Influence of active muscle mass on glucose homeostasis during exercise in humans

To study the effect of increasing amounts of exercising muscle mass on the relationship between glucose mobilization and peripheral glucose uptake, seven young men (23-28 yr) bicycled for 70 min at a work load of 55-60% VO2max. From minute 30 to 50, arm cranking was added and total work load increased to 82 +/- 4% VO2max. During leg exercise, hepatic glucose production (Ra) increased in parallel with peripheral glucose uptake (Rd) and euglycemia was maintained. During arm + leg exercise, Ra increased more than Rd and accordingly plasma glucose increased from 5.11 +/- 0.22 to 8.00 +/- 0.66 mmol/l (P less than 0.05). Plasma catecholamines increased three- to four-fold more during arm + leg exercise than during leg exercise. Leg glucose uptake increased with time regardless of arm cranking. Net leg lactate release during leg exercise was reverted to a net leg lactate uptake during arm + leg exercise. The rate of glycogen breakdown in exercising leg muscle was not altered by addition of arm cranking. In conclusion, when large amounts of muscle mass are active, plasma catecholamines increase sharply and mobilization of glucose exceeds peripheral glucose uptake. This indicates that mechanisms other than feedback regulation to maintain euglycemia are involved in hormonal and substrate mobilization during intense exercise in humans.     

Glucoregulatory and hormonal responses to repeated bouts of intense exercise in normal male subjects.

Glucose turnover and its regulation were studied during and after two identical bouts of intense exhaustive exercise separated by 1 h to define differences in response. Six lean young postabsorptive male subjects exercised at approximately 100% maximal O2 uptake (3.7 +/- 0.3 l/min) for 13.0 +/- 0.7 min for the first (EX1) and 13.2 +/- 0.8 min for the second (EX2) bout. Plasma glucose increased during EX1 and peaked at 7.0 +/- 0.6 mmol/l in early recovery but to 5.8 +/- 0.5 mmol/l (P less than 0.05) after EX2, and both the hyperglycemic and the hyperinsulinemic responses were less after EX2 (P less than 0.015, analysis of variance). The hyperglycemia was due to lesser increments in glucose utilization (Rd) (3-fold resting) than glucose production (Ra) (7-fold) toward exhaustion and for 7 min of recovery. The rise in Rd was more rapid (P less than 0.05) and metabolic clearance rate was greater during (P = 0.015) and from 9 to 60 min after EX2, and Ra also remained higher during recovery (P less than 0.05). Marked and similar increments in plasma norepinephrine (18-fold) and epinephrine (14-fold) occurred with both bouts. Plasma glucagon increments were small and not different. Therefore, 1) more circulating glucose was used with EX2, 2) greater metabolic clearance rate during and after EX2 suggests local muscle adaptations due to EX1, and 3) significant correlations (P less than 0.002) between plasma norepinephrine and Ra (r = 0.82) and Ra - Rd (r = 0.52) and between epinephrine and Ra (r = 0.71) and Ra - Rd (r = 0.48) suggest a major regulatory role for the catecholamine responses.     

Muscle accounts for glucose disposal but not blood lactate appearance during exercise after acclimatization to 4,300 m.

We hypothesized that the increased blood glucose disappearance (Rd) observed during exercise and after acclimatization to high altitude (4,300 m) could be attributed to net glucose uptake (G) by the legs and that the increased arterial lactate concentration and rate of appearance (Ra) on arrival at altitude and subsequent decrease with acclimatization were caused by changes in net muscle lactate release (L). To evaluate these hypotheses, seven healthy males [23 +/- 2 (SE) yr, 72.2 +/- 1.6 kg], on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6-D2]glucose (Brooks et al., J. Appl. Physiol. 70: 919-927, 1991) and [3-13C]lactate (Brooks et al., J. Appl. Physiol. 71:333-341, 1991) and rested for a minimum of 90 min, followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 uptake (65 +/- 2% of both acute altitude and acclimatization peak O2 uptake). Glucose and lactate arteriovenous differences across the legs and arms and leg blood flow were measured. Leg G increased during exercise compared with rest, at altitude compared with sea level, and after acclimatization. Leg G accounted for 27-36% of Rd at rest and essentially all glucose Rd during exercise. A shunting of the blood glucose flux to active muscle during exercise at altitude is indicated. With acute altitude exposure, at 5 min of exercise L was elevated compared with sea level or after acclimatization, but from 15 to 45 min of exercise the pattern and magnitude of L from the legs varied and followed neither the pattern nor the magnitude of responses in arterial lactate concentration or Ra. Leg L accounted for 6-65% of lactate Ra at rest and 17-63% during exercise, but the percent Ra from L was not affected by altitude. Tracer-measured lactate extraction by legs accounted for 10-25% of lactate Rd at rest and 31-83% during exercise. Arms released lactate under all conditions except during exercise with acute exposure to high altitude, when the arms consumed lactate. Both active and inactive muscle beds demonstrated simultaneous lactate extraction and release. We conclude that active skeletal muscle is the predominant site of glucose disposal during exercise and at high altitude but not the sole source of blood lactate during exercise at sea level or high altitude.     

