Gunvor Ahlborg

Substrate Turnover during Prolonged Exercise in Man: SPLANCHNIC AND LEG METABOLISM OF GLUCOSE, FREE FATTY ACIDS, AND AMINO ACIDS

Arterial concentrations and substrate exchange across the leg and splanchnic vascular beds were determined for glucose, lactate, pyruvate, glycerol, individual acidic and neutral amino acids, and free fatty acids (FFA) in six subjects at rest and during 4 h of exercise at approximately 30% of maximal oxygen uptake. FFA turnover and regional exchange were evaluated using (14)C-labeled oleic acid. The arterial glucose concentration was constant for the first 40 min of exercise, but fell progressively thereafter to levels 30% below basal. The arterial insulin level decreased continuously, while the arterial glucagon concentration had risen fivefold after 4 h of exercise. Uptake of glucose and FFA by the legs was markedly augmented during exercise, the increase in FFA uptake being a consequence of augmented arterial levels rather than increased fractional extraction. As exercise was continued beyond 40 min, the relative contribution of FFA to total oxygen metabolism rose progressively to 62%. In contrast, the contribution from glucose fell from 40% to 30% between 90 and 240 min. Leg output of alanine increased as exercise progressed. Splanchnic glucose production, which rose 100% above basal levels and remained so throughout exercise, exceeded glucose uptake by the legs for the first 40 min but thereafter failed to keep pace with peripheral glucose utilization. Total estimated splanchnic glucose output was 75 g in 4 h, sufficient to deplete approximately 75% of liver glycogen stores. Splanchnic uptake of gluconeogenic precursors (lactate, pyruvate, glycerol, alanine) had increased 2- to 10-fold after 4 h of exercise, and was sufficient to account for 45% of glucose release at 4 h as compared to 20-25% at rest and at 40 min of exercise. In the case of alanine and lactate, the increase in precursor uptake was a consequence of a rise in splanchnic fractional extraction. It is concluded that during prolonged exercise at a low work intensity (a) blood glucose levels fall because hepatic glucose output fails to keep up with augmented glucose utilization by the exercising legs; (b) a large portion of hepatic glycogen stores is mobilized and an increasing fraction of the splanchnic glucose output is derived from gluconeogenesis; (c) blood-borne substrates in the form of glucose and FFA account for a major part of leg muscle metabolism, the relative contribution from FFA increasing progressively; and (d) augmented secretion of glucagon may play an important role in the metabolic adaptation to prolonged exercise by its stimulatory influence on hepatic glycogenolysis and gluconeogenesis.

Lactate and Glucose Exchange across the Forearm, Legs, and Splanchnic Bed during and after Prolonged Leg Exercise

