Endogenous Fuels Research Articles

Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration

ObjectiveGlucocorticoids are one of the most commonly prescribed classes of anti-inflammatory drugs; however, chronic treatment promotes iatrogenic (drug-induced) diabetes. As part of their physiological role, glucocorticoids stimulate lipolysis to spare glucose. We hypothesized that persistent stimulation of lipolysis during glucocorticoid therapy plays a causative role in the development of iatrogenic diabetes. MethodsMale C57BL/6J mice were given 100 μg/mL corticosterone (Cort) in the drinking water for two weeks and were fed either normal chow (TekLad 8640) or the same diet supplemented with an adipose triglyceride lipase inhibitor (Atglistatin - 2 g/kg diet) to inhibit the first step of lipolysis. ResultsHerein, we report for the first time that glucocorticoid administration promotes a unique state of substrate excess and energetic overload in skeletal muscle that primarily results from the rampant mobilization of endogenous fuels. Inhibiting lipolysis protected mice from Cort-induced gains in fat mass, excess ectopic lipid accrual, hyperinsulinemia, and hyperglycemia. The role lipolysis plays in Cort-mediated pathology appears to differ between tissues. Within skeletal muscle, Cort-induced lipolysis facilitated diversion of glucose-derived carbons toward the pentose phosphate and hexosamine biosynthesis pathways but contributed to <3% of the Cort-induced genomic adaptations. In contrast, Cort stimulation of lipolysis accounted for ∼35% of the genomic changes in the liver but had minimal impact on hepatic metabolites reported. ConclusionsThese data support the idea that activation of lipolysis plays a causal role in the progression toward iatrogenic diabetes during glucocorticoid therapy with differential impact on skeletal muscle and liver.

Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial

BackgroundKetone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. Methods and resultsThis was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, β-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178–377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156–240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34–94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21–42 µmol/L) ( P < .001), whereas β-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. ConclusionsCirculating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.

Acclimatory gene expression of primed clams enhances robustness to elevated pCO2.

Sublethal exposure to environmental challenges may enhance ability to cope with chronic or repeated change, a process known as priming. In a previous study, pre-exposure to seawater enriched with pCO2 improved growth and reduced antioxidant capacity of juvenile Pacific geoduck Panopea generosa clams, suggesting that transcriptional shifts may drive phenotypic modifications post-priming. To this end, juvenile clams were sampled and TagSeq gene expression data were analysed after (i) a 110-day acclimation under ambient (921 μatm, naïve) and moderately elevated pCO2 (2870 μatm, pre-exposed); then following (ii) a second 7-day exposure to three pCO2 treatments (ambient: 754 μatm; moderately elevated: 2750μatm; severely elevated: 4940 μatm), a 7-day return to ambient pCO2 and a third 7-day exposure to two pCO2 treatments (ambient: 967 μatm; moderately elevated: 3030 μatm). Pre-exposed geoducks frontloaded genes for stress and apoptosis/innate immune response, homeostatic processes, protein degradation and transcriptional modifiers. Pre-exposed geoducks were also responsive to subsequent encounters, with gene sets enriched for mitochondrial recycling and immune defence under elevated pCO2 and energy metabolism and biosynthesis under ambient recovery. In contrast, gene sets with higher expression in naïve clams were enriched for fatty-acid degradation and glutathione components, suggesting naïve clams could be depleting endogenous fuels, with unsustainable energetic requirements if changes in carbonate chemistry persist. Collectively, our transcriptomic data indicate that pCO2 priming during post-larval periods could, via gene expression regulation, enhance robustness in bivalves to environmental change. Such priming approaches may be beneficial for aquaculture, as seafood demand intensifies concurrent with increasing climate change in marine systems.

NIR Light-Propelled Janus-Based Nanoplatform for Cytosolic-Fueled microRNA Imaging.

