Endogenous Fuels Research Articles

Forearm Substrate Utilization during Exercise after a Meal Containing Both Fat and Carbohydrate

1. Whilst the provision of exogenous carbohydrate has been shown to be beneficial to endurance exercise performance, little attention has been paid to the possibility of dietary manipulation of the availability of fat. 2. Ten normal subjects were studied on two occasions: after an overnight fast (postabsorptive state) and after a meal containing 80 g of fat and 80 g of carbohydrate (fed state). Forearm substrate exchange was studied during 60 min of isometric forearm exercise (5 s contraction, 5 s relaxation). 3. In the fed state concentrations of plasma triacylglycerol (1510 +/- 150 versus 850 +/- 80 mumol/l, P < 0.01), blood ketone bodies (151 +/- 21 versus 80 +/- 10 mumol/l, P < 0.01) and plasma insulin (17 +/- 3 versus 7 +/- 1 m-units/l, P < 0.01) were elevated compared with the postabsorptive state; plasma glucose and non-esterified fatty acid concentrations were not significantly different. 4. Forearm blood flow and O2 consumption each increased about 6-fold during exercise, with no differences between the two nutritional states. The potential contribution of individual substrates to forearm O2 consumption (a calculation which is independent of blood flow) was assessed: for triacylglycerol it was significantly greater in the fed state (P < 0.01). The sum of the potential contributions of triacylglycerol, non-esterified fatty acids, glucose and ketone bodies to forearm O2 consumption was significantly greater, both before and during exercise, in the fed than in the postabsorptive state (P < 0.05), implying the sparing of endogenous (forearm) fuels. 5. These studies highlight the potential for manipulation of substrate supply during exercise by feeding meals containing both carbohydrate and fat.

Does the integrated level of all plasma nutrients control daily food intake?

Studies on two different types of one-way crossed-intestines rats have shown that daily food intake is controlled by either endogenous gut signals or absorbed nutrients and their metabolic consequences, or both. If the amount of incoming ingested food is metered somewhere in the body, this could only occur in the gut or liver. The capacity of the liver to determine the amount of water-soluble nutrient absorbed was assessed by portacaval shunt and found to be inadequate. Infusion of nutrients directly into the bloodstream show that plasma nutrients provide part of the signal that inhibits daily food intake, but that endogenous gut signals must play some role. Insulin, an important hormone in the movement of plasma nutrients into cells, was found to stimulate food intake at low infusion doses. IV nutrients raise the level of plasma nutrients and lower daily food intake, while insulin, which inhibits the release of endogenous fuels and moves exogenous fuels into cells, lowers plasma nutrients and stimulates daily intake. Thus, the integrated level of all plasma nutrients may be a major controller of daily food intake.

Postnatal Age and the Metabolism of Medium- and Long-Chain Fatty Acids by Isolated Hepatocytes from Small-for-Gestational-Age and Appropriate-for-Gestational-Age Piglets

Hepatocytes were isolated from full-term small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) piglets at 6 or 48 h postpartum and incubated with 1 mmol/L [1-14C]-octanoate (8:0), -nonanoate (9:0) or -oleate (18:1). The cells oxidized [nmol 1-C/(h.10(6) cells)] 9:0 to carbon dioxide (12.5) and acid soluble products (28.9) faster than 8:0 (10.9, 20.6, respectively), and both were oxidized faster than 18:1 (3.9, 9.9) regardless of the piglet age or weight. Oleate accumulated in lipid products eightfold faster than did 8:0 and 9:0. No differences between cells from SGA and AGA piglets were detected. Recovery of 1-C in CO2 was 48% higher in incubations with cells from 48-h-old than from 6-h-old piglets. This increase was attributable to a 70% higher O2 consumption by 48-h-old cells. Theoretical O2 consumption rates were computed from the fatty acid flux data and compared with measured O2 consumption. Hepatocytes from SGA and AGA piglets were equally capable of satisfying greater than 75% of their energy needs from fatty acid oxidation. The O2 consumption attributable to 9:0 metabolism was 30% higher than observed for 8:0 and 18:1. All fatty acids apparently spared endogenous fuels to a greater degree in 6-h-old than in 48-h-old piglets.

Effect of fasting on myocardial substrates in male and female rats

Adult male and female rats were fasted for 1, 2, or 3 days to determine its effect on circulating and endogenous fuels available to the heart. Liver glycogen was depleted within the first 24 h of food restriction. Plasma glucose decreased approximately 2.5 mM in both sexes during the 3 days. Fasting significantly increased plasma beta-hydroxybutyrate to approximately the same level in female and male rats. Plasma free fatty acid (FFA) increased approximately 0.2 mM in both groups during the first 24 h without food and remained elevated over the next 2 days. FFA concentrations were higher in fed female than in fed male rats and remained significantly higher in female rats throughout the experimental period. Myocardial glycogen increased 64% during the first 2 days of fasting in the male rats and stayed elevated on the third day of fasting. In contrast, heart glycogen of female rats remained unchanged from an initial value of 3.13 mg/g throughout the 3-day fasting period. Endogenous triglyceride (TG) of male rats decreased from 2.14 +/- 0.09 to 1.41 +/- 0.21 mumol/g during the first 24 h without food and remained at that level during the second and third days. Heart TG in female rats fell progressively from 2.36 +/- 0.19 to 1.02 +/- 0.12 mumol/g during the fasting period. Cardiac FFA were higher in female than in male animals throughout the entire experiment. These data indicate that quantitative and qualitative metabolic differences exist between male and female rats stressed by fasting.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of glycolysis in adenylate depletion and repletion during work and recovery in teleost white muscle.

