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Biomedical subjects

R R Wolfe

Publications and source records attributed to R R Wolfe.

At least 217 records · Page 12Linked to original sources
PubMed1990

Role of the glucose cycle in control of net glucose flux in exercising humans.

The hepatic glucose cycle involves the production of plasma glucose from glucose 6-phosphate and the simultaneous conversion of glucose back to glucose 6-phosphate. We have evaluated the role of the glucose cycle in the regulation of plasma glucose concentration during exercise at 70% of maximal O2 uptake and during recovery in five normal volunteers. Total glucose flux was measured by use of [2-2H]glucose (Ra2), net glucose flux through the glucose cycle was determined with [6,6-2H2]glucose (Ra6), and the rate of glucose cycling was determined by Ra2 - Ra6. Gas chromatography-mass spectrometry was used for analysis of isotopic enrichment. At rest, 33% of total glucose flux was recycled. In exercise, total flux increased 300%, but so did glucose cycling, which means that there was no change in the percentage of flux recycled. In recovery, both total flux and the rate of recycling returned rapidly to the resting value. We therefore conclude that whereas total glucose production can respond extremely quickly to large changes in energy requirements caused by exercise, thereby enabling maintenance of a constant blood glucose concentration, glucose cycling does not have an important role in amplifying the control of net hepatic glucose flux through the glucose cycle.

Adult↗
PubMed1990

Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer.

Whole-body lipolytic rates and the rate of triglyceride-fatty acid cycling (reesterification of fatty acids released during lipolysis) were measured with stable isotopic tracers in the basal state and during beta-adrenergic blockade with propranolol infusion in five cachectic patients with squamous cell carcinoma of the esophagus, five cachectic cancer-free, nutritionally-matched control patients, and 10 healthy volunteers. Resting energy expenditure and plasma catecholamines were normal in all three groups. The basal rate of glycerol appearance in blood in the patients with cancer (2.96 +/- 0.45 mumol.kg-1.min-1) was similar to that in the nutritionally matched controls (3.07 +/- 0.28 mumol.kg-1.min-1), but 48% greater than in the normal-weight volunteers (2.00 +/- 0.16 mumol.kg-1.min-1) (P = 0.028). The antilipolytic effect of propranolol and the rate of triglyceride-fatty acid cycling in the patients with cancer were also similar in the cachectic control group and approximately 50% greater than in the normal-weight volunteers, but the differences were not statistically significant because of the variability in the data. We conclude that the increase in lipolysis and triglyceride-fatty acid cycling in "unstressed" cachectic patients with esophageal cancer is due to alterations in their nutritional status rather than the presence of tumor itself. Increased beta-adrenergic activity may be an important contributor to the stimulation of lipolysis.

Adult↗
PubMed1990

Isotopic measurement of glucose and lactate kinetics.

A variety of isotopic tracers can be used to quantitate glucose kinetics in vivo. Using the standard approach to calculate the rate of appearance (Ra) of glucose from kinetic data, different rates of Ra glucose are obtained depending on the nature and position of the label in glucose. If total glucose production is considered to be all glycogen breakdown and gluconeogenesis, then that value can be calculated using the following stable isotopic tracers, or, in most cases their radioactive counterparts: 6, 6-2H-glucose; 1-13C, 6-13C; and U-13C-glucose. In the case of the 13C-labeled glucose, account must be taken of the extent of recycling of labeled carbons. If U-13C-glucose is used and recycling of isotope not quantitated, the resulting calculated value for Ra glucose will represent the rate of production from non-recycled carbons, plus some recycled carbons, due to potential dilution of 13C in the oxaloacetate pool and some loss of 13C in the PEPCK reaction. Traditional calculation of Ra glucose using 2-2H-glucose will include the rate of total glucose production and the contribution from the glucose cycle, and use of 3-2H-glucose will include the rate of total glucose production and contribution of the fructose cycle. The traditional methodology used to measure lactate production, in contrast to glucose, has a major conceptual flaw. It requires the assumption that there is no isotopic exchange between lactate and other compounds, yet experimental evidence indicates that lactate and pyruvate are in rapid equilibrium. Consequently, this approach will overestimate the true rate of net lactate production, possibly by as much as 400%.

Carbon Isotopes↗
PubMed1990

Effects of kinins on glucose metabolism in vivo.