The net exchange of glucose and lactate across the leg and the splanchnic bed and the arterialdeep venous (A-DV) differences for these substrates in the forearm were determined in healthy subjects during 3-3.5 h of leg exercise (bicycle ergometer) at 58% maximum O(2) uptake and during a 40-min post-exercise recovery period. Leg glucose uptake rose 16-fold during exercise and throughout the exercise period exceeded splanchnic glucose output. The latter reached a peak increment (3.5 times basal) at 90 min and fell by 60% during the third hour. As a result, blood glucose declined 40%, reaching frank hypoglycemia (blood glucose, <45 mg/dl) in 50% of subjects at 3.5 h. Splanchnic lactate uptake rose progressively during exercise to values four times the basal rate at 3 h in association with a rise in arterial lactate to 1.5 mM. There was, however, no significant net output of lactate from the legs beyond 90 min of exercise. In contrast, the A-DV lactate difference in the forearm became progressively more negative throughout exercise, reaching values three times the basal level at 3.5 h. The rise in arterial lactate during exercise was proportional to the elevation in plasma epinephrine, which rose ninefold. During recovery, splanchnic lactate uptake rose further to values six times the basal rate, whereas lactate output by the legs was no greater than in the basal state. The A-DV lactate difference in the forearm became even more negative than during exercise, reaching values four times basal. During exercise as well as recovery, forearm uptake of blood glucose could account for no more than 25-67% of forearm lactate release. Leg glucose uptake during recovery was threefold to fivefold higher than in the basal state in the face of plasma insulin concentrations that were 60% below basal and in association with a respiratory exchange ratio of 0.7. We conclude that (a) during prolonged leg exercise at 58% maximum O(2) uptake an imbalance between splanchnic glucose production and leg glucose utilization results in a fall in blood glucose that may reach hypoglycemic levels in healthy subjects; (b) there is a marked increase in the uptake of lactate by the splanchnic bed that cannot be attributed to increased output of lactate from the exercising legs; (c) lactate is released by forearm muscle and, together with other relatively inactive muscle, may be an important source of the increased lactate turnover during and after prolonged leg exercise; (d) the increasingly negative A-DV lactate difference in the forearm cannot be accounted for by uptake of blood glucose, suggesting the breakdown of glycogen in forearm muscle during and after leg exercise; (e) increased glucose uptake by the legs in association with hypoinsulinemia during recovery suggests an increase in insulin sensitivity that permits glycogen repletion in previously exercising muscle in the absence of food ingestion; and (f) the evidence for increased lactate output in the forearm and augmented glucose uptake in the legs during recovery raises the possibility that after leg exercise glycogen stores are decreasing in muscle that was relatively inactive (e.g., that of the forearm) while increasing in the previously exercising leg muscles.

Importance of a Novel Oxidative Mechanism for Elimination of Intracellular Cholesterol in Humans

We have recently demonstrated that cultured human alveolar macrophages efficiently convert cholesterol into excretable 27-oxygenated products. We show here that increasing the intracellular concentration of cholesterol by a factor of 10 leads to about a twofold increase in the excretion of 27-oxygenated products from cultured macrophages. Inhibition of the sterol 27-hydroxylase caused a significant intracellular accumulation of cholesterol. A direct comparison was made between flux of cholesterol and 27-oxygenated products from macrophages preloaded with [4-14C]cholesterol. Under the specific conditions employed with fetal calf serum in the culture medium, the flux of 27-oxygenated products was about 10% of that of cholesterol. Since the sterol 27-hydroxylase, which converts cholesterol to 27-oxygenated products, is present in many cell types, we suggest that 27-oxygenation is a general mechanism for removal of intracellular cholesterol. To evaluate this hypothesis, we measured the net uptake by the human liver of circulating 27-oxygenated products, which was found to be about 20 mg/24 h. This uptake corresponds to approximately 4% of the bile acid production, assuming quantitative conversion into bile acids. It is concluded that the 27-hydroxylase pathway is of significance for elimination of extrahepatic cholesterol.

Plasma Glucagon Levels in Exercising Man

THE hyperglycemic, glycogenolytic and gluconeogenic actions of glucagon have been recognized for some time.1 The physiologic importance of this hormone, however, has only recently been substantiate...

Splanchnic and Peripheral Glucose and Lactate Metabolism during and after Prolonged Arm Exercise

Splanchnic and peripheral exchange of glucose and gluconeogenic substrates was examined in 12 healthy subjects during 2 h of arm or leg exercise on a bicycle ergometer and during a 40-min postexercise recovery period. The work intensity corresponded to 30% of the maximal pulmonary oxygen uptake. The regional exchange of substrates was evaluated using catheter technique and indicator dilution methods for blood flow measurements. Our findings indicate that prolonged arm exercise as compared with exercise with the legs results in a greater increase in heart rate (25-40%) and a more marked reduction in splanchnic blood flow (10-30%) as well as higher arterial concentrations of lactate, free fatty acids, and catecholamines. The respiratory exchange ratio was consistently higher with arm exercise. In addition, arm exercise results in a greater fractional extraction and utilization of glucose by exercising muscle as well as a greater hepatic gluconeogenesis from lactate and glycerol. During recovery from prolonged arm exercise, leg muscle becomes an important site of lactate release to the splanchnic bed, despite a lack of net glucose uptake by the leg. Simultaneously, arm muscle shows an increase in glucose uptake in the absence of a net release of lactate. These coincident but discordant processes in the leg and arm during recovery suggest the occurrence of a redistribution of muscle glycogen from previously resting (leg) muscle to previously exercising (arm) muscle.

