Relationship between growth hormone in vivo bioactivity, the insulin-like growth factor-I system and bone mineral density in young, physically fit men and women.

CONTEXT: Bone mineral density (BMD) is influenced by growth factors, such as growth hormone (GH) and insulin-like growth factor-I (IGF-I). The in vivo bioassay for GH (bioGH) provides a more physiologically relevant measurement than an in vitro immunoassay, since bioGH is quantified on a biological outcome. OBJECTIVE: To determine if bioGH and components of the IGF-I system were associated with BMD in age-matched men (M; n=41, 19.1+/-0.2 year, 70+/-3 kg, 163+/-25 cm) and women (W; n=39, 18.6+/-0.3 year, 66+/-3 kg, 141+/-15 cm). DESIGN: Blood was analyzed for growth-related hormones [bioGH, immunoreactive growth hormone (iGH), IGF-I and associated binding proteins], and BMD was measured by pDXA, pQCT, and central DXA (spine, hip). For the bioGH assay, hypophysectomizied female Sprague-Dawley rats were injected with a s.c. bolus of either a GH standard or unknown (each subject's plasma) in four daily injections. The tibia was then examined for epiphyseal growth plate width from which bioGH concentrations were extrapolated. RESULTS: M had greater (P<0.05) calcaneal BMD when measured by pDXA (M: 1.27+/-0.02; W: 1.14+/-0.02 g/cm2), while pQCT-assessed BMD at the tibia was not different (M: 777+/-16; W: 799+/-16 g/cm2). bioGH was similar between M (5388+/-800 microg/L) and W (4282+/-643 microg/L) and was not correlated with BMD. The only BMD-related biomarkers in women were acid-labile subunit (ALS; r=0.40) and IGFBP-3 (r=0.42) with DXA-measured spine and femoral neck BMD, and ALS (r=0.47) with pQCT-assessed tibial BMD and cortical thickness, respectively. CONCLUSION: Although bioGH was not associated with BMD, IGF-I and associated binding proteins (IGFBP-3 and ALS) emerged as correlates in W only.

Exercise in the heat: effects of an adenosine antagonist.

The purpose of this experiment was to examine the effects of an adenosine antagonist on cardiovascular, thermoregulatory, and exercise performance in the heat. Two doses (1 mg/kg and 10 mg/kg) of a selective adenosine A1 antagonist (1,3-di-n-propyl-8-[4-hydroxyphenyll]xanthine) (DPHPX) were tested in a rat model of exercise exhaustion, treadmill 11 m/min, 6 degrees incline, in the heat 30 degrees C. Pretreatment with the experimental adenosine antagonist caused a slight improvement p > 0.05 in run time (41+/-4 vs. 44+/-3 mm) at a low dose but reduced performance (41+/-4 vs. 29+/-3 mm) at a high dose despite elevated plasma lactate (6.41+/-0.82 vs. 9.91+/-1.0 and 12.42+/-1.1 micromole/L) levels in both dosage groups. At the low dose the antagonist provided a clear benefit in thermoregulation as evidenced by reduced heating rates (0.079+/-0.005 vs. 0.050+/-0.009 degrees C/min). Heart rate and blood pressure tended to be preserved in the low dose group also. Blood gases remained closer to normal with either dosage of drug with arterial PO2 being remarkably preserved after exercise whereas venous PO2 was not different suggesting increased oxygen delivery and extraction. The results of this investigation indicate that antagonizing the effects of adenosine at a low dose with this agent did improve cardiovascular and thermoregulatory responses but did not provide a substantial overall benefit in exercise performance in the heat.

Effects of almitrine bismesylate in a microswine model of hypoxemic hypothermia.