Various nanoplatforms have been developed to visualize intracellular microRNAs (miRNAs) because of their clinical significance in tumor progression and diagnosis. However, the diffusion-limited motion of the nanoplatforms penalizes the miRNA imaging efficiency in cells. Herein, we fabricated a near-infrared (NIR) light-propelled Janus-based nanoplatform to advance the imaging response. The Janus nanomotor covered with an Au half-shell was loaded by the endocytosis adjuvant of the MnO2 nanosheet for delivering a miRNA-responsive hQN (hairpin DNA quadrangular nanostructure) probe with a catalyzed hairpin assembly (CHA). Once the nanoplatform entered into cells, the MnO2 nanosheet was degraded to Mn2+ by endogenous fuels (such as glutathione) to release the hQN probe. The NIR light irradiation of the nanoplatform generated a heat gradient and thus propelled motion of the nanoplatform. This process accelerated the intracellular reaction of the hQN probe with miRNAs to trigger the cascade CHA amplification with an enhanced fluorescence readout.

The HNF‐1a variant induces endogenous glucose production and Ketonuria in female mice

BACKGROUNDType 2 diabetes (T2D) diagnoses in the Anishininiiwuk (Oji‐Cree) linguistic group of central Canada are among the highest in the world. A genetic variant in the transcription factor hepatic nuclear factor‐1a (HNF‐1a), known as HNF‐1a G319S is present in this population which has been strongly associated with earlier onset of T2D. Historically, T2D was rare in Anishininiiwuk communities provided an active lifestyle required for land‐based food procurement, and potentially with prolonged periods of fasting. As a result of colonization, this lifestyle was abruptly altered leading to a decrease in hunter‐gatherer societies. In the liver, HNF‐1a plays an important role in glucose homeostasis and suppression of hepatic steatosis, but it is unclear if the G319S variant affects liver function. We hypothesize that the G319S variant promotes greater hepatic fuel production and confers a metabolic advantage in the fasted state.METHODSCRISPR/Cas9 gene editing was used to knock‐in the HNF‐1a G319S G&gt;A 955 single nucleotide substitution into C57BL6 mice. These mice express the G319S variant at endogenous levels and in appropriate tissues. Mice fed chow diet ad libitum were sacrificed at 6 months of age, and liver tissues were collected for gene expression analysis, glycogen content measurements, and for hematoxylin and eosin staining. In addition, pyruvate tolerance tests were performed, and urine ketone levels measured in mice fasted for 12 hours.RESULTSDifferences in hepatic steatosis and glycogen content were not observed between the wildtype (G/G), heterozygous (G/S), and homozygous (S/S) HNF‐1a mice. Female mice with two copies of the variant S‐allele (S/S) displayed elevated endogenous glucose production on a pyruvate tolerance test, as well as elevated ketones in the urine.MAIN FINDINGS/CONCLUSIONSIndependent of hepatic steatosis, female homozygous (S/S) HNF‐1a mice show greater endogenous glucose production, and higher ketone levels in their urine, indicative of a greater capacity to generate and mobilize endogenous fuels.Support or Funding InformationThis work was supported by a CIHR project grant awarded to CAD (PJT‐159633).

Shifts in metabolic fuel use coincide with maximal rates of ventilation and body surface rewarming in an arousing hibernator.

It is well established that hibernating mammals rely predominantly on lipid stores to fuel metabolism throughout the hibernation season. However, it is unclear if other endogenous fuels contribute to the rapid, ~400-fold increase in metabolic rate during the early phase of arousal from torpor. To investigate this issue, we used cavity ring-down spectroscopy, a technique that provides a real-time indication of fuel use by measuring the ratio of 13C to 12C in the exhaled CO2 of arousing 13-lined ground squirrels (Ictidomys tridecemlineatus). We used infrared thermography to simultaneously measure ventilation and surface temperature change in various body regions, and we interpreted these data in light of changing plasma metabolite abundances at multiple stages of arousal from torpor. We found that hibernating squirrels use a combination of lipids and, likely, carbohydrates to fuel the initial ~60 min of arousal before switching to predominantly lipid oxidation. This fuel switch coincided with times of maximal rates of ventilation and rewarming of different body surface regions, including brown adipose tissue. Infrared thermography revealed zonal rewarming, whereby the brown adipose tissue region was the first to warm, followed by the thoracic and head regions and, finally, the posterior half of the body. Consistent with the results from cavity ring-down spectroscopy, plasma metabolite dynamics during early arousal suggested a large reliance on fatty acids, with a contribution from carbohydrates and glycerol. Because of their high oxidative flux rates and efficient O2 use, carbohydrates might be an advantageous metabolic fuel during the early phase of arousal, when metabolic demands are high but ventilation rates and, thus, O2 supply are relatively low.