Long-lasting vasoconstriction and efficient regional extraction of endothelin-1 in human splanchnic and renal tissues

Six healthy subjects were given endothelin-1, intravenously in a dose of 4 pmol.kg-1.min-1 for 20 min. Blood samples were drawn from arterial, hepatic and renal vein catheters for determinations of splanchnic and renal blood flows and the extraction of endothelin-1 in these vascular beds. Intravenous infusion of endothelin-1 increased the mean arterial blood pressure by 6.8 +/- 2.0 mm Hg (p less than 0.05) and reduced splanchnic and renal blood flows by 34% (p less than 0.005) and 26% (p less than 0.001) respectively. Return to basal flow values occurred after about 1 hr for the splanchnic and 3 hrs for the renal blood flow. The fractional extractions of endothelin-1-like immunoreactivity corresponded to 75 +/- 2% and 60 +/- 2% in the splanchnic and renal vascular beds, respectively. The disappearance curve in plasma and two half-lives of 1.4 +/- 0.1 min and 35 +/- 2.8 min respectively.

Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm : reversal by ETA receptor blockade in patients with atherosclerosis

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ET(A) receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60 min intra-arterial infusion of ET-1 (n=10) significantly blunted EDV in young healthy males (33 +/- 13% compared with 271 +/- 74% increase in FBF induced by 10 mug/min acetylcholine; P<0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60 min intra-arterial infusion of the selective ET(A) receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis (n=10; 109 +/- 45% compared with 255 +/- 101% increase in FBF induced by 10 microg/min acetylcholine; P<0.01), whereas no significant change was observed in healthy age-matched controls (n=9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ET(A) receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ET(A)-receptor-mediated mechanism.

Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis

Endothelin (ET)-1 causes vasoconstriction via ETA and ETB receptors located on vascular smooth muscle cells and vasodilatation via ETB receptors on endothelial cells. Studies in vitro indicate an upregulation of ETB receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ETB receptor antagonist BQ788 evoked a significant increase in FBF (31±13%) in the patients, whereas a 20±9% reduction was observed in the control subjects. The ETA receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102±25%) in the patients compared with no effect in the control subjects (−3±9%, P <0.001 versus patients). The ETA receptor antagonist BQ123 increased FBF to a similar degree in patients (39±11%) as in control subjects (41±11%). The increase in FBF evoked by selective ETA receptor blockade was significantly (P <0.05) less than that evoked by combined ETA/ETB receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1–mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ETB-mediated vasoconstriction.

Influence of Lactate Infusion on Glucose and FFA Metabolism in Man

Sodium L(+)-lactate was infused at rates of 5 to 12 mmol/min intravenously for 30 min in health volunteers, and the exchange of lactate, glucose, and free fatty acids (FFA) was measured in the leg, the forearm muscle, and the splanchnic region. Arterial lactate levels were 3 to 5 mmol/l during the infusion. Leg blood flow increased about 2.5-fold and leg oxygen uptake rose by 35%. Blood flow, oxygen uptake, and glucose production in the splanchnic area remained unaltered. The fractional uptake of lactate by the leg, the splanchnic region, and the forearm decreased during the course of the infusion.

Uptake of Individual Amino Acids by the Human Brain

Summary Individual plasma amino acids were determined in simultaneously drawn arterial and jugular venous blood samples obtained from healthy postabsorptive subjects. Consistently positive A-V differences were observed for virtually all amino acids, indicating a net uptake of essential and nonessential amino acids by the brain in intact man. The authors are grateful to Chester Meyers for skillful technical assistance.