Current concepts of the physiological importance of the kinin/prostaglandin system view these tissue factors as part of a defense system, which protects tissues from potentially noxious factors, such as hypoxia or destructive inflammatory reactions. This kinin-triggered defense reaction includes an improvement in cellular energy metabolism. The latter is brought about in peripheral tissues by an increased availability of glucose for anaerobic and aerobic glycolysis, whereas in liver tissue, energy-consuming reactions such as gluconeogenesis are attenuated. There is evidence that such favorable effects can also be produced in man when kinins are administered systemically. Prostaglandins are most likely the second messengers of kinin-induced metabolic effects. Thus, it may be advantageous to increase the availability of kinins either by exogenous infusion or by inhibiting endogenous degradation during postoperative stress or in diseases such as diabetes mellitus, in which glucose metabolism is severely disturbed.

Blood Glucose↗
PubMed1990

Kinin/prostaglandin system: its therapeutic value in surgical stress.

Multiple system organ failure as a consequence of injury or sepsis remains the major reason for death in critically ill patients. One of the treatment concepts that has recently attracted clinical attention is the administration of kinins and prostaglandins (PGs). On the basis of experimental data, there is reason to believe that these compounds may have the potential to manipulate favorably certain processes and mechanisms (such as inflammatory or ischemic reactions) thought to be important in the pathophysiology of surgical stress. However, thus far, information on those effects in humans is still scarce. On the other hand, administration of kinins and PGs is technically possible and can be performed safely, even in intensive care patients. Therefore, different techniques, effects, and side-effects of kinin/PG therapy deserve clinical testing. It remains to be seen whether this concept will be useful in the treatment of critically ill surgical patients.

Animals↗
PubMed1989

Bacteremia-induced suppression of alveolar surfactant production.

Sepsis is characterized by Adult Respiratory Distress Syndrome (ARDS)-like pulmonary dysfunction largely attributed to alveolar capillary endothelial cell injury which causes increased microvascular permeability and interstitial edema formation. In addition, quantitative and qualitative abnormalities of the pulmonary surfactant system may be important features of some clinical and experimental lung injuries. This study was designed to investigate the relationship of bacteremia and endotoxemia to pulmonary surfactant production in vivo. A technique for estimation of pulmonary surfactant phospholipid synthesis measuring incorporation of a stable isotope precursor [( 2-13C]acetate) into dipalmitoylphosphatidylcholine (DPPC) in alveolar lavage fluid was developed. Male 350 g Sprague-Dawley rats had placement of central venous catheters. After overnight recovery, sublethal bacteremia (Escherichia coli, 1 x 10(8) organisms, iv) and sublethal endotoxemia (Difco; 10 mg/kg, iv) were induced. Both were associated with lung microvascular permeability increases consistent with capillary endothelial injury. Eight-hour infusions of [2-13C]acetate were given. After sacrifice, bronchoalveolar washings and lung tissue were obtained and [2-13C] incorporation into lavage and lung DPPC was measured by gas chromatography mass spectroscopy. Endotoxin-treated animals had a 21.5% reduction in label incorporation into DPPC [1.215 +/- 0.145 APE (%) sham versus 0.954 +/- 0.144 APE (%) experimental, P greater than 0.05] and bacteremic animals had a 56.9% diminution of [2-13C]acetate incorporation [1.215 +/- 0.145 APE (%) sham versus 0.524 +/- 0.56 APE (%) experimental, P less than 0.05]. Bacteremia-induced dysfunction of alveolar type II epithelial cells manifested as diminished alveolar surfactant phospholipid production may be a contributing factor to sepsis-induced respiratory failure.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1989

Hyper and hypodynamic models of sepsis in guinea pigs.

The acute metabolic response following experimentally induced sepsis can generally be classified as either hypodynamic ("low flow") or hyperdynamic ("high flow"). We have found that in conscious guinea pigs the bolus infusion of 10(10) live Escherichia coli bacteria can elicit either response, depending on the route of administration of the bacteria. Intravenous infusion results in the hypodynamic condition of septic shock in which oxygen consumption (VO2) is reduced to approximately 60% of the control level, plasma glucose is elevated 4 hr after infusion with a reversal to extreme hypoglycemia 12 hr after infusion, and body temperature is reduced by approximately 5 degrees C in 12 hr. In contrast, subcutaneous injection results in increased VO2, body temperature, and plasma glucose. In both models the concentration of cortisol, catecholamines and glucagon were elevated, but the responses were more pronounced in the hypodynamic model. In both cases, insulin concentration was decreased. These models of sepsis are useful because many aspects of response are comparable to man, they are simple to create, and they are consistent and reproducible.

