administration has recently been proposed as a simple and convenient method to measure protein synthesis rates.2 H2O administration results in deuterium labeling of free amino acids such as alanine, and incorporation into proteins of labeled alanine can then be used to measure protein synthesis rates. We examined first whether during 2 H2O administration plasma free alanine enrichment is a correct estimate of the enrichment in the tissue amino acid pools used for protein synthesis. We found that, after 2 H2O administration, deuterium labeling in plasma free alanine equilibrated rapidly with body water, and stable enrichment values were obtained within 20 min. Importantly, oral administration of 2 H2O induced no difference of labeling between portal and peripheral circulation except for the initial 10 min after a loading dose. The kinetics of free alanine labeling were comparable in various tissues (liver, skeletal muscle, heart) and in plasma with identical plateau values. We show next that increased glycolytic rate or absorption of unlabeled amino acids from ingested meals do not modify alanine labeling. Calculated synthesis rates of mixed proteins were much higher (20-to 70-fold) in plasma and liver than in muscle and heart. Last, comparable replacement rates of apoB100-VLDL were obtained in humans by using the kinetics of incorporation into apoB100 of infused labeled leucine or of alanine labeled by 2 H2O administration. All of these results support 2 H2O as a safe, reliable, useful, and convenient tracer for studies of protein synthesis, including proteins with slow turnover rate. protein synthesis; stable isotope; mass spectrometry; alanine BODY PROTEINS ARE CONTINUOUSLY SYNTHESIZED and degraded. These synthesis and degradation rates are highly variable among individual proteins and are modified by physiological factors and pathological situations. Since maintainance of adequate amounts of whole body protein store, but also of a given protein in plasma or tissue, is essential for health, much effort has been devoted to the measurement of protein synthesis rate, particularly in humans, and several approaches have been proposed (26,28). Most measure protein synthesis using the precursor-product method, i.e., by following the incorporation into proteins of a labeled amino acid after acute (bolus) or prolonged (infusion) administration of this labeled molecule. A central problem in this method is to correctly measure the enrichment in the true precursor pool, the tRNA-bound amino acid for protein synthesis. Enrichment of the precursor by the tracer administered is usually measured in the plasma, the only pool that can be easily sampled, particularly in humans, as ethical considerations limit access to tissues. Assuming that enrichment of amino acid in the plasma pool reflects enrichment in the true precursor pool is questionable. It has been proposed that measuring the enrichment of plasma ␣-ketoisocaproate (KIC) during the infusion of labeled leucine (21), or of urinary hippurate during the infusion of labeled...
Background: Diabetic cardiomyopathy (DCM) contributes to cardiac failure in diabetic patients. It is characterized by excessive lipids accumulation, with increased triacylglycerol (TAG) stores, and fibrosis in left ventricle (LV). The mechanisms responsible are incompletely known and no specific treatment is presently defined. We evaluated the possible usefulness of two molecules promoting lipid oxidation, fenofibrate and metformin, in an experimental model of DCM, the Zucker diabetic rat (ZDF).
No specific treatment for nonalcoholic hepatic fatty liver disease has been defined. We followed the spontaneous evolution of liver steatosis and tested the therapeutic usefulness of metformin and fenofibrate in a model of steatosis, the Zucker diabetic fatty (ZDF) rat. ZDF and control rats were studied at 7, 14, and 21 weeks. After initial study at 7 weeks, ZDF rats received no treatment, metformin or fenofibrate until studies at 14 or 21 weeks. ZDF rats were obese, hypertriglyceridemic, insulin resistant at 7 weeks, type 2 diabetic at 14, diabetic with insulin deficiency at 21. They had steatosis at 7 weeks with increased hepatic expression and activity of lipogenesis. Steatosis was unchanged at 14 and 21 weeks despite lower expression and activity of lipogenesis. Metformin and fenofibrate did not modify energy intake or expenditure or the evolution of diabetes. Both compounds decreased plasma triacylglycerol (TAG) concentrations. Hepatic TAG content was reduced by fenofibrate at 14 and 21 weeks but only at 21 weeks by metformin. Metformin had no significant effects on the expression in liver of genes of fatty acids metabolism. The beneficial effect of fenofibrate occurred despite increased expression of genes involved in the uptake and activation of fatty acids. Acyl‐CoA oxidase (ACO) and carnitine palmitoyltransferase I (CPTI) mRNA levels were increased by fenofibrate showing evidence of increased lipid oxidation. To conclude, metformin had only moderate effects on liver steatosis. The effects of fenofibrate was more marked but remained mild.
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