Lactate as substrate for glycogen resynthesis after exercise

Muscle glycogen levels in the perfused rat hemicorpus preparation were reduced two-thirds by electrical stimulation plus exposure to epinephrine (10(-7) M) for 30 min. During the contraction period muscle lactate concentrations increased from a control level of 3.6 +/- 0.6 to a final value of 24.1 +/- 1.6 mumol/g muscle. To determine whether the lactate that had accumulated in muscle during contraction could be used to resynthesize glycogen, glycogen levels were determined after 1-3 h of recovery from the contraction period during which time the perfusion medium (flow-through system) contained low (1.3 mmol/l) or high (10.5 or 18 mmol/l) lactate concentrations but no glucose. With the low perfusate lactate concentration, muscle lactate levels declined to 7.2 +/- 0.8 mumol/g muscle by 3 h after the contraction period and muscle glycogen levels did not increase (1.28 +/- 0.07 at 3 h vs. 1.35 +/- 0.09 mg glucosyl U/g at end of exercise). Lactate disappearance from muscle was accounted for entirely by output into the venous effluent. With the high perfusate lactate concentrations, muscle lactate levels remained high (13.7 +/- 1.7 and 19.3 +/- 2.0 mumol/g) and glycogen levels increased by 1.11 and 0.86 mg glucosyl U/g, respectively, after 1 h of recovery from exercise. No more glycogen was synthesized when the recovery period was extended. Therefore, it appears that limited resynthesis of glycogen from lactate can occur after the contraction period but only when arterial lactate concentrations are high; otherwise the lactate that builds up in muscle during contraction will diffuse into the bloodstream.     

Effects of training on glucose metabolism of gluconeogenesis-inhibited short-term-fasted rats

To evaluate the effects of endurance training on gluconeogenesis and blood glucose homeostasis, trained as well as untrained short-term-fasted rats were injected with mercaptopicolinic acid (MPA), a gluconeogenic inhibitor, or the injection vehicle. Glucose kinetics were assessed by primed-continuous venous infusion of [U-14C]- and [6-3H]glucose at rest and during submaximal exercise at 13.4 m/min on level grade. Arterial blood was sampled for the determination of blood glucose and lactate concentrations and specific activities. In resting untrained sham-injected rats, blood glucose and lactate were 7.6 +/- 0.2 and 1.3 +/- 0.1 mM, respectively; glucose rate of appearance (Ra) was 71.1 +/- 12.1 mumol.kg-1.min-1. MPA treatment lowered blood glucose, raised lactate, and decreased glucose Ra. Trained animals had significantly higher glucose Ra at rest and during exercise. At rest, trained MPA-treated rats had lower blood glucose, higher blood lactate, and similar glucose Ra and disappearance rates (Rd) than trained sham-injected animals. Exercising sham-injected untrained animals had increased blood glucose and glucose Ra compared with rest. Exercising trained sham-injected rats had increased blood glucose and glucose Ra and Rd but no change in blood lactate compared with untrained sham-injected animals. In the trained animals during exercise, MPA treatment increased blood lactate and decreased blood glucose and glucose Ra and Rd. There was no measurable glucose recycling in trained or untrained MPA-treated animals either at rest or during submaximal exercise. There was no difference in running time to exhaustion between trained and untrained MPA-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose and lactate kinetics in the neonate.