Animals↗
PubMed1989

Differentiation between septic and postburn insulin resistance.

Sepsis and extensive burn injury produce clinical syndromes characterized in part by "insulin resistance," but it is unclear if these insulin resistant states are identical. To test if the maximal biological effectiveness of insulin is altered in septic or burned patients, eight septic patients and eight nonseptic patients recovering from severe burn injury were studied using the hyperinsulinemic eukalemic euglycemic clamp technique. Compared with bed-rested controls, the septic patients showed an insulin-induced plasma clearance of potassium, which was 183% higher (P less than .001), and a concomitant glucose clearance, which was 52% lower (P less than .001). Nonseptic burn patients also had a 91% increase in potassium clearance (P less than .05), but their maximal insulin-stimulated glucose uptake was not different from that of bedrested controls. When septic patients were compared with their nonseptic burned counterparts, there was no difference in potassium clearance in response to insulin, but glucose uptake by the septic patients was 47% lower (P less than .001). Insulin infusion completely suppressed hepatic glucose production in both septic patients and in nonseptic burn patients. The percent of whole body glucose uptake that was oxidized was not different between the septic patients and the nonseptic postburn patients in both the basal and insulin-stimulated states (38% and 51% v 38% and 42%, respectively). It is concluded that septic and postburn insulin resistance differ in that peripheral glucose uptake in sepsis, but not nonseptic burn injury, is refractory to pharmacologic insulin stimulation, whereas in both states insulin effectively stimulates potassium uptake.

Adult↗
PubMed1989

Glucagon and hepatic glucose production: modulation by low-dose bradykinin infusion.

The effect of a low-dose bradykinin (BK) infusion (30 ng/kg min) on glucagon-induced hepatic glucose production and glucose cycling was studied in five normal volunteers. Studies were performed during constant insulin concentration as achieved by simultaneous somatostatin infusion and insulin replacement. In the basal period glucagon was infused at a rate of 0.5 ng/kg min. Then, glucagon infusion rate was increased to 3 ng/kg min to test the response to hyperglucagonemia. In a second set of experiments BK was infused concomitantly with the high dose glucagon. Each subject served as his own control. BK infusion did not prevent the glucagon-induced rise in hepatic glucose production and glucose cycling. However, at a later stage BK accelerated the negative feedback mechanisms activated by glucagon (decrease in hepatic glucose production) significantly. These findings suggest that intravenous BK may interact with mechanisms involved in the down-regulation of hepatic glucagon effects.

Adult↗
PubMed1989

Protein and energy metabolism during prolonged exercise in trained athletes.

UNLABELLED: Eight elite triathlon athletes participated in a laboratory study of the effects of endurance exercise on protein and energy metabolism. The study consisted of 3 h of cycling and 5 h of treadmill running; 3.5 h before beginning the exercise, a primed constant infusion of 1-13C leucine and 6,6(-2)H glucose was begun. Serial blood samples were collected during the rest and exercise periods for isotopic analysis. Respiratory gas exchange was determined every half hour. RESULTS: the subjects exercised at an average of 53% +/- 3% of peak VO2. During the 8-h exercise period there was a decline in glucose utilization and an increase in lipid oxidation. For the first part of the exercise, most of the glucose oxidized was of muscle origin. Hepatic glucose production increased with exercise from 20 g/h to a maximum of about 60 g/h after 4 h of exercise and then decreased toward the pre-exercise rate. The plasma urea concentration was unchanged during the study. The leucine flux decreased during the first 4 h of exercise and then attained a new plateau about 20% lower than the pre-exercise value indicating an adaptive reduction in protein turnover.

Adult↗
PubMed1989

A long-term metabolic study to assess the nutritional value of and immunological tolerance to two soy-protein concentrates in adult humans.

