Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used an animal model of insulin resistance-the obese Zucker (fa/fa) rat-to test whether oral administration of the non-sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, trandolapril, alone or in combination with the Ca2+-channel blocker, verapamil, can induce a beneficial effect on insulin-stimulated glucose transport and metabolism in skeletal muscle. Insulin-stimulated 2-deoxyglucose (2-DG) uptake in the isolated epitrochlearis muscle was less than 50% as great in obese animals compared with lean (Fa/-) controls (P < .05), but was significantly improved in the obese group by both short-term (6 hours, +33%) and long-term (14 days,+70%) oral treatment with trandolapril. Verapamil treatment alone did not alter insulin-stimulated 2-DG uptake in muscle, but simultaneous administration of verapamil and trandolapril resulted in the most pronounced effect on insulin-stimulated 2-DG uptake (+106%). Long-term treatment with trandolapril alone and in combination with verapamil significantly increased muscle glycogen (+26% to 27%), glucose transporter GLUT-4 protein (+27% to 31%), and hexokinase activity (+21% to 49%), and decreased plasma insulin levels (-23% to -29%). Muscle citrate synthase activity was enhanced only when trandolapril and verapamil were administered in combination (+24%). We conclude that the long-acting, non-sulfhydryl-containing ACE inhibitor, trandolapril, alone and in combination with the Ca2+-channel blocker, verapamil, can significantly improve insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat, and that this improvement is associated with favorable adaptive responses in GLUT-4 protein levels, glycogen storage, and activities of relevant intracellular enzymes of glucose catabolism.
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PMID:Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle. 862 94

Sixteen prepubertal Friesian heifers were used to examine the effect of bovine growth hormone (GH) and ovariectomy (OVX) at 2.5 mo of age (2 x 2 factorial design) on growth, carcass quality, and fiber types, capillarization, and metabolic potentials of the longissimus muscle, and serum concentrations of estradiol-17beta (E2beta), insulin, GH, IGF-I, and IGF-binding proteins (IGFBP). Treatment with GH (15 mg/d) started at 147 +/- 3 kg BW and lasted for 15 wk. Heifers were fed a mixed roughage-based diet. Growth hormone increased ADG (P < .001), improved gain:feed (P < .007), and had a small but positive influence on lean accretion. Growth hormone reduced fat thickness (P < .009), carcass fat trim (P < .009) and i.m. fat (P < .09). Ovariectomy did not affect performance but increased dressing percentage (P < .03), full rib weight (P < .003), and fat thickness (P < .04). Ovariectomy reduced E2beta (P < .001) and insulin (P < .02), and increased the 32-kDa IGFBP (IGFBP-2) (P < .09). Growth hormone treatment increased GH, IGF-I, the 28-kDa IGFBP, and the 40- to 43-kDa IGFBP (IGFBP-3) (P < .004 or P < .001). Neither GH nor ovariectomy affected the proportion and relative area of the individual muscle fiber types, but GH tended to increase type I fiber area (P < .10). Number of capillaries per fiber increased in OVX GH-treated heifers (GH x OVX interaction, P < .02). Activities of citrate synthetase were higher in GH-treated (P < .05) and OVX (P < .02) heifers, indicating increased oxidative capacity of the longissimus muscle. The effects of GH on performance and carcass fattening were in accordance with the observed hormonal changes. When slaughter occurs before puberty, ovariectomy has no effect on performance, only few effects on carcass quality, and small effects on hormone concentrations.
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PMID:Effects of growth hormone and ovariectomy on performance, serum hormones, insulin-like growth factor-binding proteins, and muscle fiber properties of prepubertal Friesian heifers. 865 31

Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into midthigh muscle was performed using positron emission tomography during basal and insulin-stimulated conditions (40 mU/m2 per min), in eight lean nondiabetic, eight obese nondiabetic, and eight obese subjects with NIDDM. In additional studies, vastus lateralis muscle was obtained by percutaneous biopsy during basal and insulin-stimulated conditions for assay of hexokinase and citrate synthase, and for immunohistochemical labeling of Glut 4. Quantitative confocal laser scanning microscopy was used to ascertain Glut 4 at the sarcolemma as an index of insulin-regulated translocation. In lean individuals, insulin stimulated a 10-fold increase of 2-deoxy-2[18F]fluoro-D-glucose (FDG) clearance into muscle and significant increases in the rate constants for inward transport and phosphorylation of FDG. In obese individuals, the rate constant for inward transport of glucose was not increased by insulin infusion and did not differ from values in NIDDM. Insulin stimulation of the rate constant for glucose phosphorylation was similar in obese and lean subjects but reduced in NIDDM. Insulin increased by nearly twofold the number and area of sites labeling for Glut 4 at the sarcolemma in lean volunteers, but in obese and NIDDM subjects translocation of Glut 4 was attenuated. Activities of skeletal muscle HK I and II were similar in lean, obese and NIDDM subjects. These in vivo and ex vivo assessments indicate that impaired glucose transport plays a key role in insulin resistance of NIDDM and obesity and that an additional impairment of glucose phosphorylation is evident in the insulin resistance of NIDDM.
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PMID:The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. 867 80

Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese Zucker (fa/fa) rat--an animal model of muscle insulin resistance--was used to test whether acute (100 mg/kg body wt for 1 h) and chronic (5-100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant alpha-lipoic acid (ALA) could improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and glucose oxidation were determined in the isolated epitrochlearis muscles in the absence or presence of insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake, glycogen synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30 mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P < 0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was associated with a significantly greater (21%) in vivo muscle glycogen concentration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15-17%) plasma levels of insulin and free fatty acids. No significant effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase and citrate synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhances the capacity of the insulin-stimulatable glucose transport system and of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle.
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PMID:The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. 869 Jan 47

Hindlimb weight bearing after a 3-day period of hindlimb suspension (reweighting) of juvenile rats results in a marked transient elevation in soleus glycogen concentration that cannot be explained on the basis of the activities of glycogen synthase and phosphorylase. We have hypothesized that enhanced glucose transport activity could underlie this response. We directly tested this hypothesis by assessing the response of insulin-dependent and insulin-independent glucose transport activity (in vitro 2-[1,2-3H]deoxy-D-glucose uptake) as well as glucose transporter (GLUT-4) protein levels during a 48-h reweighting period. After a net glycogen loss (from 29 +/- 2 to 16 +/- 1 nmol/mg muscle; P < 0.05) during the first 2 h of reweighting, glycogen accumulated at an average rate of 1.4 nmol.mg-1.h-1 up to 18 h, reaching an apex of 38 +/- 1 nmol/mg. During this same reweighting period, insulin-independent, but not insulin-dependent, glucose transport activity was significantly enhanced (P < 0.05 vs. weight-bearing control values) and was associated with an elevated level of GLUT-4 protein and the specific activity of total hexokinase. The specific activity of citrate synthase was also increased. By 24 h of reweighting, although insulin-independent glucose transport activity and GLUT-4 protein remained elevated, glycogen accumulation had ceased, likely due to enhanced phosphorylase activity at this time point. These results are consistent with the interpretation that the glycogen supercompensation seen during reweighting of the rat soleus may be regulated in part by an enhanced glucose flux arising from an increase in insulin-independent glucose transport activity and hexokinase activity.
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PMID:Role of glucose transport in glycogen supercompensation in reweighted rat skeletal muscle. 872 37

