Metabolism of glucose in hyper- and hypo-thyroid rats in vivo. Glucose-turnover values and futile-cycle activities obtained with 14C- and 3H-labelled glucose.
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ABSTRACT:
SUBMITTER: Okajima F
PROVIDER: S-EPMC1161338 | biostudies-other | 1979 Aug
REPOSITORIES: biostudies-other
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Project description:1. In euthyroid rats, treatment with reserpine of 6-hydroxydopamine, which deprived neuronal terminals of catecholamines, resulted in increases in rates and rate coefficients for blood glucose turnover in the starved states as determined by decay of [U-14C,6-3H]-glucose. Conversely, the injection of adrenaline or noradrenaline into starved euthyroid rats caused a marked decrease in rate coeeficients for glucose turnover. There was no change in the percentage glucose recycling under these conditions. 2. Adrenaline and noradrenaline caused more pronounced hyperglycaemia in hyperthyroid than in euthyroid rats owing to the greater activation of hepatic glucose production. 3. The increase in glucose turnover characteristics of hyperthyroidism was observed even after treatment with an alpha- or beta-adrenergic antagonist, showing the insignificant role of the balance between alpha- and beta-adrenergic receptors in the thyroid-dependent metabolic changes. 4. Rate coefficients for glucose turnover were not affected by reserpine treatment or catecholamine injections when rats had been rendered hyperthyroid. 5. Thus catecholamines are direct determinants of glucose-turnover rates in the starved state, and depend to some extent on the prevailing thyroid state.
| S-EPMC1161340 | biostudies-other
Project description:1. Rates and rate coefficients of glucose utilization and replacement (glucose turnover) as well as its recycling were determined in rats by using [U-14C]- and [2-3H]-, [3-3H]- or [6-3H]-glucose. 2. In euthyroid rats, the blood concentration of glucose was 1.5 times and its turnover rate was 2 times as high in the fed state as in the starved state; consequently the rate coefficient, a measure of the capacity of rats to utilize blood glucose, was also higher in the former than in the latter. 3. Induction of mild diabetes by streptozotocin exerted little influence on the content and turnover of blood glucose in the starved state, whereas it caused hyperglycaemia and a decrease in the rate coefficient after feeding. 4. Induction of hyperthyroidism caused increases in rates and rate coefficients of glucose turnover to substantially the same extent whether or not the plasma concentration of insulin was lowered by treatment with streptozotocin or injection with anti-insulin serum. 5. It is concluded that thyroid hormones are capable of enhancing glucose turnover in the starved state independently of endogenous insulin, which plays a significant role in increasing glucose utilization in the fed state.
| S-EPMC1161339 | biostudies-other
Project description:1. Glucose labelled with (3)H in position 2 and uniformly with (14)C was administered simultaneously to rabbits and rats either as a single injection or by continuous infusion. Plasma glucose specific radioactivity and the yield of (3)H in the plasma water were monitored. 2. The rates of synthesis, recycling of carbon and total body mass of glucose were calculated, without assuming a multicompartmental model and without fitting data by exponential expressions. 3. The rate of synthesis of glucose in starved-overnight rabbits was 4mg/min per kg (range 3-4.5mg/min per kg) and 25-35% of the glucose carbon was recycled. The mass of total body glucose in starved rabbits was 290mg/kg (range 220-390mg/kg). About one-third of the total body glucose equilibrates nearly instantaneously with plasma glucose. 4. In rats starved overnight, glucose synthesis was about 10mg/min per kg and recycling of carbon ranged from 30-40%. Total body mass (per kg body weight) is similar to that in rabbits. 5. The activity in plasma water after injection of [2-(3)H]glucose was determined. The initial rate of (3)H(2)O formation is rapid, indicating that the major site of glucose catabolism is in the rapidly mixing pool. The curve of total body glucose radioactivity was obtained from the (3)H(2)O yield, and total mass of glucose was calculated. This agrees with that obtained from the (3)H specific-radioactivity curve.