To evaluate the ontogeny of neonatal glucose homeostasis, glucose production and lactate production have been measured in nine prematurely born appropriate for gestational age neonates [birth weight 1985 +/- 100 g, (SEM) gestational age 33.6 +/- 0.7 weeks] and five full term appropriate for gestational age neonates [birth weight 3254 +/- 111 g, gestational age 40.8 +/- 0.4 wks] and compared to six non pregnant, nondiabetic adults [weight of 57.7 +/- 2.2 kg, age 32 +/- 2 years]. Ra glucose (preterm) averaged 27.7 +/- 2.8 mumol.kg-1 min-1 (5.0 +/- 0.5 mg.kg-1 min-1) and Ra glucose (term) averaged 28.9 +/- 3.9 mumol.kg-1 min-1 (5.2 +/- 0.7 mg.kg-1 min-1); both were higher than the Ra glucose of the adult controls (16.1 +/- 2.8 mumol.kg-1 min-1 (2.9 +/- 0.5 mg.kg-1 min-1) (P less than 0.05 vs preterm and P less than 0.05 vs. term). Ra lactate (preterm) averaged 100 +/- 11.9 mumol.kg-1 min-1 (9.1 +/- 1.1 mg.kg-1 min-1) and Ra lactate (term) average 77.2 +/- 13.0 mumol.kg-1 min-1 (7.1 +/- 1.2 mg.kg-1 min-1); both were higher than the Ra lactate of the adult controls 35.9 +/- 6.5 mumol.kg-1 min-1 (3.3 +/- 0.6 mg.kg-1 min-1) (P less than 0.01 vs preterm and P less than 0.05 vs. term). The potential for gluconeogenesis from lactate was estimated by determining the ratio of [Ra Lactate/Ra Glucose]. The [Ra Lactate/Ra Glucose] (preterm) (187 +/- 12 (x10(-2)) was similar to that of the [Ra Lactate/Ra Glucose] (term) (136 +/- 16) (x10(-2)).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes

Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of glucose turnover at the onset of exercise in the dog.

The early responses of endogenous glucose production (Ra), glucose utilization (Rd), and glucoregulatory hormones to moderate treadmill exercise (12% incline, 100 m/min, 60 min) were examined in dogs. Rd increased rapidly and progressively from the start of exercise. The change in Ra, as estimated with a variable-volume model of glucose kinetics, was biphasic, with an abrupt increase by 8.5 +/- 2.3 mumol.min-1.kg-1, followed by a delayed further increase that matched Rd 11-22 min after the onset of exercise. The plasma glucagon-to-insulin molar ratio fell slightly at the onset of exercise and then increased gradually. The glucagon-to-insulin ratio was correlated with Ra over the entire exercise period (r = 0.63, P less than 0.0001), but not during the early part of exercise, when Ra increased rapidly. The catecholamine- (epinephrine plus norepinephrine) to-insulin molar ratio was correlated with Ra during the early period (r = 0.52, P less than 0.01) and over the entire period of exercise (r = 0.66, P less than 0.0001). Our results confirm previous demonstrations that the glucagon-to-insulin molar ratio is an important regulator of Ra during exercise. We hypothesize that the catecholamine-to-insulin molar ratio is important during the early period of exercise and possibly during late exercise as an additional regulatory factor to the glucagon-to-insulin molar ratio.     

Influence of fasting on carbohydrate and fat metabolism during rest and exercise in men

Metabolic effects of an overnight fast (postabsorptive state, PA) or a 3.5-day fast (fasted state, F) were compared in eight healthy young men at rest and during exercise to exhaustion at 45% maximum O2 uptake. Glucose rate of appearance (Ra) and disappearance (Rd) were calculated from plasma glucose enrichment during a primed, continuous infusion of [6,6-2H]glucose. Serum substrates and insulin levels were measured and glycogen content of the vastus lateralis was determined in biopsies taken before and after exercise. At rest, whole-body glucose flux (determined by the deuterated tracer) and carbohydrate oxidation (determined from respiratory exchange ratio) were lower in F than PA, but muscle glycogen levels were similar. During exercise, glucose flux, whole-body carbohydrate oxidation, and the rate of muscle glycogen utilization were significantly lower during the fast. In the PA state, glucose Ra and Rd increased together throughout exercise. However, in the F state Ra exceeded Rd during the 1st h of exercise, causing an increase in plasma glucose to levels similar to those of the PA state. The increase in glucose flux was markedly less throughout F exercise. Lower carbohydrate utilization in the F state was accompanied by higher circulating fatty acids and ketone bodies, lower plasma insulin levels, and the maintenance of physical performance reflected by similar time to exhaustion.     

