Changes In Substrate Utilization Research Articles

Considerations in the nutritional management of patients with acute renal failure

Despite improvements in medical and dialytic therapies, mortality rates for patients with complicated acute renal failure (ARF) remains tragically high-above 50%. Mortality rates also remain persistently high in patients with ARF and preexisting or hospital-acquired malnutrition. ARF causes significant changes in substrate utilization largely because of the metabolic consequences of acute uremia compounded by underlying stress from acute illness. Alterations in protein or amino acid, carbohydrate, and lipid metabolism as well as fluid, electrolyte, and acid-base balance need to be considered when providing nutritional therapy in patients with ARF. Also, the degree of renal impairment, which influences the need for renal replacement therapy (RRT), impacts nutritional requirements. As medical management is becoming highly aggressive in treating ARF with RRT, the ability to provide adequate nutrition is enhanced; however, no consensus on optimal caloric and macro-/micronutrient requirements is available. More current research is required to clarify nutritional needs of this patient population. Nevertheless, individualizing nutrition care and integrating nutritional therapies within a team setting is essential in providing optimal patient care in the presence of ARF.

Energy substrate metabolism in cardiac hypertrophy

Cardiac hypertrophy is a response to long-term pathologic (eg, hypertension) or physiologic (eg, exercise) hemodynamic overload accompanied by changes in energy substrate utilization. The pattern of substrate utilization (or metabolic phenotype) differs dramatically between pathologic and physiologic cardiac hypertrophy with directionally opposite changes in oxidation of fatty acids and glucose and glycolysis. These findings indicate that the metabolic response to long-term alterations in hemodynamic workload is not stereotypical, but is influenced by the nature of the stimulus leading to cardiac hypertrophy. Although the changes in substrate utilization are adaptive, in the case of pathologic stimuli, the changes in metabolism interfere with functional resiliency of the heart to metabolic stress, as occurs during ischemia-reperfusion. The distinct metabolic phenotypes of hearts hypertrophied in response to pathologic or physiologic stimuli are due not only to alteration in expression of metabolic enzymes and proteins, but also to post-translational modulation of metabolic enzymes and proteins.

Metabolic adaptation to high-fat and high-carbohydrate diets in children and adolescents

Difficulty adapting to high-fat (HF) and high carbohydrate (HC) diets may predispose children to obesity and diabetes. We tested the hypothesis that children have metabolic flexibility to adapt to HF and HC diets. In protocol 1, 12 children aged 6-9 y and 12 adolescents aged 13-16 y were randomly assigned in a crossover design to consume low-fat (LF), HC (25% and 60% of energy, respectively) or HF, low-carbohydrate (LC) (55% and 30% of energy, respectively) diets. In protocol 2, 12 adolescents aged 13-16 y were randomly assigned in a crossover design to consume an LF-HC diet with 11% or 40% of carbohydrate as fructose. Total energy expenditure, nonprotein respiratory quotients (NPRQs), and substrate utilization were measured by using 24-h calorimetry. Effects of sex, puberty, body fat (dual-energy X-ray absorptiometry), intraabdominal fat (magnetic resonance imaging), and fitness on substrate utilization were tested. Substrate utilization was not affected by puberty, body fat, intraabdominal fat, or fitness. Total energy expenditure was not affected by diet. In protocol 1, NPRQs and carbohydrate and fat utilization were significantly affected by diet (P = 0.001) and sex (P = 0.005). NPRQs and carbohydrate utilization increased with the LF-HC diet. NPRQs decreased and fat utilization increased with the HF-LC diet; changes in substrate utilization were less pronounced in females than in males. In protocol 2, 24-h NPRQs and 24-h substrate utilization were not significantly affected by fructose, although net carbohydrate and fat utilization were significantly lower and higher, respectively, with the high-fructose diet during fasting (P = 0.01) and in the subsequent feeding period (P = 0.05). Healthy, nonobese children and adolescents adapt appropriately to HF and HC diets.