We have developed an anesthetized microswine model of hypoxemic hypothermia and rewarming for testing prophylaxes and treatments. The respiratory stimulant almitrine bismesylate (ALM) was considered as a potential field expedient therapy for hypoxemic hypothermia. Preliminary experiments demonstrated that five consecutive 100 micrograms.kg-1 ALM intravenous (i.v.) doses given to normothermic microswine 3-4 min apart increased minute ventilation from an average of 3.4 L.min-1 to 4.5 L.min-1 (n = 2). However, when either a single i.v. ALM dose of 150 micrograms.kg-1 (n = 1) or three consecutive 100 micrograms.kg-1 i.v. doses given 15 min apart (n = 1) to hypoxemic hypothermic microswine with a mean esophageal temperature (Tes) = 28.8 degrees C, and a mean arterial O2 partial pressure (PaO2) = 49 mmHg, the hypoxemia was potentiated (mean PaO2 = 32 mmHg) and respiratory arrest ensued. Other experiments using continuous ALM i.v. infusion (1.0 microgram.kg-1.min-1) in hypoxemic hypothermic microswine (n = 6, Tes = 30.6 +/- 0.5, PaO2 = 55.4 +/- 12.9) did not demonstrate significant (p < or = 0.05) cardiorespiratory differences (ventilation, heart rate, blood pressure, blood gases) when compared to hypoxemic hypothermic controls (n = 6, Tes = 30.7 +/- 0.5, PaO2 = 53.3 +/- 13.6). These results suggest that high dose i.v. bolus administration of ALM is not indicated as a potential field expedient therapy for hypoxemic hypothermia, while further work is required to assess the potential efficacy of other continuous low dose i.v. infusion regimens.

A miniswine model of acute exertional heat exhaustion.

METHOD: We examined the thermoregulatory and hemodynamic responses of 12 miniswine (31 +/- 3.9 kg) during 25-30 min of treadmill exercise (5.4 km.h-1, 5% grade) under cool (10 degrees C), moderate (20 degrees C) and warm (30 degrees C) ambient temperature (Ta) conditions. RESULTS: Within 15-20 min of exercise at Ta = 30 degrees C, the miniswine demonstrated significant hyperventilation, hypersalivation, and unsteady gait. Exercise-heat endurance time (T) at Ta = 30 degrees C decreased by 35% and 40% in comparison to T at Ta = 20 degrees C and 10 degrees C, respectively. This resulted from a significant rise in heat strain (S)-defined as the rate of change in rectal temperature. Averaged throughout exercise, S increased from 0.04 +/- 0.01 degree C.min-1 and 0.05 +/- 0.02 degree C.min-1 at Ta = 10 degrees C and 20 degrees C, respectively, to 0.10 +/- 0.03 degree C.min-1 at Ta = 30 degrees C. Due to the comparatively large storage capacity of the porcine spleen relative to humans, splenectomized miniswine were used. This permitted calculation of percentage changes in plasma volume (% delta PVc) from hematocrit (HCT) and hemoglobin (HGB) without the confounding effects of splenic red cells released into the circulation during exercise. Independent of Ta, pre-exercise PVc decreased 3%-5% (p < or = 0.05) within the first 10 min of exercise, but increased 5%-9% (p < or = 0.05) by 10 min post-exercise. CONCLUSION: We conclude that the poor thermoregulatory ability of miniswine manifested in insignificant sweating and restricted evaporative cooling, may make them an appropriate model for acute exertional heat exhaustion in humans working in hot, humid conditions and/or wearing impermeable protective clothing. Further, evaluation of plasma volume changes from HCT and HGB in a miniswine model should consider the merit of a splenectomized design.

The effects of dichloroacetate on lactate accumulation and endurance in an exercising rat model.

Severe lactic acidosis usually accompanies intense endurance exercise. It has been postulated that glycogen depletion working in concert with elevated muscle and plasma lactate levels lead to a concomitant reduction in pH. Their cumulative effect during prolonged physical exertion now leads to muscular fatigue and eventually limit endurance capacity. Therefore in the present study, dichloroacetate (DCA), a compound which enhances the rate of pyruvate oxidation thus reducing lactate formation, has been evaluated in a validated rat model of sub-maximal exercise performance. Male rats (350 g) were divided into two groups (control-saline, i.v. and DCA 5 mg/kg, i.v.) and were exercised to exhaustion in a chamber (26 degrees C) on a treadmill (11 m/min, 6 degrees incline). When compared to controls, the DCA-treated rats had longer run times (169 vs 101 min) and a decreased heating rate (0.020 vs 0.029 degrees C/min). In addition, DCA attenuated the increase in plasma lactate (28 vs 40 mg/dl) and significantly reduced both the rate and absolute amount of depletion of muscle glycogen stores. These results suggest that the activation of pyruvate dehydrogenase activity by DCA resulted in a reduction in the rate of glycogenolysis in addition to decreasing lactate accumulation by presumably limiting the availability of pyruvate for conversion to lactate, therefore increasing muscle carbohydrate oxidation via the TCA cycle. Thus DCA effected a significant delay in muscle fatigue.