Acute glucose and lactate metabolism are associated with cognitive recovery following traumatic brain injury.

Traumatic brain injury (TBI) is associated with acute cerebral metabolic crisis (ACMC). ACMC-related atrophy appears to be prominent in frontal and temporal lobes following moderate-to-severe TBI. This atrophy is correlated with poorer cognitive outcomes in TBI. The current study investigated ability of acute glucose and lactate metabolism to predict long-term recovery of frontal-temporal cognitive function in participants with moderate-to-severe TBI. Cerebral metabolic rate of glucose and lactate were measured by the Kety-Schmidt method on days 0-7 post-injury. Indices of frontal-temporal cognitive processing were calculated for six months post-injury; 12 months post-injury; and recovery (the difference between the six- and 12-month scores). Glucose and lactate metabolism were included in separate regression models, as they were highly intercorrelated. Also, glucose and lactate values were centered and averaged and included in a final regression model. Models for the prediction frontal-temporal cognition at six and 12 months post-injury were not significant. However, average glucose and lactate metabolism predicted recovery of frontal-temporal cognition, accounting for 23% and 22% of the variance, respectively. Also, maximum glucose metabolism, but not maximum lactate metabolism, was an inverse predictor in the recovery of frontal-temporal cognition, accounting for 23% of the variance. Finally, the average of glucose and lactate metabolism predicted frontal-temporal cognitive recovery, accounting for 22% of the variance. These data indicate that acute glucose and lactate metabolism both support cognitive recovery from TBI. Also, our data suggest that control of endogenous fuels and/or supplementation with exogenous fuels may have therapeutic potential for cognitive recovery from TBI.

Tissue-specific seasonal changes in mitochondrial function of a mammalian hibernator.

Mammalian hibernators, such as golden-mantled ground squirrels (Callospermophilus lateralis; GMGS), cease to feed while reducing metabolic rate and body temperature during winter months, surviving exclusively on endogenous fuels stored before hibernation. We hypothesized that mitochondria, the cellular sites of oxidative metabolism, undergo tissue-specific seasonal adjustments in carbohydrate and fatty acid utilization to facilitate or complement this remarkable phenotype. To address this, we performed high-resolution respirometry of mitochondria isolated from GMGS liver, heart, skeletal muscle, and brown adipose tissue (BAT) sampled during summer (active), fall (prehibernation), and winter (hibernation) seasons using multisubstrate titration protocols. Mitochondrial phospholipid composition was examined as a postulated intrinsic modulator of respiratory function across tissues and seasons. Respirometry revealed seasonal variations in mitochondrial oxidative phosphorylation capacity, substrate utilization, and coupling efficiency that reflected the distinct functions and metabolic demands of the tissues they support. A consistent finding across tissues was a greater influence of fatty acids (palmitoylcarnitine) on respiratory parameters during the prehibernation and hibernation seasons. In particular, fatty acids had a greater suppressive effect on pyruvate-supported oxidative phosphorylation in heart, muscle, and liver mitochondria and enhanced uncoupled respiration in BAT and muscle mitochondria in the colder seasons. Seasonal variations in the mitochondrial membrane composition reflected changes in the supply and utilization of polyunsaturated fatty acids but were generally mild and inconsistent with functional variations. In conclusion, mitochondria respond to seasonal variations in physical activity, temperature, and nutrient availability in a tissue-specific manner that complements circannual shifts in the bioenergetic and thermoregulatory demands of mammalian hibernators.

History of oocyte and embryo metabolism.