Dissociation of AMPK activity and ACCβ phosphorylation in human muscle during prolonged exercise

During prolonged, low intensity exercise, the type of substrate utilized varies with time. If 5 ′AMP-activated protein kinase (AMPK) regulates muscle metabolism during exercise, signaling through AMPK would be expected to change in concordance with changes in substrate utilization. Six healthy, young males cycled (∼45% VO 2peak) until exhaustion (∼3.5 h). During exercise, leg glucose uptake and rate of glycogenolysis gradually decreased whereas free fatty acid uptake gradually increased. In the thigh muscle, the α AMPK subunits became progressively more phosphorylated on Thr 172 during exercise eliciting a parallel increase in α2 but not α1 AMPK activity. In contrast, after 1 h of exercise, Ser 221 phosphorylation of acetyl-CoA carboxylase-β (ACCβ) peaked at 1 h of exercise and returned to resting levels at exhaustion. Protein expression of α2 AMPK, α1 AMPK or ACCβ did not change with time. These data suggest that AMPK signaling is not a key regulatory system of muscle substrate combustion during prolonged exercise and that marked activation of AMPK via phosphorylation is not sufficient to maintain an elevated ACC β Ser 221 phosphorylation during prolonged exercise.

A COMPARISON OF INTERVAL VS. STEADY-STATE EXERCISE ON SUBSTRATE UTILIZATION IN OVERWEIGHT WOMEN

PURPOSE: This study investigated changes in substrate utilization during exercise following 8 weeks of interval versus steady-state training in 15 obese women. (Age: 33.8 ± 8.2 yr; HT: 165.7 ± 6.8 cm; WT: 88.0 ± 21.4 kg; BMI: 31.8 ± 6.6 kg/m2; % body fat: 42.9 ± 6.8%). METHODS: Subjects were randomized to either a high intensity interval group (IT (n = 7): 2 minutes at 95% of VO2 max alternating with 3 minutes of 25% of VO2 max) or a lower intensity steady state training group (ST (n = 8): 50% of VO2 max). There were no statistical differences between the IT and ST group prior to training in fitness or body composition. During training, each group was monitor by indirect calorimetry so they had the same mean intensity, duration, and caloric expenditure (300 kcals) during the workouts. VO2 (1/min and ml/kg/min), kcal/min, kcal/min/kgBW, and kcal/min/kgFFW were calculated at specific RER values 0.80, 0.85, 0.90, 0.95, and 1.00 both prior to and following training. RESULTS: The results indicated, that despite similar average exercise training intensities, only the IT group showed significant improvements after training. Using the 0.85 RER value (The cross-over point for fat to CHO usage), the IT showed a significant increase in VO2 (13.59 ± 3.85 to 16.53 ± 2.70 ml/kg/min; p < 0.05), kcal/min/kgBW (0.066 ± 0.18 to 0.081 ± 0.013; p < 0.05), and kcal/min/kgFFW (0.113 ± 0.026 to 0.143 to 0.018; p = 0.01) and trends toward significance in absolute VO2 (1.21 ± 0.26 to 1.49 ± 0.28 L/min; p = 0.08) & kcal/min (5.88 ± 1.27 to 7.26 ± 1.35; p = 0.08). Similar improvements were observed at 0.90 and 1.0 RER values. In contrast, no significant changes were found in the ST group. CONCLUSIONS: These results suggest that high intensity interval training independent of total workload, significantly improved caloric expenditure at a given RER value. Consequently, a significant increase in absolute fat utilization during submaximal exercise resulted which lead to improvements in fat losses in the IT group as we've previously reported (King, 2001 ACSM annual meeting).

Metabolic Modulation

featured in this issue of Circulation presents data showingthat pyruvate, which dose-dependently improved perfor-mance in myocardium from failing human hearts, may be onesuch agent.A number of abnormalities in both energy metabolism andcontractile function have been identified in failing cardiacmuscle. Metabolic changes include decreases in high energyphosphorylation potential, decreases in mitochondrial oxida-tive phosphorylation capacity, and a switch to a more fetalglycolytic metabolism.

Increase in skeletal muscle fatty acid binding protein (FABPC) content is directly related to weight loss and to changes in fat oxidation following a very low calorie diet.