Effects of chronic hypoxia on the pharmacokinetics of caffeine and cardio-green in micro swine.

METHODS: The pharmacokinetics of caffeine and cardio-green (ICG) were examined in four micro swine at sea level (SEA) and following 21 d continuous exposure to 4600 m (ALT) in a hypobaric chamber. Caffeine (84.7 mg) and ICG (10 mg) were administered as separate intravenous boluses and sequential blood samples collected. RESULTS: Caffeine clearance significantly (p < 0.05) increased in ALT (96.8 +/- 20.0 ml.min-1) as compared to SEA (53.6 +/- 24.8 ml.min-1), demonstrating that liver function increased in ALT. There was no significant change in the ratio of primary metabolites to caffeine, suggesting that the increase in clearance was not due to a change in the rate of caffeine metabolism. ICG clearance significantly increased in ALT (179.8 +/- 57.4 ml.min-1) as compared to SEA (84.4 +/- 28.9 ml.min-1) indicating that hepatic blood flow (HBF) increased. CONCLUSION: These results demonstrate that chronic exposure to 4600 m increases the clearance of caffeine and ICG in the micro swine model and suggests that the increase in caffeine clearance is related to HBF.

Effects of altitude (4300 m) on the pharmacokinetics of caffeine and cardio-green in humans.

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardio-green (ICG) were examined in eight healthy males (23-35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg. kg-1) was administered as an intravenous bolus and caffeine (4 mg. kg-1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in a caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g.l-1.min-1), and increased clearance (117 vs 86 ml.min-1.70 kg-1). In ALT the area under the curve the ICG significantly decreased (85 vs 207 mg.l-1.min-1) and the volume of distribution and clearance increased (5.2 vs 2.4 l and 532 vs 234 ml.min-1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.

Fluid shifts induced by the administration of 7.5% sodium chloride in 6% dextran 70 (HSD) in dehydrated swine.

This study determined the effects of HSD administration on fluid distribution, following dehydration in Female Yucatan micro pigs. Dehydration at 33 degrees C resulted in: significantly increased core temperature (37.2 +/- 0.2 (mean +/- SE) to 39.0 +/- 0.1 degrees C), and decreased (4.4 +/- 0.4%) body weight and plasma volume (PV, 43 +/- 2 to 37 +/- 1 ml/kg). HSD but not saline administration resulted in significant increases (over postdehydration levels) in PV (46 +/- 3 ml/kg), sodium concentration (141 +/- 1 to 150 +/- 2 mEq/L), and osmolality (291 +/- 2 to 307 +/- 11 mOsm). Following return of water to the animals, these values returned to baseline levels. Since insensible (respiratory and transdermal) water loss for the 24 hr at 23 degrees C was 714 +/- 64 ml, and for the 24 hr at 33 degrees C was 653 +/- 64 ml, increasing the ambient temperature did not result in increased dehydration in swine. HSD administration restored PV to baseline levels despite prior water loss dehydration.

Cytophotometric assessment of Feulgen-DNA and coomassie-total cell protein in adrenocortical fasciculata cells of noise-exposed Wistar rats.

The present investigation was undertaken to examine possible noise-induced alterations in adrenal fasciculata cell (AFC) metabolism, and also to determine if the magnitude of these changes differs in male versus female rats. Wistar rats approximately 3 months old were exposed to intense noise for 60 min (100 dB, re 2 x 10(-5) N(m2)-1, 350-20,000 Hz); control rats were housed under identical conditions, at an ambient noise level of 40-60 dB. Adrenal fasciculata cells (AFC) from each animal were examined for noise-induced alterations in Feulgen-DNA reactivity (as an indicator of chromatin template activity) and Coomassie-total cell protein levels using scanning-integrating cytophotometry. The results provide evidence that intense noise elicited a marked AFC metabolic enhancement in both male and female rats; the degree of this enhancement was more pronounced in males. This disparity may be due to pre-existing differences in male versus female AFC enzymatic capability and subsequent responsiveness to noise-induced activation.