There is evidence that insulin resistance and obesity are associated with relative increases in the proportion of glycolytic type IIb muscle fibers and decreases in the proportion of oxidative type I fibers. Futhermore, insulin resistance and obesity are associated with the fatty acid (FA) profile of structural membrane lipids. The present study was undertaken to define interrelationships between muscle fiber type and oxidative capacity, muscle membrane FA composition, and insulin action and obesity. Muscle morphology, insulin action, and body fat content were measured in 48 male nondiabetic Pima Indians. Percent body fat (pFAT, determined by hydrodensitometry) correlated negatively with percentage of type I fibers (r = -0.44, P = 0.002) and positively with percentage of type IIb fibers (r = 0.40, P = 0.005). Consistent with this finding, pFAT was also significantly related to oxidative capacity of muscle, as assessed by NADH staining (r = -0.47, P = 0.0007) and citrate synthase (CS) activity (r = -0.43, P = 0.008). Insulin action was correlated with oxidative capacity (CS; r = 0.41, P = 0.01) and weakly correlated with percentage of type IIb fibers (r = -0.29, P = 0.05). In addition, relationships were shown between muscle fiber type and FA composition (e.g., percentage of type I fibers related to n-3 FA; r = 0.37, P = 0.01). Thus leaness and insulin sensitivity are associated with increased oxidative capacity and unsaturation of membranes in skeletal muscle. Present studies support the hypothesis that muscle oxidative capacity and fiber type may play a genetically determined or an environmentally modified role in development of obesity and insulin resistance.
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PMID:Interrelationships between muscle morphology, insulin action, and adiposity. 876 1

The effects of a similar exercise training stimulus on maximal insulin-stimulated (MIS) plasma membrane glucose transporter number and glucose transport were determined in lean and obese SHHF/Mcc-facp rats. Six-week-old lean and obese male rats were randomly divided into four groups: lean sedentary (LSed), obese sedentary (OSed), lean exercise (LEx), and obese exercise (OEx). An 8- to 12-wk treadmill running program equalized daily muscular work for LEx and OEx. Plasma membranes were isolated from control and MIS muscles of mixed fiber types. MIS significantly increased glucose transport (3.4- and 2.8-fold) in LSed and OSed, respectively. MIS significantly increased glucose transporter number (2.5-fold) in LSed, but there was no increase in glucose transporter number in OSed. Peak oxygen uptake and citrate synthase activity were increased a similar amount for LEx and OEx groups, demonstrating a similar training stimulus. MIS significantly and similarly increased glucose transport in LEx and OEx (4.4- and 5.1-fold, respectively). The effects of MIS on plasma membrane glucose transporter number in the exercise-trained rats were similar to the responses observed in the sedentary lean and obese groups. MIS significantly increased glucose transporter number (2.6-fold) in LEx, whereas there was no increase in glucose transporter number in OEx. The reduction in MIS glucose transport in OSed appears to be related to a defect in the processes associated with the translocation of glucose transporters to the plasma membrane. Exercise training of the obese rats apparently did not alter this defect. Similar increases in peak oxygen uptake, citrate synthase, and MIS glucose transport in LEx and OEx groups suggest that insulin resistance does not limit the ability of the glucose transport system to adapt to exercise training in the obese male SHHF/Mcc-facp rats.
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PMID:Exercise training and the glucose transport system in obese SHHF/Mcc-fa(cp) rats. 890 85

We tested the hypothesis that improved ischemia tolerance in an isolated working rat heart preparation can be achieved by interventions other than ischemic preconditioning. Hearts were perfused at near-physiological workload with bicarbonate buffer containing glucose (10 mM). A preischemic period of 25 min was followed by 15 min of global ischemia and 30 min of reperfusion under preischemic conditions. Hearts came from either fed or fasted animals (groups 1 and 2). In group 3 lactate (10 mM) and insulin (10 mU/ml) were added to the perfusate of fasted animals. In group 4 hearts from fed animals were perfused with glucose (10 mM) and were ischemically preconditioned by one cycle of ischemia between 10 and 15 min of the preischemic perfusion. Cardiac power and glucose uptake were measured continuously to assess functional and metabolic recovery. In addition, we measured the time to return of aortic flow. Glucose metabolites and the ratio of latent of free citrate synthase activity (citrate synthase ratio, a marker for the structural integrity of mitochondria) were determined at selected time points. Groups 2, 3, and 4 recovered significantly faster than group 1, whereas recovery of power showed an improvement in groups 3 and 4 only. In addition, there was an early increase in glucose uptake during reperfusion in these two groups, suggesting an early need for glucose substrate. Glycogen levels decreased with ischemia in all groups and returned to preischemic levels in groups 2, 3, and 4. The citrate synthase ratio was low in the control group and preserved in the groups showing improved functional recovery. We conclude that metabolic interventions may be as effective as ischemic preconditioning in protecting the heart from ischemic injury.
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PMID:Fasting, lactate, and insulin improve ischemia tolerance in rat heart: a comparison with ischemic preconditioning. 892 65