There is increasing evidence that intracellular fatty acid binding proteins (FABPc's; 15 kD) function as vehicles of cytosolic fatty acid transport. We studied skeletal muscle cytosolic FABPc, and enzymes reflecting beta-oxidation and oxidative capacity (3-hydroxyacyl-CoA dehydrogenase, HAD, and citrate synthase, CS) in relation to weight loss and changes in substrate utilisation in a group of 35 obese women and obese men with Type II (non-insulin-dependent) diabetes mellitus (women = 27, men = 8). Muscle biopsies (vastus lateralis), and measurements of body composition, resting energy expenditure and respiratory exchange ratio were taken before and after dietary intervention (by means of a very low calorie diet). Muscle FABPc tended to increase after diet (178 +/- 13 vs 204 +/- 12 mg x gww(-1), p = 0.06), whereas there were no changes in CS (10.5 +/- 0.7 vs 11.1 +/- 0.6 U x gww(-1)) and HAD (11.2 +/- 0.7 vs 11.7 +/- 0.6 U x gww(-1)). There was a positive relation between the increase in FABPc as result of diet and the amount of weight lost (p < 0.01; adjusted R2, 15.4 %), even when adjusted for mean body weight, and changes in CS and in HAD by partial regression analysis. Interestingly, the increase in FABPc was positively related to increases in resting fat oxidation (adjusted R2, 24 %), even when adjusted for mean resting fat oxidation, and changes in CS and in HAD. In conclusion, the ability to increase muscle FABPc could be directly related to weight loss and to changes in fat oxidation following dietary intervention in obesity and Type II (non-insulin-dependent) diabetes mellitus.

Factors affecting performance in an ultraendurance triathlon.

In the recent past, researchers have found many key physiological variables that correlate highly with endurance performance. These include maximal oxygen uptake (VO2max), anaerobic threshold (AT), economy of motion and the fractional utilisation of oxygen uptake (VO2). However, beyond typical endurance events such as the marathon, termed 'ultraendurance' (i.e. >4 hours), performance becomes harder to predict. The ultraendurance triathlon (UET) is a 3-sport event consisting of a 3.8 km swim and a 180 km cycle, followed by a 42.2 km marathon run. It has been hypothesised that these triathletes ride at approximately their ventilatory threshold (Tvent) during the UET cycling phase. However, laboratory assessments of cycling time to exhaustion at a subject's AT peak at 255 minutes. This suggests that the AT is too great an intensity to be maintained during a UET, and that other factors cause detriments in prolonged performance. Potential defeating factors include the provision of fuels and fluids due to finite gastric emptying rates causing changes in substrate utilisation, as well as fluid and electrolyte imbalances. Thus, an optimum ultraendurance intensity that may be relative to the AT intensity is needed to establish ultraendurance intensity guidelines. This optimal UET intensity could be referred to as the ultraendurance threshold.

Manipulating the metabolic response to injury.

In this short review we will concentrate on just one of the features of the metabolic response to injury (classified as accidental trauma, injury or sepsis) which are collectively known as the 'flow' phase. These include an increase in energy expenditure (hypermetabolism), changes in substrate utilisation (insulin resistance) and the focus of this chapter muscle wasting or catabolism. It is recognised that the three features are interrelated, for example insulin is believed to be an important factor in controlling amino acid flux in skeletal muscle and increasing environmental temperature which may reduce flow phase hypermetabolism has been shown to reduce postoperative nitrogen excretion (a marker of protein catabolism). However, we will concentrate on muscle wasting and refer the reader to other reviews on insulin resistance and metabolic rate.

Is the mouse a good model for the human with respect to the development of the preimplantation embryo in vitro?

A comparison has been made of various aspects of preimplantation development of mouse and human embryos in vitro. Changes in substrate utilization follow similar patterns in both species. This similarity in metabolic parameters between the two species has facilitated the use of the mouse as a model to study the formulation of culture media to be used at different stages over the preimplantation period from fertilization to the fully expanded blastocyst stage. It has also prescribed the mouse embryo as a practical tool for quality control testing of the laboratory system in human in-vitro fertilization. Aspects of the physiology of both species that require further study are the physiological levels of endogenous inorganic phosphate in the female reproductive tract, the requirement for inorganic phosphate in culture medium, the specificity of the amino acid requirements for optimal development before and after compaction and the importance of including EDTA in culture medium.