Hypobaric hypoxia (380 Torr) decreases intracellular and total body water in goats.

The effects of prolonged hypoxia on body water distribution was studied in four unanesthetized adult goats (Capra lircus) at sea level and after 16 days in a hypobaric chamber [(380 Torr, 5,500 m, 24 +/- 1 degrees C); arterial PO2 = 27 +/- 2 (SE) Torr]. Total body water (TBW), extracellular fluid volume (ECF), and plasma volume (PV) were determined with 3H2O, [14C]inulin, and indocyanine green dye, respectively. Blood volume (BV) [BV = 100PV/(100 - hematocrit)], erythrocyte volume (RCV) (RCV = BV - PV), and intracellular fluid (ICF) (ICF = TBW - ECF) and interstitial fluid (ISF) (ISF = ECF - PV) volumes were calculated. Hypoxia resulted in increased pulmonary ventilation and arterial pH and decreased arterial PCO2 and PO2 (P less than 0.05). In addition, body mass (-7.1%), TBW (-9.1%), and ICF volume (-14.4%) all decreased, whereas ECF (+11.7%) and ISF (+27.7%) volumes increased (P less than 0.05). The decrease in TBW accounted for 89% of the loss of body mass. Although PV decreased significantly (-15.3%), BV was unchanged because of an offsetting increase in RCV (+39.5%; P less than 0.05). We conclude that, in adult goats, prolonged hypobaric hypoxia results in decreases in TBW volume, ICF volume, and PV, with concomitant increases in ECF and ISF volumes.

Adverse effects of dietary and furosemide-induced sodium depletion on thermoregulation.

In this study, the diuretic furosemide was used in combination with dietary sodium (Na) restriction to quantify the effects of moderate to severe Na depletion on heat tolerance in a validated model of heat stress in rats. Rats were subjected to an Na depletion regimen as follows: a control group (I, n = 17) had free access to a normal diet and tap water; group II (n = 20) consumed the same normal diet and tap water, but was treated with the diuretic furosemide at a dose of 10 mg.kg-1.d-1, ip; group III (n = 18) had free access to an Na-free diet and deionized drinking water; group IV (n = 21) consumed the same Na-free diet and electrolyte-free water, but was also treated with furosemide. Both the dietary and drug manipulations affected significant (p less than 0.05) negative electrolyte and water balances. Group IV consistently exhibited the greatest decrements. Following the 4-d depletion all four groups were acutely exposed to a 42 degrees C, 25-30% rh environmental heat stress during which time core body temperature increased. The time required for rectal temperature to reach 42.6 degrees C was significantly (p less than 0.05) decreased from a time of 242 +/- 8 min in the control group to 176 +/- 14, 181 +/- 8, and 111 +/- 11 min in groups II, III and IV, respectively. We concluded that Na deprivation and diuretic treatment can elicit a 25-50% reduction in heat tolerance due to electrolyte depletion and dehydration. These data confirm that during environmental heat stress uncompensated negative Na balance may predispose an individual to heat illnesses.

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.

Novel approaches to the pathophysiology of heatstroke: the energy depletion model.

De-emphasis of the role of anhydrosis as the primary cause of heatstroke has resulted in increased usage and acceptance of animal models for heatstroke research. When the total amount of work achieved by the running rat prior to exhaustion was plotted against the rate of heat storage, a heretofore unrecognized relationship emerged. These new data suggest that physical exhaustion and heat exhaustion represent opposite ends of a continuum related to the rate of heat storage. Changes in thermoregulatory and/or physical performance can be estimated by a two-dimensional shift in the work-output/thermal storage ratio. Potassium depletion reduces thermoregulatory/physical performance; a combination of atropine plus diazepam appears to improve it. The role of the cholinergic nervous system in eliciting alterations in thermoregulatory and physical ability is reviewed; endurance training, shivering, acclimatization, set-point theory, the anticholinergic syndrome, lithium intoxication, and choline deficiency are discussed.