The basic pattern of metabolism in mammalian oocytes and early embryos was established in the 1960s and 1970s, largely in terms of the consumption of oxygen and the utilisation of nutrients present in culture media at the time, mainly glucose, pyruvate and lactate. The potential importance of endogenous fuels was also recognised but was largely ignored, only to be rediscovered quite recently. The 1980s and 1990s saw the arrival of a 'new generation' of culture media, characterised metabolically by the addition of amino acids, an initiative driven strongly by the need to improve embryo culture and selection methods in assisted reproductive technologies. This trend has continued alongside some basic metabolic studies and the general recognition of the importance of metabolism in all aspects of biology. A framework for future studies on oocyte and early embryo metabolism has been provided by: (1) the developmental origins of health and disease concept and recognition of the relationship between development, epigenetics and metabolism; (2) the need to understand cell signalling within, and between the cells of, the early embryo; and (3) the importance of identifying the mechanisms underlying dialogue between the oocyte and early embryo and the female reproductive tract.

Exploring the nutritional basis of starvation resistance in Drosophila melanogaster

Summary Food limitation is the most common environmental challenge faced by animals and the capacity of animals to survive prolonged periods of starvation is linked to their diet and nutritional status. The fruit flies of the genus Drosophila have been widely used to study the ecology and evolution of starvation resistance (SR), but the nutritional basis of their resistance to starvation has not yet been fully explored. We have taken a nutritionally explicit approach to investigate the quantitative and qualitative effects of nutrition on SR in Drosophila melanogaster using state‐space geometric models of nutrition. Experimental flies were given ad libitum access to artificial diets differing in concentrations and ratios of protein and carbohydrate for 5 days before they were assayed for starvation time, body composition and life‐history parameters. The main objectives of this study were to determine the most critical nutritional factor of SR and to understand the utilization patterns of endogenous metabolic fuels during starvation in Drosophila. Starvation resistance in Drosophila was greatly influenced by the dietary protein : carbohydrate (P : C) ratio, but neither by the caloric content of the diet nor by carbohydrate alone. SR was strongest at the lowest P : C ratio and decreased with rising P : C ratio. When fed on low P : C diets, Drosophila not only deposited more lipids, but also lowered the minimum body weight required for tolerating starvation. During starvation, Drosophila exhibited a dramatic transition in the utilization of endogenous fuels. In the early phase of starvation, Drosophila exclusively used nonlipid substrates, but switched to the late phase during which they mobilized lipids to maintain life under starvation. Our results highlight the important role that nutrition plays in determining the phenotypic expression of SR in Drosophila and provide broad implications for understanding starvation responses in other species, including humans. This study introduces how the recent advances in nutritional physiology can offer new insights into the ecology and evolution of starvation responses.

Beyond muscle hypertrophy: why dietary protein is important for endurance athletes.

Recovery from the demands of daily training is an essential element of a scientifically based periodized program whose twin goals are to maximize training adaptation and enhance performance. Prolonged endurance training sessions induce substantial metabolic perturbations in skeletal muscle, including the depletion of endogenous fuels and damage/disruption to muscle and body proteins. Therefore, increasing nutrient availability (i.e., carbohydrate and protein) in the post-training recovery period is important to replenish substrate stores and facilitate repair and remodelling of skeletal muscle. It is well accepted that protein ingestion following resistance-based exercise increases rates of skeletal muscle protein synthesis and potentiates gains in muscle mass and strength. To date, however, little attention has focused on the ability of dietary protein to enhance skeletal muscle remodelling and stimulate adaptations that promote an endurance phenotype. The purpose of this review is to critically discuss the results of recent studies that have examined the role of dietary protein for the endurance athlete. Our primary aim is to consider the results from contemporary investigations that have advanced our knowledge of how the manipulation of dietary protein (i.e., amount, type, and timing of ingestion) can facilitate muscle remodelling by promoting muscle protein synthesis. We focus on the role of protein in facilitating optimal recovery from, and promoting adaptations to strenuous endurance-based training.