Measurements of metabolite concentrations before and immediately after swimming of trout to exhaustion indicate that all three potential endogenous fuels of anaerobic metabolism [glycogen, phosphocreatine (PCr) and adenosine triphosphate (ATP)] are utilized during anaerobic white muscle work. Lactate, H+, creatine Pi, NH4+ and inosine monophosphate (IMP) are formed in the process. Glycolysis is considered to be functionally (if loosely) coupled to adenylate depletion by setting up conditions favouring AMP-deaminase-catalysed formation of IMP and NH3. During recovery under these experimental conditions, glycolysis appears to outcompete oxidative metabolism as an ADP acceptor; therefore, in this kind of white muscle, glycolysis is also linked to IMP reconversion to AMP and thus to adenylate replenishment. The net process generates H+, which is why ATP replenishment must be completed before PCr concentrations can be returned to pre-exercise values.

The effect of increased respiratory resistance on glycogen and triglyceride levels in the respiratory muscles of the rat.

The effect of increased respiratory resistance (stenosis of the trachea) on glycogen and triglyceride levels in the diaphragm (D) and intercostal (external-IE, internal-II) muscles was studied in the rat. Tracheal stenosis resulted in a reduction of glycogen level in the muscles. For the fed rats the reductions were: D-45 and 79%, IE-14 and 30%, II-14 and 35%, 0.5 and 3 h after stenosis, respectively. For rats fasted for 24 h the reductions were: D-64 and 86%, IE-33 and 71%, II-40 and 82%, after 0.5 and 3 h respectively. The level of triglycerides in the muscles was stable during stenosis in the fed group, whereas in the fasted group it were reduced in the diaphragm by 50% after 0.5 h, and by 52% after 3 h. It is concluded that both endogenous and blood-born energy fuels are utilized by the respiratory muscles during increased resistance breathing.

Fuels and pathways as designed systems for support of muscle work.

Muscle in all animals relies upon four potential sources of energy: ATP hydrolysis, phosphagen hydrolysis, fermentations or oxidative metabolism. Although the relative contributions of different fuels varies greatly in different organisms, in none is there a simple reliance on stored ATP. Muscle work therefore requires a balance between rates of utilization and formation of ATP, a provision supplied by one of the three remaining fuels and metabolic pathways. Useful endogenous fuels must be storable at high level, and rapidly mobilizable with minimal perturbation of [ATP] and with minimal end-product effects on pH, charge or osmotic balance. In addition to displaying these properties, good exogenous fuels must be transferable at high rates between depot sites and muscle; actual flux rates of exogenous fuels depend upon respective ATP yields and are lowest for fuels which most amplify the yield of ATP per mol substrate oxidized. Substrate flux rates must be matched with O2 flux rates and with rates of endogenous substrate mobilization in order that the right energy-yielding pathways are activated at the right times. Of various control possibilities, an effective competition for ADP (and possibly Pi) seems at this time to be the dominant strategy for assuring integration of aerobic and anaerobic ATP-yielding pathways.

Respiration and insulin release in mouse pancreatic islets: Effects of l-leucine and 2-ketoisocaproate in combination with d-glucose and l-glutamine

In order to further evaluate the importance of B-cell metabolism for the stimulation of insulin release, respiration and insulin release were studied in mouse pancreatic islets. Leucine and 2-ketoisocaproate stimulated insulin release during an initial 1-h period, whereas there was no stimulation during two subsequent 1-h periods. This effect was in contrast to that of 16.7 mM glucose, which was a potent stimulator through all the 3 h. Furthermore, the presence of glucose (5.6 mM) or glutamine together with either leucine or 2-ketoisocaproate enhanced the insulin release and prolonged the stimulation. When the kinetics of islet respiration were studied both leucine and 2-ketoisocaproate exerted an initial stimulation on the O 2 uptake which, however, was short-lived (less than 30 min). The presence of 5.6 mM glucose strongly delayed the respiratory retardation seen after the initial stimulation. Similarly, glutamine enhanced the leucine- and 2-ketoisocaproate-stimulated respiratory rates and prevented the respiratory retardation otherwise observed. Leucine (20 mM) and 2-ketoisocaproate (10 and 20 mM) stimulated the oxidation of glucose (5.6 mM). It is concluded that there is a strong correlation between respiratory stimulation and the enhancement of insulin release and that leucine and 2-ketoisocaproate depend on the presence of endogenous fuels for their ability to stimulate islet functions in vitro.