| S-EPMC1168223 | biostudies-other
Project description:1. [2-(3)H,U-(14)C]- or [3-(3)H,U-(14)C]-Lactate was administered by infusion or bolus injection to overnight-starved rats. Tracer lactate was injected or infused through indwelling cannulas into the aorta and blood was sampled from the vena cava (A-VC mode), or it was administered into the vena cava and sampled from the aorta (V-A mode). Sampling was continued after infusion was terminated to obtain the wash-out curves for the tracer. The activities of lactate, glucose, amino acids and water were followed. 2. The kinetics of labelled lactate in the two modes differed markedly, but the kinetics of labelled glucose were much the same irrespective of mode. 3. The kinetics of (3)H-labelled lactate differed markedly from those for [U-(14)C]lactate. Isotopic steady state was attained in less than 1h of infusion of [(3)H]lactate but required over 6h for [U-(14)C]lactate. 4. (3)H from [2-(3)H]lactate labels glucose more extensive than does that from [3-(3)H]lactate. [3-(3)H]Lactate also labels plasma amino acids. The distribution of (3)H in glucose was determined. 5. Maximal radioactivity in (3)HOH in plasma is attained in less than 1min after injection. Near-maximal radioactivity in [(14)C]glucose and [(3)H]glucose is attained within 2-3min after injection. 6. The apparent replacement rates for lactate were calculated from the areas under the specific-radioactivity curves or plateau specific radioactivities after primed infusion. Results calculated from bolus injection and infusion agreed closely. The apparent replacement rate for [(3)H]lactate from the A-VC mode averaged about 16mg/min per kg body wt. and that in the V-A mode about 8.5mg/min per kg body wt. The apparent rates for [(14)C]lactate (;rate of irreversible disposal') were 8mg/min per kg body wt. for the A-VC mode and 5.5mg/min per kg body wt. for the V-A mode. Apparent recycling of lactate carbon was 55-60% according to the A-VC mode and 35% according to the V-A mode. 7. The specific radioactivities of [U-(14)C]glucose at isotopic steady state were 55% and 45% that of [U-(14)C]lactate in the A-VC and V-A modes respectively. We calculated, correcting for the dilution of (14)C in gluconeogenesis via oxaloacetate, that over 70% of newly synthesized glucose was derived from circulating lactate. 8. Recycling of (3)H between lactate and glucose was evaluated. It has no significant effect on the calculation of the replacement rate, but affects considerably the areas under the wash-out curves for both [2-(3)H]- and [3-(3)H]-lactate, and calculation of mean transit time and total lactate mass in the body. Corrected for recycling, in the A-VC mode the mean transit time is about 3min, the lactate mass about 50mg/kg body wt. and the lactate space about 65% of body space. The V-A mode yields a mass and lactate space about half those with the A-VC mode. 9. The area under the wash-out curve for [(14)C]lactate is some 20-30 times that for [(3)H]lactate, and apparent carbon mass is 400-500mg/kg body wt. and presumably includes the carbon of glucose, pyruvate and amino acids, which are exchanging rapidly with that of lactate.
| S-EPMC1162777 | biostudies-other
Project description:L-[3-3H,U-14C]Lactate was administered to starved rats either as a bolus or by continuous infusion. Tracer administration was performed two ways: injection into the vena cava and sampling from the aorta (V-A mode), or injection into the aorta and sampling from the vena cava (A-VC mode). The specific-radioactivity curves after infusion or injection differed markedly with the two procedures. However, the specific radioactivities of 14C-labelled glucose derived from [U-14C]lactate were similar in the two modes. The apparent turnover rates of lactate calculated from the 3H specific-radioactivity curves in the V-A mode were about half those obtained from the 3H specific-radioactivity curves in the A-VC mode. The apparent contribution of lactate carbon to glucose carbon calculated from specific-radioactivity curves of the A-VC mode was greater than that obtained from the V-A mode. The apparent recycling of lactate carbon calculated from the specific radioactivities for [U-14C]- and [3-3H]-lactate was greater in the A-VC mode than the V-A mode. [U-14C] Glucose was administered in the two modes, but in contrast with lactate the specific radioactivities were only slightly different. An analysis to account for these observations is presented. It is shown that the two modes represent sampling from different pools of lactate. The significance of sites of tracer administration and sampling for the interpretation of tracer kinetics of compounds present in intracellular and extracellular spaces, and with a high turnover rate, is discussed. We propose that for such compounds, including lactate, alanine and glycerol, the widely used V-A mode leads to a marked underestimate of replacement, mass and carbon recycling, and that the A-VC mode is the preferred method for the assessment of these parameters.
| S-EPMC1162776 | biostudies-other
Project description:Chronic hepatitis C virus (HCV) infection is a leading cause of liver cancer. HCV propagation and oncogenicity depend in part on the phosphorylation states of its non-structural protein 5A (NS5A); however, little is known about how hypo- or hyper-phosphorylated NS5A functions. Here, we segregated hypo- from hyper-phosphorylated NS5A in HCV-infected Huh7.5.1 cells with two custom-made specific antibodies and differentiated their interacting proteins with dimethyl labeling-based quantitative proteomics. Bioinformatics analysis revealed that hyper-phosphorylated NS5A preferentially binds the polymerase II-associated factor 1 complex known to alter host gene expression involved in cancer progression. In contrast, hypo-phosphorylated NS5A binds proteins involved in host antiviral response. Moreover, we found that the hypo-phosphorylated NS5A binds DNA-dependent protein kinase catalytic subunit (DNA-PKcs) predicted to phosphorylate NS5A at serine 232, a key amino acid that governs NS5A transition from hypo- to hyper-phosphorylation state. Inhibition of DNA-PKcs with an inhibitor or via gene-specific knockdown significantly reduced serine 232 phosphorylation and NS5A hyper-phosphorylation. Collectively, we have identified a protein kinase that regulates a delicate balance of NS5A between hypo- and hyper-phosphorylation states respectively involved in host antiviral responses and liver cancer progression.