Influence of moderate daily wine consumption on body weight regulation and metabolism in healthy free-living males.

Although previous studies have clearly demonstrated that energy from alcohol may not be efficiently utilized to maintain body weight when it comprises 20% or more of the daily caloric intake, there is considerable debate regarding the influence of moderate alcohol consumption (< or = 5% of the total daily caloric intake) upon metabolism, substrate utilization and body weight regulation. Consequently, the objectives of this study were to determine whether moderate alcohol consumption could influence body weight via changes in substrate utilization, oxygen consumption or alterations in dietary macronutrient content.Fourteen male subjects (mean age = 32.1 years) participated in a 12-week, free-living, crossover trial in which they either drank red wine (270 ml; 13% v/v ethanol) daily for 6 weeks and then abstained for the next 6 weeks or vice-versa.Whether wine was imbibed or not, no significant differences (p > 0.05) were demonstrated for any of the following variables: body weight, body fat percentage, skinfold thickness, resting metabolic rate, respiratory quotient, caloric intake, dietary macronutrient content, or fasting insulin or glucose concentrations.In free-living subjects over a 6-week period, the addition of two glasses of red wine to the evening meal does not appear to influence any measured variable which may adversely affect body weight or promote the development of obesity during this time period.

Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment.

1. Heat acclimation was induced in eight subjects by asking them to exercise until exhaustion at 60% of maximum oxygen consumption rate (VO2) for 9-12 consecutive days at an ambient temperature of 40 degrees C, with 10% relative humidity (RH). Five control subjects exercised similarly in a cool environment, 20 degrees C, for 90 min for 9-12 days; of these, three were exposed to exercise at 40 degrees C on the first and last day. 2. Acclimation had occurred as seen by the increased average endurance from 48 min to 80 min, the lower rate of rise in the heart rate (HR) and core temperature and the increased sweating. 3. Cardiac output increased significantly from the first to the final heat exposure from 19.6 to 21.4 l min-1; this was possibly due to an increased plasma volume and stroke volume. 4. The mechanism for the increased plasma volume may be an isosmotic volume expansion caused by influx of protein to the vascular compartment, and a sodium retention induced by a significant increase in aldosterone. 5. The exhaustion coincided with, or was elicited when, core temperature reached 39.7 +/- 0.15 degrees C; with progressing acclimation processes it took progressively longer to reach this level. However, at this point we found no reduction in cardiac output, muscle (leg) blood flow, no changes in substrate utilization or availability, and no recognized accumulated 'fatigue' substances. 6. It is concluded that the high core temperature per se, and not circulatory failure, is the critical factor for the exhaustion during exercise in heat stress.

Enteral feeding in the critically injured patient.

Metabolic support is an integral component in the care of the critically injured patient. When hypermetabolism occurs, there are increases in energy demands along with changes in substrate utilization. This article reviews the prospective randomized clinical trials that were undertaken at Denver General Hospital over the past decade that address both the timing of nutritional support and the route of administration in this critically injured population. Also discussed is a review of a meta-analysis that attests to the feasibility of early postoperative enteral feeding with the possibility of decreased septic morbidity in high-risk surgical patients. With the clinical knowledge gained from these trials, an algorithm for nutritional intervention was developed that represents our current standard of practice.

Energy expenditure during synthetic surfactant replacement therapy for neonatal respiratory distress syndrome

Little information is available on the energy expenditure of infants with increased work of breathing from respiratory distress syndrome (RDS). A study was carried out to determine whether surfactant replacement therapy modifies respiratory gas exchange in newborn infants with RDS and an arterial-alveolar oxygen tension ratio of less than 0.22. In a double-blind, placebo-controlled, rescue trial, infants received either two 5 ml/kg doses of a synthetic surfactant, Exosurf Neonatal, or air placebo. Of 23 infants ventilated for RDS, 11 were randomly assigned to receive air and 12 to receive surfactant. Oxygen consumption, carbon dioxide production, respiratory quotient, and metabolic rate were measured by computerized, closed-circuit, indirect calorimetry. Concomitantly, transcutaneous oxygen and carbon dioxide tension were continuously recorded. Oxygen consumption and carbon dioxide production remained constant during the period infants received surfactant. In patients randomly assigned to surfactant, a decrease in respiratory quotient was observed after the first (p less than 0.025) but not the second dose. This decrease was possibly related to a change in substrate utilization. The improved clinical outcomes reported among infants receiving surfactant were not accompanied by changes in energy expenditure.