1. To examine metabolic correlates of insulin resistance in skeletal muscle, we used 31P magnetic resonance spectroscopy to study glycogenolytic and oxidative ATP synthesis in leg muscle of lean and obese Zucker rats in vivo during 6 min sciatic nerve stimulation at 2 Hz. 2. The water content of resting muscle was reduced by 21 +/- 7% in obese (insulin-resistant) animals compared with lean animals, whereas the lipid content was increased by 140 +/- 70%. These results suggest that intracellular water content was reduced by 17% in obese animals. 3. During exercise, although twitch tensions were not significantly different in the two groups, rates of total ATP synthesis (expressed per litre of intracellular water) were 48 +/- 20% higher in obese animals, suggesting a 50 +/- 8% reduction in intrinsic "metabolic efficiency'. Changes in phosphocreatine and ADP concentration were significantly greater in obese animals than in lean animals, whereas changes in intracellular pH did not differ. 4. These results imply that oxidative ATP synthesis during exercise is activated earlier in obese animals than in lean animals. This difference was not fully accounted for by the greater increase in the concentration of the mitochondrial activating signal ADP. Neither the post-exercise recovery kinetics of phosphocreatine nor the muscle content of the mitochondrial marker enzyme citrate synthase was significantly different in the two groups. The increased oxidative ATP synthesis in exercise must therefore be due to altered kinetics of mitochondrial activation by signals other than ADP. 5. Thus, the insulin-resistant muscle of obese animals may compensate for its decreased efficiency (and consequent increased need for ATP) by increased reliance on oxidative ATP synthesis.
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PMID:Increased oxidative and delayed glycogenolytic ATP synthesis in exercising skeletal muscle of obese (insulin-resistant) Zucker rats. 897 4

Skeletal muscle glucose transport can be regulated by hormonal factors such as insulin and insulin-like growth factor I (IGF-I). Although it is well established that exercise training increases insulin action on muscle glucose transport, it is currently unknown whether exercise training leads to an enhancement of IGF-I-stimulated glucose transport in skeletal muscle. Therefore, we measured glucose transport activity [by using 2-deoxy-D-glucose glucose (2-DG) uptake] in the isolated rat epitrochlearis muscle stimulated by submaximally and maximally effective concentrations of insulin (0.2 and 13.3 nM) or IGF-I (5 and 50 nM) after 1, 2, and 3 wk of voluntary wheel running (WR). After 1 wk of WR, both submaximal and maximal insulin-stimulated 2-DG uptake rates were significantly (P < 0.05) enhanced (43 and 31%) compared with those of sedentary controls, and these variables were further increased after 2 (86 and 57%) and 3 wk (71 and 70%) of WR. Submaximal and maximal IGF-I-stimulated 2-DG uptake rates were significantly enhanced after 1 wk of WR (82 and 61%, and these increases did not expand substantially after 2 (71 and 58%) and 3 wk (96 and 70%) of WR. This enhancement of hormone-stimulated 2-DG uptake in WR muscles preceded any alteration in glucose transporter (GLUT-4) protein level, which increased only after 2 (24%) and 3 wk (54%) of WR. Increases in GLUT-4 protein were significantly correlated (r = 0.844) with increases in citrate synthase. These results indicate that exercise training can enhance both insulin-stimulated and IGF-I-stimulated muscle glucose transport activity and that these improvements can develop without an increase in GLUT-4 protein.
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PMID:Voluntary exercise training enhances glucose transport in muscle stimulated by insulin-like growth factor I. 904 30


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