Physiological responses to food deprivation in the house sparrow, a species not adapted to prolonged fasting

Many wild birds fast during reproduction, molting, migration, or because of limited food availability. Species that are adapted to fasting sequentially oxidize endogenous fuels in three discrete phases. We hypothesized that species not adapted to long fasts have truncated, but otherwise similar, phases of fasting, sequential changes in fuel oxidization, and similar changes in blood metabolites to fasting-adapted species. We tested salient predictions in house sparrows (Passer domesticus biblicus), a subspecies that is unable to tolerate more than ~32 h of fasting. Our main hypothesis was that fasting sparrows sequentially oxidize substrates in the order carbohydrates, lipids, and protein. We dosed 24 house sparrows with [(13)C]glucose, palmitic acid, or glycine and measured (13)CO(2) in their breath while they fasted for 24 h. To ascertain whether blood metabolite levels reflect fasting-induced changes in metabolic fuels, we also measured glucose, triacylglycerides, and β-hydroxybutyrate in the birds' blood. The results of both breath (13)CO(2) and plasma metabolite analyses did not support our hypothesis; i.e., that sparrows have the same metabolic responses characteristic of fasting-adapted species, but on a shorter time scale. Contrary to our main prediction, we found that recently assimilated (13)C-tracers were oxidized continuously in different patterns with no definite peaks corresponding to the three phases of fasting and also that changes in plasma metabolite levels accurately tracked the changes found by breath analysis. Notably, the rate of recently assimilated [(13)C]glycine oxidization was significantly higher (P < 0.001) than that of the other metabolic tracers at all postdosing intervals. We conclude that the inability of house sparrows to fast for longer than 32 h is likely related to their inability to accrue large lipid stores, separately oxidize different fuels, and/or spare protein during fasting.

Birds unadapted to prolonged fasting may not follow the mass loss pattern characteristic of fasting‐adapted species

Birds, such as penguins and long distance migrants, which are considered adapted to long fasts, sequentially oxidize endogenous carbohydrates, lipids and proteins to meet energy demands. The pattern of nutrient use, metabolic biochemistry, and body mass changes during fasting are generally characterized in three phases; I ‐ post‐absorptive phase; II ‐ protein sparing phase; and III ‐ lethal phase. Little is known about how birds that are not so adapted use endogenous fuels during fasting or food restriction. We hypothesized that those small birds, that do not regularly undergo long fasts have truncated, but otherwise similar fasting phases and sequential changes in fuel oxidation and blood metabolites to fasting‐adapted species. We tested our hypothesis in house sparrows (Passer domesticus) using artificially enriched 13C stable isotope tracers (glucose, palmitic acid, and glycine) and measuring 13CO2 in their breath. We predicted that fasted birds, dosed with 13C enriched tracers, have 13CO2 enrichments in exhaled breath reflecting the sequential changes in fuel oxidation during fasting, each phase being represented by a specific tracer. Our initial data show continuous, parallel oxidation of the tracers during fasting, with no clear division into phases, rather than sequential changes of fuel oxidation similar to fasting‐adapted species and, therefore, do not support our hypotheses.

Fruit bats (Pteropodidae) fuel their metabolism rapidly and directly with exogenous sugars

Previous studies reported that fed bats and birds mostly use recently acquired exogenous nutrients as fuel for flight, rather than endogenous fuels, such as lipids or glycogen. However, this pattern of fuel use may be a simple size-related phenomenon because, to date, only small birds and bats have been studied with respect to the origin of metabolized fuel, and because small animals carry relatively small energy reserves, considering their high mass-specific metabolic rate. We hypothesized that approximately 150 g Egyptian fruit bats (Rousettus aegyptiacus Pteropodidae), which are more than an order of magnitude heavier than previously studied bats, also catabolize dietary sugars directly and exclusively to fuel both rest and flight metabolism. We based our expectation on the observation that these animals rapidly transport ingested dietary sugars, which are absorbed via passive paracellular pathways in the intestine, to organs of high energy demand. We used the stable carbon isotope ratio in exhaled CO(2) (delta(13)C(breath)) to assess the origin of metabolized substrates in 16 Egyptian fruit bats that were maintained on a diet of C3 plants before experiments. First, we predicted that in resting bats delta(13)C(breath) remains constant when bats ingest C3 sucrose, but increases and converges on the dietary isotopic signature when C4 sucrose and C4 glucose are ingested. Second, if flying fruit bats use exogenous nutrients exclusively to fuel flight, we predicted that delta(13)C(breath) of flying bats would converge on the isotopic signature of the C4 sucrose they were fed. Both resting and flying Egyptian fruit bats, indeed, directly fuelled their metabolism with freshly ingested exogenous substrates. The rate at which the fruit bats oxidized dietary sugars was as fast as in 10 g nectar-feeding bats and 5 g hummingbirds. Our results support the notion that flying bats, irrespective of their size, catabolize dietary sugars directly, and possibly exclusively, to fuel flight.