Endurance training increases fatty acid turnover, but not fat oxidation, in young men.

We examined the effects of exercise intensity and a 10-wk cycle ergometer training program [5 days/wk, 1 h, 75% peak oxygen consumption (VO2 peak)] on plasma free fatty acid (FFA) flux, total fat oxidation, and whole body lipolysis in healthy male subjects (n = 10; age = 25.6 +/- 1.0 yr). Two pretraining trials (45 and 65% of VO2 peak) and two posttraining trials (same absolute workload, 65% of old VO2 peak; and same relative workload, 65% of new VO2 peak) were performed by using an infusion of [1-13C]palmitate and [1,1,2,3, 3-2H]glycerol. An additional nine subjects (age 25.4 +/- 0.8 yr) were treated similarly but were infused with [1,1,2,3,3-2H]glycerol and not [1-13C]palmitate. Subjects were studied postabsorptive for 90 min of rest and 1 h of cycling exercise. After training, subjects increased VO2 peak by 9.4 +/- 1.4%. Pretraining, plasma FFA kinetics were inversely related to exercise intensity with rates of appearance (Ra) and disappearance (Rd) being significantly higher at 45 than at 65% VO2 peak (Ra: 8.14 +/- 1.28 vs. 6.64 +/- 0.46, Rd: 8. 03 +/- 1.28 vs. 6.42 +/- 0.41 mol. kg-1. min-1) (P 相似文献   

The responses of the catecholamines and beta-endorphin to brief maximal exercise in man

The responses to brief maximal exercise of 10 male subjects have been studied. During 30 s of exercise on a non-motorized treadmill, the mean power output (mean +/- SD) was 424.8 +/- 41.9 W, peak power 653.3 +/- 103.0 W and the distance covered was 167.3 +/- 9.7 m. In response to the exercise blood lactate concentrations increased from 0.60 +/- 0.26 to 13.46 +/- 1.71 mmol.l-1 (p less than 0.001) and blood glucose concentrations from 4.25 +/- 0.45 to 5.59 +/- 0.67 mmol.l-1 (p less than 0.001). The severe nature of the exercise is indicated by the fall in blood pH from 7.38 +/- 0.02 to 7.16 +/- 0.07 (p less than 0.001) and the estimated decrease in plasma volume of 11.5 +/- 3.4% (p less than 0.001). The plasma catecholamine concentrations increased from 2.2 +/- 0.6 to 13.4 +/- 6.4 nmol.l-1 (p less than 0.001) and 0.2 +/- 0.2 to 1.4 +/- 0.6 nmol.l-1 (p less than 0.001) for noradrenaline (NA) and adrenaline (AD) respectively. The plasma concentration of the opioid beta-endorphin increased in response to the exercise from less than 5.0 to 10.2 +/- 3.9 p mol.l-1. The post-exercise AD concentrations correlated with those for lactate as well as with changes in pH and the decrease in plasma volume. Post-exercise beta-endorphin levels correlated with the peak speed attained during the sprint and the subjects peak power to weight ratio. These results suggest that the increases in plasma adrenaline are related to those factors that reflect the stress of the exercise and the contribution of anaerobic metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lactate metabolism in the perfused rat hindlimb.

