvate Dehydrogenase Complex ◽  
Diabetic Rats ◽  
Atp Depletion ◽  
Heart Mitochondria ◽  
Active Complex ◽  
Phosphate Complex ◽  
Rat Hearts ◽  
Dehydrogenase Complex

1. The conversion of inactive (phosphorylated) pyruvate dehydrogenase complex into active (dephosphorylated) complex by pyruvate dehydrogenase phosphate phosphatase is inhibited in heart mitochondria prepared from alloxan-diabetic or 48h-starved rats, in mitochondria prepared from acetate-perfused rat hearts and in mitochondria prepared from normal rat hearts incubated with respiratory substrates for 6 min (as compared with 1 min). 2. This conclusion is based on experiments with isolated intact mitochondria in which the pyruvate dehydrogenase kinase reaction was inhibited by pyruvate or ATP depletion (by using oligomycin and carbonyl cyanide m-chlorophenylhydrazone), and in experiments in which the rate of conversion of inactive complex into active complex by the phosphatase was measured in extracts of mitochondria. The inhibition of the phosphatase reaction was seen with constant concentrations of Ca2+ and Mg2+ (activators of the phosphatase). The phosphatase reaction in these mitochondrial extracts was not inhibited when an excess of exogenous pig heart pyruvate dehydrogenase phosphate was used as substrate. It is concluded that this inhibition is due to some factor(s) associated with the substrate (pyruvate dehydrogenase phosphate complex) and not to inhibition of the phosphatase as such. 3. This conclusion was verified by isolating pyruvate dehydrogenase phosphate complex, free of phosphatase, from hearts of control and diabetic rats an from heart mitochondria incubed for 1min (control) or 6min with respiratory substrates. The rates of re-activation of the inactive complexes were then measured with preparations of ox heart or rat heart phosphatase. The rates were lower (relative to controls) with inactive complex from hearts of diabetic rats or from heart mitochondria incubated for 6min with respiratory substrates. 4. The incorporation of 32Pi into inactive complex took 6min to complete in rat heart mitocondria. The extent of incorporation was consistent with three or four sites of phosphorylation in rat heart pyruvate dehydrogenase complex. 5. It is suggested that phosphorylation of sites additional to an inactivating site may inhibit the conversion of inactive complex into active complex by the phosphatase in heart mitochondria from alloxan-diabetic or 48h-starved rats or in mitochondria incubated for 6min with respiratory substrates.

THIAMINE-RESPONSIVE LACTIC ACIDOSIS IN A PATIENT WITH DEFICIENT LOW-KM PYRUVATE CARBOXYLASE ACTIVITY IN LIVER

PEDIATRICS ◽  
1972 ◽  
Vol 50 (5) ◽  
pp. 702-711
Author(s):  
Michèle G. Brunette ◽  
Edgard Delvin ◽  
Bernard Hazel ◽  
Charles R. Scriver
Keyword(s):  
Lactic Acidosis ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Acid Metabolism ◽  
Psychomotor Retardation ◽  
Dietary Control ◽  
Carboxylase Activity ◽  
Cultured Skin ◽  
Carbohydrate Feeding ◽  
Partial Deficiency

The cause of severe intermittent lactic acidosis was investigated in a female infant with profound psychomotor retardation. Hypoglycemia, hyperpyruvic acidemia, and hyperalaninemia were identified in the newborn period. A triad of lactate, pyruvate, and alanine accumulation persisted throughout infancy, and ACTH, anorexia, and high carbohydrate feeding further provoked their accumulation. Careful dietary control or thiamine-HCl supplementation (5 to 20 mg/day) ameliorated the metabolic abnormality. Pyruvate dehydrogenase activity (which is thiamine-dependent) was normal in leukocytes and cultured skin fibroblasts. Hepatic pyruvate carboxylase activity (which is biotin-dependent) was found to comprise more than one component. There was a partial deficiency of total hepatic pyruvate carboxylase activity in the patient. The loss of activity was confined to the low-Km component of the enzyme which serves pvruvate metabolism in the physiological range. A defect in glucogenesis causing hypoglycemia, pyruvate accumulation with lactic acidosis, and aberrant amino acid metabolism can be attributed to the abnormality of pyruvate carboxylase. The response to thiamine in our patients may reflect activation of a normal "shunt" mechanism for pyruvate disposal via pyruvate dehydrogenase.

scholarly journals Emerging regulatory roles of mitochondrial sirtuins on pyruvate dehydrogenase complex and the related metabolic diseases: Review