Utilization of Nutrients by Isolated Epithelial Cells of the Rat Colon

Isolated suspensions of colonocytes from the rat were used to assess utilization, interaction, and fate of metabolic substrates normally obtained from colonic bacteria (acetate, propionate, butyrate) or derived from the blood circulation to the colonic mucosa (D-glucose, acetoacetate, L-glutamine). The short-chain fatty acid n-butyrate (10 mM), on its own, accounted for 86% of the total oxygen consumption and suppressed oxidation of endogenous fuel by 82%. Ths value was not altered by the addition of acetoacetate (5 mM), of L-glutamine (5 mM), or of D-glucose (10 mM). Activation of short-chain fatty acids by colonocytes proceeded in the order of butyrate greater than acetate greater than propionate. D-Glucose on its own accounted for 30% of the oxygen consumption by colonocytes and hardly suppressed utilization of endogenous fuels. Colonocytes utilized ketone bodies (acetoacetate) and produced them (acetoacetate and beta-hydroxybutyrate) from short-chain fatty acids. Considering the interaction of substrates, isolated colonic epithelial cells utilized respiratory fuels in the preferential order of butyrate greater than acetoacetate greater than glutamine greater than glucose. The high rate of CO2 production from butyrate should be a worthwhile means of examining the functional activity of the colonic mucosa clinically and in vivo.

Computer simulation of energy metabolism in acidotic cardiac ischemia.

Construction and fit to experimental data of a computer model of glycolysis, the tricarboxylic acid cycle, and related metabolism in the perfused rat heart involving 63 enzyme submodels is described. The experimental preparation simulated is a rat heart perfused with Krebs bicarbonate solution containing glucose and insulin whose pH was lowered to 6.6 by equilibration with 35% CO2-65% O2. The glycolytic rate falls sharply and ischemia results, becoming apparent after 3.5 min. The model initially ascribes the fall in glycolysis largely to inhibition of hexokinase by accumulated glucose 6-phosphate and inactivation of phosphofructokinase by the low pH and subsequently to cytoplasmic glucose depletion owing to limitation of glucose uptake by the external acidosis. At the same time there is insufficiently deep hypoxia to trigger substantial mobilization of endogenous fuels (e.g., glycogenolysis or fatty acid mobilization, so that these hearts become ischemic primarily owing to a shortage of metabolic fuel.

The stimulus secretion coupling of glucose-induced insulin release: Effect of lactate upon islet function

In isolated rat pancreatic islets, exogenous l-lactate causes a dose-related enhancement of glucose-induced insulin release and shifts the sigmoidal curve relating insulin output to ambient glucose concentrations to the left. l-Lactate also enhances α-ketoisocaproate-induced insulin release and glucose-induced proinsulin biosynthesis. l-Lactate rapidly accumulates in the islet cells, is converted to pyruvate and CO 2, and raises the intracellular concentration of both ATP and NAD(P)H. On a molar basis, the insulinotropic capacity of nutrients ranges as follows d-glucose ⪢ l-lactate > pyruvate = d/ l-lactate > d-lactate and does not correlate with their respective oxidation rates. However, when allowance is made for the intracellular interconversion of these exogenous nutrients, for their reciprocal influence upon oxidation rates, and for their sparing action on the utilization of endogenous fuels, a close correlation is found between the aptitude of glucose, l-lactate, and pyruvate to generate reducing equivalents and to stimulate insulin release. It is proposed that the concentration of NAD(P)H in islet cells affects the ionophoretic fluxes of cations (K +, Ca 2+) across membrane systems and, hence, regulates the net uptake of Ca 2+ and subsequent release of insulin. The effect of l-lactate upon Ca 2+ handling is sufficiently rapid to account for the immediate secretory response to this nutrient.

Alpha- and beta-cell interrelationships in health and disease

The variations in secretory responses of the pancreatic alpha and beta cells in response to variations in nutrient supply and demand in health and disease are demonstrated. The biologic capability of insulin and glucagon to control on a moment-to-moment basis the disposition of exogenous and endogenous fuels is considered. An appropriate insulin-glucagon response ensures the most efficient storage of ingested nutrients, while maintaining fuel requirements from endogenous sources when food is not available. The glucose supply, both present and past, seems to influence the insulin-glucagon response to all other nutrients, to hormones, and to neural influences more than any other factor. The intracellular entry and metabolism of glucose appears to be required to suppress alpha cell secretion below the basal level and to prevent its hyperresponsiveness to various stimuli. An inappropriately low concentration of insulin and/or high level of glucagon relative to fuel availability is observed in genetic diabetes, and in a variety of stressful illnesses such as severe infection, trauma, burns, fetal distress, and other conditions, all of which are characterized by a negative nitrogen balance. The use of amino acids to produce glucose and urea at the expense of protein synthesis is presumably promoted by a low insulin: glucagon ratio and may be a factor in the catabolic manifestations of these diseases.