A preparation of isolated rat hindleg was perfused with a medium consisting of bicarbonate buffer containing Ficoll and fluorocarbon, containing glucose and/or lactate. The leg was electrically prestimulated to deplete partially muscle glycogen. The glucose was labelled uniformly with 14C and with 3H in positions 2, 5 or 6, and lactate uniformly with 14C and with 3H in positions 2 or 3. Glucose carbon was predominantly recovered in glycogen, and to a lesser extent in lactate. The 3H/14C ration in glycogen from [5-3H,U-14C]- and [6-3H,U-14C]-glucose was the same as in glucose. Nearly all the utilized 3H from [2-3H]glucose was recovered as water. Insulin increased glucose uptake and glycogen synthesis 3-fold. When the muscle was perfused with a medium containing 10 mM-glucose and 2 mM-lactate, there was little change in lactate concentration. 14C from lactate was incorporated into glycogen. There was a marked exponential decrease in lactate specific radioactivity, much greater with [3H]- than with [14C]-lactate. The 'apparent turnover' of [U-14C]lactate was 0.28 mumol/min per g of muscle, and those of [2-3H]- and [3-3H]-lactate were both about 0.7 mumol/min per g. With 10 mM-lactate as sole substrate, there was a net uptake of lactate, at a rate of about 0.15 mumol/min per g, and the apparent turnover of [U-14C]lactate was 0.3 mumol/min per g. The apparent turnover of [3H]lactate was 3-5 times greater. When glycogen synthesis was low (no prestimulation, no insulin), the incorporation of lactate carbon into glycogen exceeded that from glucose, but at high rates of glycogen deposition the incorporation of lactate carbon was much less than that of glucose. Lactate incorporation into glycogen was similar in fast-twitch white and fast-twitch red muscle, but was very low in slow-twitch red fibres. We find that (a) pyruvate in muscle is incorporated into glycogen without randomization of carbon, and synthesis is not inhibited by mercaptopicolinate or cycloserine; (b) there is extensive lactate turnover in the absence of net lactate uptake, and there is a large dilution of 14C-labelled lactate from endogenous supply; (c) there is extensive detritiation of [2-3H]- and [3-3H]-lactate in excess of 14C utilization.     

Carbohydrate metabolism during and after exercise in rats: studies with radioglucose

Carbohydrate metabolism in exercise, including regulation of glucose production, was studied by isotope-dilution methods, and these were evaluated. Chronically catheterized rats were examined before, during, and after 45 min of running at either low (LIE) or moderate (MIE) intensity. Glucose production (Ra) and disappearance (Rd), as well as muscular glycogen breakdown (Gly), were estimated by primed constant infusions of [3-3H]- and [U-14 C]glucose, and pyruvate oxidation was estimated by sampling of expired 14CO2. During exercise, Ra increased faster than Rd and was, as were steady-state glucose concentration (G) and Gly, directly related to exercise intensity. During recovery Ra and G decreased rapidly, but after MIE, G showed a rebound increase. 14C estimates and chemical measurements sometimes disagreed. Methodological evaluation showed marked incorporation of label in glycogen, lipid, and protein at rest and mobilization of label during exercise. 14CO2 recovery in expired air ranged from only 50% at rest to 77% during MIE. In conclusion, during exercise, mobilization of hepatic glycogen is a primary event and not secondary to increased muscular demand. During and after exercise, plasma glycogen is not precisely controlled at euglycemic levels. Isotope methods may be used to study carbohydrate metabolism in exercising rats, but the results (especially 14C data) should be interpreted with caution.     

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 +/- 14 vs. 113 +/- 11 pM; 0.153 +/- 0.029 vs. 0.156 +/- 0.026 nM; and 64.7 +/- 11.5 vs. 65.8 +/- 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 +/- 0.2 to a nadir of 4.1 +/- 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 +/- 2.8 to 19.1 +/- 2.8 micromol. kg-1. min-1 (P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.     

Muscle glycogen utilization during shivering thermogenesis in humans

The purpose of the present study was to clarify the importance of skeletal muscle glycogen as a fuel for shivering thermogenesis in humans during cold-water immersion. Fourteen seminude subjects were immersed to the shoulders in 18 degrees C water for 90 min or until rectal temperature (Tre) decreased to 35.5 degrees C. Biopsies from the vastus lateralis muscle and venous blood samples were obtained before and immediately after the immersion. Metabolic rate increased during the immersion to 3.5 +/- 0.3 (SE) times resting values, whereas Tre decreased by 0.9 degrees C to approximately 35.8 degrees C at the end of the immersion. Intramuscular glycogen concentration in the vastus lateralis decreased from 410 +/- 15 to 332 +/- 18 mmol glucose/kg dry muscle, with each subject showing a decrease (P less than 0.001). Plasma volume decreased (P less than 0.001) markedly during the immersion (-24 +/- 1%). After correcting for this decrease, blood lactate and plasma glycerol levels increased by 60 (P less than 0.05) and 38% (P less than 0.01), respectively, whereas plasma glucose levels were reduced by 20% after the immersion (P less than 0.001). The mean expiratory exchange ratio showed a biphasic pattern, increasing initially during the first 30 min of the immersion from 0.80 +/- 0.06 to 0.85 +/- 0.05 (P less than 0.01) and decreasing thereafter toward basal values. The results demonstrate clearly that intramuscular glycogen reserves are used as a metabolic substrate to fuel intensive thermogenic shivering activity of human skeletal muscle.     

