Fundamental Limitations of [ 18 F]2-Deoxy-2-Fluoro- d -Glucose for Assessing Myocardial Glucose Uptake
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Background The glucose tracer analog [ 18 F]2-deoxy-2-fluoro- d -glucose (FDG) is widely used for assessing regional myocardial glucose metabolism in vivo. The reproducibility of this method has recently been questioned because of a discordant affinity of hexokinase for its substrates glucose and 2-deoxyglucose. We therefore compared rates of glucose utilization simultaneously with tissue time-activity curves of FDG uptake before and after changes in the physiological environment of the heart. Methods and Results Isolated working rat hearts were perfused for 60 minutes with recirculating Krebs buffer containing glucose (10 mmol/L), FDG (1 μCi/mL), [2- 3 H]glucose (0.05 μCi/mL), and [U- 14 C]2-deoxyglucose (2-DG; 0.025 μCi/mL). Myocardial glucose uptake was measured by tracer ([2- 3 H]glucose) and tracer analog methods (FDG and 2-DG) before and after the addition of either insulin (1 mU/mL), epinephrine (1 μmol/L), lactate (40 mmol/L), or d,l -β-hydroxybutyrate (40 mmol/L) at 30 minutes of perfusion and after acute changes in cardiac workload. Under steady-state conditions, myocardial rates of glucose utilization as measured by tritiated water ( 3 H 2 O) production from metabolism of [2- 3 H]glucose, FDG uptake, and 2-DG retention were linearly related. The addition of competing substrates decreased glucose utilization immediately. The addition of insulin increased the rate of glucose utilization as measured by the glucose tracer but not as measured by the tracer analogs. The ratio of 3 H 2 O release/myocardial FDG uptake increased by 111% after the addition of insulin, by 428% after the addition of lactate, and by 232% after the addition of β-hydroxybutyrate. Epinephrine increased rates of glucose utilization and contractile performance, whereas there was no increase in glucose uptake with a comparable increase in workload alone. There was no change in the relation between the glucose tracer and the tracer analog either with epinephrine or with acute changes in workload. Conclusions The uptake and retention of FDG in heart muscle is linearly related to glucose utilization only under steady-state conditions. Addition of insulin or of competing substrates changes the relation between uptake of the glucose tracer and FDG. These observations preclude the determination of absolute rates of myocardial glucose uptake by the tracer analog method under non–steady-state conditions.Keywords:
Carbohydrate Metabolism
Deoxyglucose
Hexokinase
Objectives The aim of this study was to evaluate the effects of Hwanggi-tang on glucose digestion, uptake, and metabolism in murine C2C12 myotubes. Methods Hwanggi-tang was prepared according to the Dong-ui-bo-gam (âªæ±é«å¯¶éâ«) prescription by 70% ethanol extraction. The effect on glucose digestion was examined by determining the inhibitory effect of Hwanggi-tang on α-glucosidase activity. We also compared and verified the gene and protein expression of genes related to glucose uptake in C2C12 myotubes treated with Hwanggi-tang or insulin. Glucose metabolism was assessed by the expression levels of associated enzymes. Results Hwanggi-tang caused a dose-dependent inhibition of α-glucosidase activity, induced glucose uptake by activation of the PI3K/Akt/mTOR pathway in the insulin signaling pathway, and promoted glucose oxidation and β-oxidation. Conclusions Hwanggi-tang exerts an anti-diabetic effect on murine myotubes by inhibiting glucose digestion and inducing glucose uptake and consumption. Keywords: carbohydrate metabolism, diabetes mellitus, herbal medicine, skeletal muscle fiber
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Abstract Glucose consumption of skeletal muscle differentiated in vitro was studied under various experimental conditions by means of the [ 3 H]deoxyglucose ([ 3 H]DG) uptake technique. The results show that glucose uptake by skeletal muscle is a function of its activity; when the muscle is electrically stimulated to contract the uptake of [ 3 H]DG is increased, and when spontaneous activity is inhibited, the uptake of [ 3 H]DG is decreased. While electrical stimulation (ES) did not affect the uptake of 3‐ O ‐methyl‐glucose (3‐OMG), DG uptake was enhanced in spite of the presence of cycloheximide in electrically stimulated cultures, suggesting that muscle contraction probably activates the enzyme hexokinase. Thus our data show that the uptake of [ 3 H]DG can be a tool for measuring muscle contraction.
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Research conducted over the last 50 yr has provided insight into the mechanisms by which insulin stimulates glucose transport across the skeletal muscle cell membrane Transport alone, however, does not result in net glucose uptake as free glucose equilibrates across the cell membrane and is not metabolized. Glucose uptake requires that glucose is phosphorylated by hexokinases. Phosphorylated glucose cannot leave the cell and is the substrate for metabolism. It is indisputable that glucose phosphorylation is essential for glucose uptake. Major advances have been made in defining the regulation of the insulin-stimulated glucose transporter (GLUT4) in skeletal muscle. By contrast, the insulin-regulated hexokinase (hexokinase II) parallels Robert Frost's "The Road Not Taken." Here the case is made that an understanding of glucose phosphorylation by hexokinase II is necessary to define the regulation of skeletal muscle glucose uptake in health and insulin resistance. Results of studies from different physiological disciplines that have elegantly described how hexokinase II can be regulated are summarized to provide a framework for potential application to skeletal muscle. Mechanisms by which hexokinase II is regulated in skeletal muscle await rigorous examination.
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Abstract: The effects of metrizamide on the kinetics of rat brain hexokinase were compared in vitro with those of 2‐deoxyglucose and glucosamine. Although metrizamide, 2‐deoxyglucose, and glucosamine are known to be competitive inhibitors of approximately equal potency for glucose of yeast hexokinase ( K 1 approximately 0.7 m m for all three), metrizamide is a much weaker competitive inhibitor ( K i about 20 m m ) of rat brain hexokinase than either 2‐deoxyglucose or glucosamine ( K i about 0.3 m m for both). This indicates a greater active site specificity of rat brain hexokinase than of yeast hexokinase. Rat brain hexokinase activity is enhanced approximately threefold in the presence of 0.05, 0.2, and 0.8 mg/ml bovine serum albumin, while yeast hexokinase is only enhanced by 50% under these conditions. Despite the high K i value for metrizamide, interference with glucose metabolism may occur whenever metrizamide is present in much higher concentrations than glucose. Myelography in humans is one such situation.
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