2019-06-17 | PXD012767 | Pride
Project description:1. Thyroidectomized rats injected daily with 0, 0.1, 2 or 25mug of l-thyroxine/100g body wt. were compared with intact controls. In plasma, the protein-bound iodine was decreased in the rats given the 0 or 0.1mug doses and increased in those given the 25mug dose. 2. Blood glucose decreased in those given 2mug and was augmented in those given 25mug, and ketone bodies were the same in all the groups. 3. Plasma insulin was lowest in the rats given the 0 or 0.1mug doses and was highest in those given the 2 or 25mug doses of thyroxine. 4. After 48h starvation, the decrease in blood glucose and increase in ketone bodies observed in all the groups was greatest in the group not supplemented with thyroxine. 5. Plasma insulin concentrations remained at the value for fed animals in the rats given the 25mug dose of thyroxine but decreased in the other groups. 6. In fed animals, concentrations of hepatic DNA P, citrate, total fatty acids and acetyl-CoA were similar in all the groups, and glycogen was low only in the rats given the 25mug dose of thyroxine. 7. After 48h starvation, liver DNA P, total fatty acids and acetyl-CoA increased in all the groups, except in the rats given the 25mug dose, where both total fatty acids and acetyl-CoA remained at the value for fed animals. Liver citrate did not change in the groups given the 0 or 25mug doses of thyroxine, but decreased in the other groups. 8. The results are discussed in relation to the regulation of intermediary metabolism in hypo- and hyper-thyroidism.
| S-EPMC1173811 | biostudies-other
Project description:In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.
| S-EPMC3968552 | biostudies-literature
Project description:Amino acids labelled with 18(O) on both carboxy oxygen atoms have the potential for use as non-recyclable tracers to measure protein turnover. During protein synthesis one of the labelled oxygen atoms is removed, and thus release of the mono-labelled amino acid could be used to determine proteolysis. Primary cultures of embryonic-chick skeletal-muscle cells were used to test the use of 18(O2)-labelled Leu to measure proteolysis. For 9-day cultures, prelabelled on days 2-8 with medium containing one-half the Leu as [18O2]Leu and one-half as [2H3]Leu, release of [18(O)]Leu was less than 50% that of [2H]Leu over 24 h, suggesting a loss of the 18O label by a mechanism other than protein synthesis. Medium containing [18(O2)]Leu, [2H3]Leu, [18O2]Phe and [13C]Phe was then incubated with 9-day cultures to compare the rate of loss of the 18(O)-label from Leu and Phe with the rate of uptake of the non-carboxy-oxygen-labelled amino acids. Results for Leu demonstrated an 81% loss of the 18(O) label compared with a 33% decrease in [2H]Leu over 12 h. Loss of the 18(O) label was four times as great for Leu as for Phe. Loss of the 18(O) label was not decreased by addition of cycloheximide or by addition of a 3-fold excess of Ile, Val and Tyr; thus the loss of label was not due to protein synthesis alone or to misbinding to incorrect tRNAs. Infusion of the isotopes into pigs showed that the 18(O) label of Leu was not lost during transamination to alpha-ketoisocaproate (alpha-oxoisohexanoate). The most probable explanation is that the 18(O) label is lost as a result of the enzymic deacylation of tRNA, that this process is substantially faster for Leu than for Phe, and that this represents a potentially costly futile cycle for Leu.
| S-EPMC1134471 | biostudies-other
Project description:Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question 'What characterizes the exceptions: the mutants that functionally respond either not or extremely well'. A functional response is the product of the number of CFTR molecules on the cell surface, open probability, and conductivity of the CFTR chloride channel. By combining biosynthetic radiolabeling with protease-susceptibility assays, we have followed CF-causing mutants during the early and late stages of folding in the presence and absence of modulators. Most CFTR mutants showed typical biochemical responses for each modulator, such as a TMD1 conformational change or an increase in (cell-surface) stability, regardless of a functional response. These modulators thus should still be considered for hypo-responder genotypes. Understanding both biochemical and functional phenotypes of outlier mutations will boost our insights into CFTR folding and misfolding, and lead to improved therapeutic strategies.
| S-EPMC9735543 | biostudies-literature