Effect of age, weight, and metabolic rate on endurance, hyperthermia, and heatstroke mortality in a small animal model.

Since exercise performance in man is a function of the age, body weight, and metabolic efficiency interrelationship, this investigation was designed to investigate in rats the effects of these variables on endurance, thermoregulation, and heatstroke mortality at a relatively mild environmental temperature (26 degrees C). The results indicate that light rats (250 g) are able to run (11 m X min-1, 6 degrees incline) longer (221 min), have the lowest rate of heat gain (0.019 C degrees X min-1) than the other groups and thereby experience low heatstroke mortality (20%) despite a large proportion of fluid loss (6.1%). Alternatively, heavier and older rats (350 g-12 week, 500 g-16 week, 500 g-30 week) demonstrated significantly reduced run times (108, 67, and 54 min), more rapid accumulation of metabolic heat (0.040, 0.057 and 0.062 degrees C X min-1) and much higher mortalities (50, 69, and 50%) despite lower percentages of fluid loss (5.2, 3.7, or 4.2%). Although the mechanisms responsible for these varying thermoregulatory responses to exercise-induced exhaustion are not fully understood, the present data indicate that the rate of fluid loss, body weight, and age are important variables in the etiology of thermoregulatory failure culminating in heatstroke and death.

Simultaneous determination of fluid shifts during thermal stress in a small-animal model.

We have developed methodology to simultaneously measure fluid redistribution among the major compartments during moderate and severe hypohydration. Total body water (TBW) was determined using tritiated water, extracellular fluid volume (ECF) was measured using a single-injection [14C]inulin technique, and plasma volume (PV) was determined by indocyanine green dye dilution. Moderate (10% decrease in body wt) and severe (15%) hypohydration resulted in significant losses in TBW, ECF, and PV. Plasma volume was decreased by approximately 25% in both groups, and other fluid compartments were differentially affected. For example, the moderately dehydrated group maintained PV by shifting fluid from the interstitial fluid volume (ISF) compartment while preserving the intracellular fluid volume (ICF); conversely, the severely dehydrated group maintained PV by redistributing fluid from both the ISF and ICF compartments. The data indicated that the initial response to fluid loss was the movement of fluid from the ISF pool to sustain both PV and ICF. In severely hypohydrated rats, PV was maintained at the expense of ICF. These experiments indicated that PV and ICF were maximally protected, probably to preserve the integrity of the cardiovascular system and to minimize organ injury.

Effect of sepsis on VLDL kinetics: responses in basal state and during glucose infusion.

The effect of gram-negative sepsis on the kinetics and oxidation of very low-density lipoprotein (VLDL) fatty acids was assessed in conscious dogs in the normal state and 24 h after infusion of live Escherichia coli. VLDL, labeled with [2-3H]glycerol and [1-14C]palmitic acid, was used to trace VLDL kinetics and oxidation, and [1-13C]palmitic acid bound to albumin was infused simultaneously to quantify kinetics and oxidation of free fatty acid (FFA) in plasma. Sepsis caused a fivefold increase in the rate of VLDL production (RaVLDL). In the control dogs, the direct oxidation of VLDL-fatty acids was not an important contributor to their overall energy metabolism, but in dogs with sepsis, 17% of the total rate of CO2 production could be accounted for by VLDL-fatty acid oxidation. When glucose was infused into dogs with insulin and glucagon levels clamped at basal levels (by means of infusion of somatostatin and replacement of the hormones), RaVLDL increased significantly in the control dogs, but it did not increase further in dogs with sepsis. We conclude that the increase in triglyceride concentration in fasting dogs with gram-negative sepsis is the result of an increase in VLDL production and that the fatty acids in VLDL can serve as an important source of energy in sepsis.

Role of very low density lipoproteins in the energy metabolism of the rat.