Seventeen healthy young adult men participated in a long-term metabolic study (11 wk) to evaluate the tolerance to and protein nutritional value of two commercially produced soy-protein concentrates. Danpro-S (nine subjects) and Danprotex-H 40 (eight subjects) (Aarhus Oliefabrik A/S, Aarhus, Denmark). Each test protein (0.8 g.kg-1.d-1) served as the sole source of dietary nitrogen. Subjects remained healthy, no problems of clinical or metabolic significance appeared, body weight remained constant, and body composition indices (lean body mass by H2(18)O dilution and creatinine excretion) and basal metabolic rate did not change. N balances fluctuated around body N equilibrium. Immunological studies confirmed the absence of any allergic responses in these subjects. It is concluded that these protein concentrates can be consumed as the sole source of dietary protein for protein nutritional maintenance and with excellent tolerance.

Adult↗
PubMed1989

An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Studies in the basal state and the response to total parenteral nutrition.

A series of isotopic infusions were performed in 43 severely ill patients suffering from blunt trauma (mean injury severity score of 31). The patient data have been compared with data obtained from 32 normal volunteers, and in addition the metabolic response of the trauma patient to total nutritional support (TPN) has been assessed. The rate of VO2 was elevated in the trauma patients compared with that of the volunteers (160 mumol/kg/minute vs. 103 mumol/kg/minute). Glucose production was significantly increased in the patients compared with the volunteers (21 +/- 2 mumol/kg/minute vs. 14 +/- 1 mumol/kg/minute), but the trauma patients had an impaired capacity to directly oxidize plasma glucose. The percentage of glucose uptake oxidized in the volunteers was 36 +/- 2%, and the percentage of glucose uptake recycled was 10 +/- 1%. By contrast, in the trauma patients, 23 +/- 4% of the glucose uptake was directly oxidized, and 29 +/- 11% was recycled. The rate of glycerol turnover in the trauma patients (5.3 +/- 0.3 mumol/kg/minute) was significantly elevated compared with the volunteer value (2.2 +/- 0.1 mumol/kg/minute), and the basal rate of fat oxidation was twice as high in the patients as in the volunteers (2 mg/kg/minute vs. 1 mg/kg/minute). The rate of whole body protein catabolism was significantly higher in the patients (5.8 +/- 0.7 g/kg/day vs. 4.3 +/- 0.3 g/kg/day), and as a result, the rate of net protein catabolism was significantly elevated in the patients. The response to TPN (amino acids and a 50:50 mixture of glucose and fat) included an increase in the percentage of glucose uptake oxidized (up to 45 +/- 12%), a decrease in the oxidation of fat (up to 0.8 mg/kg/minute), and a significant increase in whole body protein synthesis (up to 6.1 +/- 1.1 g/kg/day) so that the rate of net protein loss was minimized but not prevented. (The rate of net protein catabolism during TPN was 1.3 +/- 0.5 g/kg/day.) There was no correlation between the injury severity score (ISS) and the degree of metabolic abnormality. The rate of NPC in the patients with ISS less than 20 was higher than in the volunteers (ISS = 0), but the values for NPC in patients with ISS 21-40, and ISS greater than 40 were virtually identical to the corresponding values in patients with ISS less than 20. It is concluded from these studies that: 1) Trauma patients have a high rate of VO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Effect of short- and long-term beta-adrenergic blockade on lipolysis during fasting in humans.

Stable isotope tracers and indirect calorimetry were used to evaluate the importance of beta-adrenergic stimulation of lipolysis and triglyceride-fatty acid cycling during fasting in healthy human volunteers. Each subject was studied after 12 and 84 h of fasting both with and without propranolol infusion (protocol 1) and when oral propranolol treatment was given throughout fasting (protocol 2). In protocol 1, the rates of appearance of glycerol and palmitic acid increased from 3.04 +/- 0.19 and 1.78 +/- 0.17 mumol.kg lean body mass-1.min-1, respectively, after 12 h of fasting to 5.28 +/- 0.31 and 3.47 +/- 0.15 mumol.kg lean body mass-1.min-1, respectively, after 84 h of fasting (P less than 0.005). The rate of triglyceride-fatty acid cycling increased from 97 +/- 8 to 169 +/- 5 mumol/min (P less than 0.005). Intravenous propranolol infusion decreased the rate of lipolysis after both 12 and 84 h of fasting, but the magnitude of the antilipolytic effect was much greater after 84 h (P less than 0.005). In protocol 2, the rate of lipolysis and triglyceride-fatty acid cycling was still increased by fasting despite beta-adrenergic blockade with oral propranolol. This study demonstrates that beta-adrenergic stimulation contributes to the mobilization of fat during fasting. However, other mechanism(s) can increase lipolysis and triglyceride-fatty acid cycling when beta-adrenergic receptors are continuously blocked.