The Role of Exercise in Weight Regulation in Nonathletes

Obesity is an extremely prevalent condition that is associated with a range of deleterious health effects. While traditionally considered a disorder primarily of energy intake, accumulating evidence underscores the importance of energy expenditure in the development and treatment of obesity. As the most variable component of energy expenditure, physical activity can influence the development of obesity as well as success in achieving both initial and long term weight loss. Among the types of exercise-related physiological and behavioural factors most likely to be involved in the development of obesity are reductions in the amount of physical activity actually performed, differences in the effect of physical activity on diet-induced thermogenesis, and modeling of deleterious dietary and exercise patterns on the part of the family and other facets of the environment. In contrast, there is relatively little evidence supporting the common belief that obese individuals have a significantly greater energy intake than nonobese individuals. With respect to weight reduction in the already obese, while increased physical activity levels often augment caloric restriction programmes in aiding initial weight loss, evidence suggests that physical activity may be particularly important in helping to sustain initial losses through increased total energy output, preservation of lean body mass, and changes in substrate utilisation. The psychological benefits received from regular participation in a physical activity programme may serve as an additional impetus for engaging in such activities over the long run. Developing programmes to aid in long term adherence to physical activity regimens remains the most critical challenge. Recent results suggest the utility of regular, brief contacts in aiding sustained physical activity participation in individuals attempting to control their weight.

Muscle Glucose Metabolism during Exercise

Substrate utilization during exercise is determined by the intensity and duration of exercise as well as by training status and the availability of substrate. The major energy source at rest and during low intensity exercise is fat oxidation while oxidation of carbohydrates and anaerobic energy utilization predominates at higher intensities. Hypoxia will induce a similar change in substrate utilization as an increase of the exercise intensity and it is suggested that O2 availability is an important determinant of muscle metabolism during exercise. Muscle glucose uptake increases during exercise and can reach values that are 30-50 times higher than at rest. The increase in muscle glucose uptake is related to the work load and the duration of the exercise, and corresponds to the output of glucose from the liver. Animal experiments have shown that muscle contraction can induce an increase in glucose uptake in the absence of insulin. Studies in man have shown that insulin and exercise at low intensity have a synergistic effect on glucose uptake, possibly due to an increased insulin inflow to the muscle. Intracellular glucose concentration is low at rest but can under certain conditions such as intensive exercise and hypoxia increase to maximum values of 3-4 mmol/l of intracellular water which demonstrates that glucose uptake under certain conditions can be in excess of the utilization of glucose.

Effect of Altering the Proportion of Dietary Fat and Carbohydrate on Exercise Gas Exchange in Normal Subjects

A low proportion of dietary calories as carbohydrate has been suggested for patients with chronic obstructive pulmonary disease, because oxidation of carbohydrate (CHO) compared to fat results in greater CO2 production (VCO2) and, at the same arterial PCO2 (PaCO2), higher alveolar and minute ventilation (VE) and increased dyspnea. We hypothesized that a low CHO-high fat diet, although reducing VCO2 and VE at rest, might result in only a small change in VCO2 and VE during exercise. Eight healthy volunteers were randomized to receive for 24 h either isocaloric diets containing 10% or 70% of total calories from CHO (remainder of nonprotein calories from fat). Measurements of VCO2, VE, and respiratory gas exchange ratio (R) were made at rest and during constant work rate cycle exercise below the anaerobic threshold. Five to seven days later, the alternate diet was given and the studies were repeated. At rest, mean VCO2 and R were significantly lower after the low CHO diet compared to the high CHO diet. Mean resting VE was less but not significantly (high CHO 9.6 [0.7] versus low CHO 8.7 [0.8] L/min, mean [SEM]). During exercise, mean VCO2 and R were significantly less after the low CHO diet, but mean VE was only slightly smaller and not significantly different between diets (high CHO 25.4 [1.1] versus low CHO 24.0 [1.0] L/min). The increase in VCO2 from rest to exercise was relatively independent of the substrate mix recently consumed, suggesting that the exercising muscles use stored muscle glycogen as substrate during short bouts of low-intensity exercise despite changes in substrate utilization by nonmuscle tissues at rest.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic inhibition of fatty acid oxidation: New model of diastolic dysfunction