Effect of aging on glucose and lipid metabolism during endurance exercise.

Endurance exercise increases the use of endogenous fuels to provide energy for working muscles. Elderly subjects oxidize more glucose and less fat during moderate intensity exercise. This shift in substrate use is presumably caused by age-related changes in skeletal muscle, including decreased skeletal muscle respiratory capacity, because adipose tissue lipolysis and plasma fatty acid availability are not rate limiting. Endurance training in elderly subjects increases muscle respiratory capacity, decreases glucose production and oxidation, and increases fat oxidation thereby correcting or compensating for the alterations in substrate oxidation associated with aging.

Role of fatty acids in the recovery of cardiac function during resuscitation from hemorrhagic shock.

This study tested the hypothesis that removal of fatty acids as a fuel source would improve cardiac efficiency at the expense of reduced cardiac contractile function in the isolated working heart after hemorrhage-retransfusion. Non-heparinized male Sprague-Dawley rats were anesthetized with ketamine-xylazine and were hemorrhaged to a mean arterial blood pressure of 40 mmHg for 1 h. Two-thirds volume of shed blood was reinfused together with 0.9% NaCl in a volume equal to 2.3 times the shed blood volume, followed by continuous infusion of 0.9% NaCl at 10 mL/kg per h for 3 h. Hearts were removed and perfused in closed, recirculating working mode for 60 min to measure hydraulic work and cardiac efficiency. Rates of glycolysis and glucose oxidation were assessed with [5-3H/U-14C] glucose (11 mM) in the absence or presence of 0.4 mM palmitate. Compared to baseline measurements, hemorrhage-retransfusion significantly reduced arterial blood glucose (228+/-7 versus 118+/-12 mg/dL) and non-esterified fatty acid concentrations (0.36+/-0.01 versus 0.30+/-0.02 mM), while elevating blood lactate (0.8+/-0.1 versus 2.5+/-0.4 mM). Perfusion of sham hearts with glucose-only did not alter cardiac work compared to shams perfused with glucose plus palmitate. However, shocked hearts perfused with glucose-only demonstrated a significant reduction in cardiac work compared to shocked hearts perfused with glucose plus palmitate and compared to sham hearts perfused with glucose only (P < 0.05, repeated measures ANOVA). Shocked hearts perfused with glucose plus palmitate showed no reduction in cardiac work compared to shams. Shocked hearts perfused with glucose-only had increased glucose oxidation rates compared to shams perfused with glucose plus palmitate. In sham hearts perfused with glucose-only, myocardial glycogen and triacylglycerol contents were significantly reduced compared to hearts freeze-clamped in situ. These endogenous fuels were not decreased in shocked hearts. These data indicate that hemorrhagic shock renders the heart unable to mobilize endogenous fuels, and suggest that withdrawal of fatty acid oxidation will impair myocardial energy metabolism during resuscitation.

A minimum of fuel is necessary for tolbutamide to mimic the effects of glucose on electrical activity in pancreatic beta-cells.

Glucose stimulation of pancreatic beta-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K+ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (>7 mM) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K+ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse beta-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 microM) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mM glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the beta-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mM glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mM was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the beta-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K+ channels is not the only mechanism by which glucose controls electrical activity in beta-cells.