The role of very low density lipoproteins (VLDL) in the energy metabolism of conscious, 24-hr fasted rats was studied. VLDL labeled with [2-3H]glycerol and [1-14C]palmitate were infused into the rats, along with [1-13C]palmitate bound to albumin and d-8-glycerol, and various metabolic factors were assessed. The rates of appearance in plasma of fatty acids in VLDL and albumin-bound free fatty acids (FFA) were about equal, on a molar basis, and only a small fraction of the FFA flux was derived from VLDL. The rate of direct oxidation of the fatty acids from VLDL was 4.4 +/- 0.9 mumol of FA/kg X min, as compared with the value of 4.0 +/- 0.42 mumol of FA/kg X min for plasma FFA. Four percent of the plasma glycerol flux was derived from VLDL. Thus, the direct oxidation of fatty acids in VLDL played an important role in the energy metabolism of the rats, accounting for a percentage of the total CO2 production that was equal to the amount that arose from the oxidation of plasma FFA. The oxidation of VLDL-fatty acids did not involve prior entry of the fatty acids into the plasma FFA pool to any significant extent.

Voluntary dehydration and alliesthesia for water.

The purpose of this experiment was to explore the complex relationship between fluid consumption and consumption factors (thirst, voluntary dehydration, water alliesthesia, palatability, work-rest cycle) during a simulated 14.5-km desert walk (treadmill, 1.34 m X s-1, 5% grade, 40 degrees C dry bulb/26 degrees C wet bulb, and wind speed of approximately 1.2 m X s-1). Twenty-nine subjects were tested (30 min X h-1, 6 h) on each of two nonconsecutive days. The subjects were randomly assigned to one of three groups: tap water (n = 8), iodine-treated tap water (n = 11), or iodine-treated flavored tap water (n = 10). The temperature of the water was 40 degrees C during one trial and 15 degrees C on the other. Mean sweat losses (6 h) varied between 1.4 kg (warm iodine-treated; 232 +/- 44 g X h-1) and 3.0 kg (cool iodine-treated flavored; 509 +/- 50 g X h-1). Warm drinks were consumed at a lower rate than cool drinks (negative and positive alliesthesia). This decreased consumption resulted in the highest percent body weight losses (2.8 and 3.2%). Cooling and flavoring effects on consumption were additive and increased the rate of intake by 120%. The apparent paradox between reduced consumption concomitant with severe dehydration and hyperthermia is attributed to negative alliesthesia for warm water rather than an apparent inadequacy of the thirst mechanism. The reluctance to drink warm iodine-treated water resulted in significant hyperthermia, dehydration, hypovolemia, and, in two cases, heat illness.

Energy metabolism in trauma and sepsis: the role of fat.

There seems little doubt that there are signals for the increased mobilization of fat in shock, trauma, and sepsis. Whether those signals are reflected by an actual increase in mobilization is dependent on many variables including cardiovascular status. A hypothetical scheme based on our own experiments in the hyperdynamics phases of response to burn injury and to sepsis is presented in Figure 8. According to this scheme, catecholamines stimulate lipolysis in the adipose tissue, resulting in the release of glycerol and FFA into the plasma at increased rates. The glycerol is cleared by the liver and converted into glucose--a process stimulated by, among other things, glucagon. Some of the increased flux of FFA is also cleared by the liver, whereupon the fatty acids are incorporated into VLDL and released again into the plasma. The increased FFA levels also exert a dampening effect on the factors stimulating hepatic glucose production. At the periphery, plasma FFA as well as VLDL fatty acids are taken up at an increased rate. The tissues are attuned to the oxidation of fat, and as a consequence most of the energy production is derived from fat oxidation. The increased fatty acids exert an inhibitory effect on the complete oxidation of glucose, so although glucose may be taken up at an accelerated rate, the relative contribution of glucose oxidation to total energy production may fall. Rather than being completely oxidized, pyruvate is reduced to lactate and released into the plasma at an accelerated rate. The lactate then contributes to the production of glucose in the liver, completing a cyclical process called the Cori Cycle. Although all aspects of this scheme are supported by data highlighted in this paper, it certainly must be an oversimplification of the overall response of substrate metabolism to trauma and sepsis. It is presented for the purpose of highlighting the potential role of fat as a controller of the metabolic response, and to suggest that the enhanced mobilization and oxidation of fat is one of the fundamental responses to stress.