The proportion of cardiac energy derived from fatty acid oxidation decreases and that derived from glucose increases during ischemia. This biochemical profile of cardiac energy production is achieved in rats and mice without ischemia by pharmacological agents such as tetradecylglycidic acid. Chronically this leads to increased cardiac stiffness, and hypertrophy in the rodent models. Elements of human cardiac dysfunction are hypothesized to develop from and/or cause similar changes in substrate utilization for energy production. For some individuals treatment that would prevent or reverse these changes may be appropriate.

Substrate utilization in leg muscle of men after heat acclimation.

Eight men were heat acclimated (39.6 degrees C and 29.2% rh) for 8 days to examine changes in substrate utilization. A heat exercise test (HET), (cycling for 60 min; 50% maximal O2 consumption) was performed before (UN-HET) and after (ACC-HET) the acclimation period. Muscle glycogen utilization (67.0 vs. 37.6 mmol/kg wet wt), respiratory exchange ratio (0.85 +/- 0.002 vs. 0.83 +/- 0.001), and calculated rate of carbohydrate oxidation (75.15 +/- 1.38 vs. 64.80 +/- 1.52 g/h) were significantly reduced (P less than 0.05) during the ACC-HET. Significantly lower (P less than 0.05) femoral venous glucose (15, 30, and 45 min) and lactate (15 min) levels were observed during the ACC-HET. No differences were observed in plasma free fatty acid (FFA) and glycerol concentrations or glucose, lactate and glycerol arteriovenous uptake/release between tests. A small but significant increase (P less than 0.05) above resting levels in FFA uptake was observed during the ACC-HET. Leg blood flow was slightly greater (P greater than 0.05) during the ACC-HET (4.64 +/- 0.13 vs. 4.80 +/- 0.13 l/min). These findings indicate a reduced use of muscle glycogen following heat acclimation. However, the decrease is not completely explained by a shift toward greater lipid oxidation or increased blood flow.

Metabolic and hemodynamic effects of nicardipine during pacing-induced angina pectoris

During repeat exercise testing in 10 patients with stable angina, individual optimal doses of nicardipine were determined. Hemodynamic values and cardiac metabolism were studied during 2 pacing periods carried out before and after this dose (mean 5.3 mg). Postpacing ST-segment depression diminished (1 mm) after nicardipine administration (p < 0.05), whereas pacing time to onset of angina did not change. Nicardipine administration increased heart rate 16% (p < 0.005) and reduced systolic (10%) and diastolic (8%) blood pressures (both p < 0.005). Coronary blood flow increased 16% (p < 0.05) and coronary vascular resistance decreased 24% (p < 0.01). Myocardial oxygen consumption was unchanged despite an 11% decrease in rate-pressure product during pacing (p < 0.02). In the control state before nicardipine administration, metabolic signs of ischemia included release of lactate across the heart in 7 patients, decreased mean free fatty acid and glutamate uptake and alanine release during pacing, together with increased glucose uptake and citrate release during recovery. After nicardipine lactate release decreased in 5 of the 7 patients, pacing no longer changed free fatty acid, glutamate and alanine uptake/release from the level at rest. During recovery glucose uptake was reduced and citrate release was unaffected. The hemodynamic data indicate that nicardipine is a systemic and coronary vasodilator, increasing oxygen supply to the ischemic myocardium. The metabolic results indicate a change in substrate utilization toward that of normal heart, suggesting improved aerobic energy supply.