Exercise challenge in Antarctic fishes: do haematology and muscle metabolite levels limit swimming performance?

Burst swimming increased haematocrit (partly from erythrocyte swelling) in the cryopelagic nototheniid Pagothenia borchgrevinki, but not in the benthic species Trematomus bernacchii. Erythrocyte nucleotides, which regulate haemoglobin-oxygen affinity, remained constant. Plasma cortisol was high in all captive fish and raised questions about the effects of chronic stress on metabolic measurements from Antarctic fish held in captivity. Glycogen was reduced in white trunk muscle, but not in the red pectoral muscle of exercised P. borchgrevinki. Red pectoral muscle glycogen was nearly 3 times higher in T. bernacchii than in P. borchgrevinki but post-exercise lactate rises were modest. Lactate values were, however, higher in exercised P. borchgrevinki white muscle than in T. bernacchii, and correlated with muscle-buffering capacity. Resting adenylate energy charge (AEC) was unexpectedly low in both species and reduced with exercise only for white muscle in P. borchgrevinki. While it appears that the capacity for burst swimming is limited by endogenous metabolic fuels, confirmation of low resting values of ATP and AEC in Antarctic fishes requires the development of methods that maintain high phosphocreatine levels in the muscle.

Plasma glucose turnover and oxidation during hemodialysis: nutritional effect of dialysis fluid

Mass transfer of glucose from dialysis fluid into patients is a source of energy and a form of nutrition during hemodialysis. The effect of glucose mass transfer on endogenous glucose metabolism and the overall nutritional importance of glucose transfer is not known. Rates of plasma glucose turnover and oxidation were determined by radioisotope-dilution techniques in patients with chronic renal failure (CRF) in the basal state, during hemodialysis, and during the infusion of glucose at a rate similar to the mass transfer rate (Mt: 6.6 +/- 0.7 mumol.min-1.kg-1). Rates of plasma glucose turnover (11.8 +/- 0.8 mumol.min-1.kg-1) and oxidation (4.0 +/- 0.4 mumol.min-1.kg-1) and contribution of glucose oxidation to the metabolic rate were similar to those of control subjects both in the basal state and during glucose infusion. During hemodialysis with acetate and glucose, the plasma glucose turnover rate was similar to that in the basal state, but the energy from glucose oxidation was less (P < or = 0.02) even though energy expenditure was increased by 21%. Immediate oxidation of plasma glucose and acetate accounted for 65% of the patients' energy expenditure. Energy (1172 kJ) from acetate Mt and glucose Mt surpassed the patients' energy requirements, offsetting the utilization of endogenous fuels, a sparing effect equivalent to 31 g fat or 70 g carbohydrate. Rates of plasma glucose turnover and oxidation during bicarbonate-glucose and glucose-free acetate hemodialysis were similar to that during acetate-glucose hemodialysis. However, without glucose or acetate in the bath fluid, a deficit as much as 669 kJ must be met by the oxidation of endogenous fuels. Addition of organic nutrients that supply energy to dialysis fluids may over time be a beneficial supplemental treatment for the malnutrition and body wasting commonly observed in CRF.

Growth and metabolic parameters in pups of undernourished lactating rats

Effects of reduced nutrition during postnatal development were studied by measuring body weight, plasma corticosterone, corticosterone-binding globulin (CBP), and metabolic parameters (plasma glucose and body composition) in preweanling Long Evans rat pups. Control litters consisted of dams that were fed chow ad lib while restricted dams were provided 1 3 the amount of chow given controls (25–30 g/day). At I 1 days, body weight of the restricted pups dropped below that of controls. Percent body lipid, plasma corticosterone and glucose of restricted pups were lower than controls. Binding capacity of CBP in controls increased without a change in binding affinity ( K d ). By contrast, binding capacity of CBP of restricted pups never matched that of controls but the K d increased. Nutritional deprivation during lactation affected production of CBP that effectively reduced the biological activity of corticosterone in circulation. Deprived of an effective cellular response to an impoverished supply of food, pups were left with little capacity to manage endogenous fuels during the growth spurt that normally occurs during the suckling period.