2020 ◽  
Vol 7 (2) ◽  
pp. 3645-3658
Author(s):  
Abolfazl Nasiri ◽  
Masoud Sadeghi ◽  
Asad Vaisi-Raygani ◽  
Sara Kiani ◽  
Zahra Aghelan ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Pyruvate Dehydrogenase ◽  
Structural Changes ◽  
Metabolic Diseases ◽  
Pyruvate Dehydrogenase Complex ◽  
Mitochondrial Protein ◽  
Krebs Cycle ◽  
Acetyl Coa ◽  
Dehydrogenase Complex

The pyruvate dehydrogenase complex (PDC) is a multi-enzyme complex of the mitochondria that provides a link between glycolysis and the Krebs cycle. PDC plays an essential role in producing acetyl-CoA from glucose and the regulation of fuel consumption. In general, PDC enzyme is regulated in two different ways, end-product inhibition and posttranslational modifications (more extensive phosphorylation and dephosphorylation subunit E1). Posttranslational modifications of this enzyme are regulated by various factors. Sirtuins are the class III of histone deacylatases that catalyze protein posttranslational modifications, including deacetylation, adenosine diphosphate ribosylation, and deacylation. Sirt3, Sirt4, and Sirt5 are mitochondrial sirtuins that control the posttranslational modifications of mitochondrial protein. Considering the comprehensive role of sirtuins in post-translational modifications and regulation of metabolic processes, the aim of this review is to explore the role of mitochondrial sirtuins in the regulation of the PDC. PDC deficiency is a common metabolic disorder that causes pyruvate to be converted to lactate and alanine rather than to acetyl-CoA. because this enzyme is in the gateway of complete oxidation, glucose products entering the Krebs cycle and resulting in physiological and structural changes in the organs. Metabolic blockage such as ketogenic diet broken up by b -oxidation and producing acetyl-CoA can improve the patients. Sirtuins play a role in the production of acetyl-CoA through oxidation of fatty acids and other pathways. Thus, we hypothesize that the targets and bioactive compounds targeting mitochondrial sirtuins can be involved in the treatment of PDC deficiency. In general, this review discusses the present knowledge on how mitochondrial sirtuins are involved in the regulation of PDC as well as their possible roles in the treatment of PDC deficiency.

scholarly journals The impact of CO2/HCO3-availability on anaplerotic flux in PDHC-deficientCorynebacterium glutamicumstrains

2019 ◽  
Author(s):  
Aileen Krüger ◽  
Johanna Wiechert ◽  
Cornelia Gätgens ◽  
Tino Polen ◽  
Regina Mahr ◽  
...  
Keyword(s):  
Corynebacterium Glutamicum ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Metabolic Flux ◽  
Pyruvate Dehydrogenase Complex ◽  
Lag Phase ◽  
Metabolic Reaction ◽  
Production Rates ◽  
The Impact ◽  
Dehydrogenase Complex

AbstractThe pyruvate dehydrogenase complex (PDHC) catalyzes the oxidative decarboxylation of pyruvate yielding acetyl-CoA and CO2. The PDHC-deficientCorynebacterium glutamicumstrain ΔaceEis therefore lacking an important decarboxylation step in central metabolism. Additional inactivation ofpyc, encoding pyruvate carboxylase, resulted in a >15 hour lag phase in the presence of glucose, while no growth defect was observed on gluconeogenetic substrates like acetate. Growth was successfully restored by deletion ofptsGencoding the glucose-specific permease of the PTS system, thereby linking the observed phenotype to the increased sensitivity of strain ΔaceEΔpycto glucose catabolism. In the following, strain ΔaceEΔpycwas used to systematically study the impact of perturbations of the intracellular CO2/HCO3-pool on growth and anaplerotic flux. Remarkably, all measures leading to enhanced CO2/HCO3-levels, such as external addition of HCO3-, increasing the pH, or rerouting metabolic flux via pentose phosphate pathway, at least partially eliminated the lag phase of strain ΔaceEΔpycon glucose medium. In accordance, inactivation of the urease enzyme, lowering the intracellular CO2/HCO3-pool, led to an even longer lag phase accompanied with the excretion of L-valine and L-alanine. Transcriptome analysis as well as an adaptive laboratory evolution experiment of strain ΔaceEΔpycrevealed the reduction of glucose uptake as a key adaptive measure to enhance growth on glucose/acetate mixtures. Altogether, our results highlight the significant impact of the intracellular CO2/HCO3-pool on metabolic flux distribution, which becomes especially evident in engineered strains suffering from low endogenous CO2production rates as exemplified by PDHC-deficient strains.ImportanceCO2is a ubiquitous product of cellular metabolism and an essential substrate for carboxylation reactions. The pyruvate dehydrogenase complex (PDHC) catalyzes a central metabolic reaction contributing to the intracellular CO2/HCO3-pool in many organisms. In this study, we used a PDHC-deficient strain ofCorynebacterium glutamicum, which was additionally lacking pyruvate carboxylase (ΔaceEΔpyc). This strain featured a >15 h lag phase during growth on glucose-acetate mixtures. We used this strain to systematically assess the impact of alterations in the intracellular CO2/HCO3-pool on growth on glucose-containing medium. Remarkably, all measures enhancing the CO2/HCO3-levels successfully restored growth emphasizing the strong impact of the intracellular CO2/HCO3-pool on metabolic flux especially in strains suffering from low endogenous CO2production rates.