Adult↗
PubMed1989

Role of insulin and glucose oxidation in mediating the protein catabolism of burns and sepsis.

We have investigated the responsiveness of protein kinetics to insulin and the role of glucose oxidation rate as a mediator of the protein catabolic response to burn injury and sepsis by assessing the response of leucine and urea kinetics to a 5-h hyperinsulinemic euglycemic clamp with and without the simultaneous administration of dichloroacetate (DCA) (to further increase glucose oxidation via stimulation of pyruvate dehydrogenase activity) in eight severely burned and eight septic patients. Leucine and urea kinetics were measured by the primed-constant infusions of [1(-13)C]leucine and [15N2]urea. Compared with controls, basal leucine kinetics (flux and oxidation) were significantly elevated (P less than 0.01) in both groups of patients. Hyperinsulinemia elicited significant (P less than 0.05) decreases in leucine kinetics in both groups of patients. Consistent with this observation, hyperinsulinemia caused urea production to decrease significantly (P less than 0.05) in both patient groups. The administration of DCA to patients during hyperinsulinemia elicited a significant increase in glucose oxidation rate compared with the clamp rate (P less than 0.05), and the percent of glucose uptake oxidized increased from 45.5 +/- 5.5 to 53.5 +/- 4.8%; yet the response of leucine and urea kinetics to the clamp plus DCA was not different from the response to the clamp alone. These results suggest that the maximal effectiveness of insulin to suppress protein breakdown is not impaired and that a deficit in glucose oxidation or energy supply is probably not playing a major role in mediating the protein catabolic response to severe burn injury and sepsis.

Adolescent↗
PubMed1989

Effect of dichloroacetate on lactate concentration in exercising humans.

The precise mechanism responsible for the increase in plasma lactate concentration during exercise in humans is not known. We have used dichloroacetate to test the hypothesis that a limitation in pyruvate dehydrogenase activity is responsible for the rise in plasma lactate. Dichloroacetate stimulates the activity of pyruvate dehydrogenase, which is normally the regulatory enzyme in the oxidation of glucose when tissue oxygenation is adequate. Six subjects were studied twice according to a randomized, crossover protocol, involving one test with saline infusion and another with dichloroacetate infusion. Exercise load on a bicycle ergometer was increased progressively until exhaustion. Blood samples were drawn each minute throughout exercise and periodically throughout 120 min of recovery. Dichloroacetate significantly lowered the lactate concentration during exercise performed at less than 80% of the average maximal O2 consumption. The peak concentration of lactate at exhaustion was not affected by dichloroacetate treatment, but dichloroacetate did lower lactate concentration throughout recovery. These results suggest that a limitation in pyruvate dehydrogenase activity contributes to the increase in plasma lactate during submaximal exercise and recovery.

Acetates↗
PubMed1988

Bed-rest-induced insulin resistance occurs primarily in muscle.

Treatment of trauma victims and patients with severe illness may contribute to their metabolic derangements by severely restricting physical activity. We sought to quantitate the impact of absolute bed rest alone on insulin regulation of glucose metabolism in six healthy subjects. Six to seven days of strict bed rest resulted in moderate deterioration in oral glucose tolerance and increased both fasting plasma insulin concentration and the insulin response to an oral glucose challenge by more than 40%. Euglycemic insulin clamp studies demonstrated the development of resistance to insulin's stimulation of whole-body glucose utilization. This change was characterized by a rightward shift of the insulin dose-response curve (insulin concentration at which 50% of maximal stimulation occurred was 45 +/- 3 (SE) microU/mL in the base line period and 78 +/- 8 microU/mL after seven days of bed rest, P less than .01) with little alteration in the maximal response in the rate of glucose uptake (baseline 15.4 +/- 1.4 mg/kg.min and bed rest 14.0 +/- 1.3 mg/kg.min). In contrast to the shift of sensitivity of whole-body glucose utilization to insulin, suppression of hepatic glucose output by insulin was unchanged by seven days of bed rest. Insulin binding to circulating mononuclear cells was not changed by bed rest. These studies demonstrate that the limited physical activity dictated by bed rest for as little as seven days is associated with substantial resistance to insulin's effects on glucose metabolism. Further, the data suggest that these effects occur primarily in skeletal muscle with little change in insulin action on the liver.

Adult↗