scholarly journals The Flavonoid Kaempferol Ameliorates Streptozotocin-Induced Diabetes by Suppressing Hepatic Glucose Production

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2338 ◽  
Author(s):  
Hana Alkhalidy ◽  
Will Moore ◽  
Yao Wang ◽  
Jing Luo ◽  
Ryan McMillan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Carboxylase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Calorie Intake ◽  
Diabetic Mice ◽  
Insulin Deficiency ◽  
Carboxylase Activity ◽  
Hepatic Glucose ◽  
Streptozotocin Induced Diabetes

In diabetes mellitus, the excessive rate of glucose production from the liver is considered a primary contributor for the development of hyperglycemia, in particular, fasting hyperglycemia. In this study, we investigated whether kaempferol, a flavonol present in several medicinal herbs and foods, can be used to ameliorate diabetes in an animal model of insulin deficiency and further explored the mechanism underlying the anti-diabetic effect of this flavonol. We demonstrate that oral administration of kaempferol (50 mg/kg/day) to streptozotocin-induced diabetic mice significantly improved hyperglycemia and reduced the incidence of overt diabetes from 100% to 77.8%. This outcome was accompanied by a reduction in hepatic glucose production and an increase in glucose oxidation in the muscle of the diabetic mice, whereas body weight, calorie intake, body composition, and plasma insulin and glucagon levels were not altered. Consistently, treatment with kaempferol restored hexokinase activity in the liver and skeletal muscle of diabetic mice while suppressed hepatic pyruvate carboxylase activity and gluconeogenesis. These results suggest that kaempferol may exert antidiabetic action via promoting glucose metabolism in skeletal muscle and inhibiting gluconeogenesis in the liver.

scholarly journals Exercise Training Increases the Activity of Pyruvate Dehydrogenase Complex in Skeletal Muscle of Diabetic Rats.

2002 ◽  
Vol 49 (5) ◽  
pp. 547-554 ◽  
Author(s):  
NAOYA NAKAI ◽  
YUTAKA MIYAZAKI ◽  
YUZO SATO ◽  
YOSHIHARU OSHIDA ◽  
MASARU NAGASAKI ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Diabetic Rats ◽  
Dehydrogenase Complex

scholarly journals Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in starved and alloxan-diabetic rats

1982 ◽  
Vol 208 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Ian D. Caterson ◽  
Stephen J. Fuller ◽  
Philip J. Randle
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pyruvate Dehydrogenase ◽  
Heart Muscle ◽  
Alloxan Diabetes ◽  
Pyruvate Dehydrogenase Complex ◽  
Diabetic Rats ◽  
Acid Oxidation ◽  
Active Complex ◽  
Perfused Hearts

Intravenous administration of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid had no effect on the proportion of pyruvate dehydrogenase complex in the active form in heart, diaphragm or gastrocnemius muscles or in liver, kidney or adipose tissue of fed normal rats. The compound reversed the effect of 48h starvation (which decreased the proportion of active complex) in heart muscle, partially reversed the effect of starvation in kidney, but had no effect in the other tissues listed. The compound failed to reverse the effect of alloxan-diabetes (which decreased the proportion of active complex) in any of these tissues. In perfused hearts of fed normal rats, 2-tetradecylglycidate reversed effects of palmitate (which decreased the proportion of active complex), but it had no effect in the absence of palmitate. In perfused hearts of 48h-starved rats the compound increased the proportion of active complex to that found in fed normal rats in the presence or absence of insulin. In perfused hearts of diabetic rats the compound normalized the proportion of active complex in the presence of insulin, but not in its absence. Palmitate reversed the effects of 2-tetradecylglycidate in perfused hearts of starved or diabetic rats. Evidence is given that 2-tetradecylglycidate only reverses effects of starvation and alloxan-diabetes on the proportion of active complex in heart muscle under conditions in which it inhibits fatty acid oxidation. It is concluded that effects of starvation and alloxan-diabetes on the proportion of active complex in heart muscle are dependent on fatty acid oxidation. Insulin had no effect on the proportion of active complex in hearts or diaphragms of fed or starved rats in vitro. In perfused hearts of alloxan-diabetic rats, insulin induced a modest increase in the proportion of active complex in the presence of albumin, but not in its absence.

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