Cortisol induces perinatal hepatic gluconeogenesis in the lamb.

To examine the influence of a prenatal increase in plasma cortisol concentration on perinatal initiation of hepatic gluconeogenesis, we infused cortisol into seven fetal sheep at 137-140 days gestation. 14C-Lactate provided tracer substrate for estimation of gluconeogenesis. We measured hepatic blood flow using radionuclide-labeled microspheres. After delivery, fetal arterial blood glucose concentration (1.33 +/- 0.4 mmol/l) increased transiently, but returned to fetal levels within 1 h after delivery. Substantial hepatic gluconeogenesis was induced in the fetus after cortisol infusion, averaging 23.4 +/- 12.2 mumol/min/100 g liver (7.8 +/- 4.4 mumol/min/kg fetal weight). Fetal hepatic glucose output was 44.4 +/- 17.7 mumol/min/100 g liver. Hepatic glucose output did not change after delivery; estimated gluconeogenesis decreased immediately, then increased by 6 h after delivery. Lactate supply to the liver fell substantially, from 1.1 +/- 0.4 mmol/min/100 g in the fetus to 0.24 +/- 0.09 at 1 h after delivery. Lactate flux across the liver decreased from 75.3 +/- 23 mumol/min/100 g in the fetus to 20.2 +/- 15.7 at 1 h after delivery. Hepatic lactate flux was significantly related to gluconeogenesis (r = 0.734, P = 0.0001). We conclude that cortisol induces substantial hepatic gluconeogenesis in fetal sheep near term. After delivery, there appears to be a transient decline in gluconeogenesis from lactate, which may be secondary to limited hepatic oxygen and substrate supply. Onset of gluconeogenesis in the fetus fails to sustain increases in either fetal or postnatal blood glucose concentrations.     

Evidence that hyperglycaemia per se does not inhibit hepatic glucose production in man

The effect of hyperglycaemia on hepatic glucose production (Ra) was investigated in nine healthy men using sequential clamp protocols during somatostatin infusion and euglycaemia (0-150 min), at plasma glucose levels of 165 mg x dl-1 (9.2 mM, 150-270 min) and during insulin infusion (1.0 mU x kg-1 x min-1, 270-360 min) in study 1 or during hypo-insulinaemia and plasma glucose levels of 220 mg x dl-1 (12.2 mM; 270-390 min) in study 2. Somatostatin decreased Ra and glucose disposal rate (Rd) but increased plasma free fatty acids (FFA) and lipid oxidation during euglycaemia. Increasing plasma glucose to 165 mg x dl-1 (9.2 mM) and hypo-insulinaemia increased Rd, but no suppressive effects on Ra, plasma FFA and lipid oxidation were observed. By contrast hyperinsulinaemia (study 1), as well as a further increase in plasma glucose (study 2), both decreased Ra. However, more pronounced hyperglycaemia increased insulin secretion despite somatostatin resulting in a fall in plasma FFA and lipid oxidation. Our data questions the accepted dogma that hyperglycaemia inhibits Ra independently of insulin action.     

Decreased reliance on lactate during exercise after acclimatization to 4,300 m

We hypothesized that the increased exercise arterial lactate concentration on arrival at high altitude and the subsequent decrease with acclimatization were caused by changes in blood lactate flux. Seven healthy men [age 23 +/- 2 (SE) yr, wt 72.2 +/- 1.6 kg] on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6-2D]glucose (Brooks et al. J. Appl. Physiol. 70:919-927, 1991) and [3-13C]lactate and rested for a minimum of 90 min followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 consumption (VO2peak; 65 +/- 2% of both acute altitude and acclimatization). During rest at sea level, lactate appearance rate (Ra) was 0.52 +/- 0.03 mg.kg-1.min-1; this increased sixfold during exercise to 3.24 +/- 0.19 mg.kg-1.min-1. On acute exposure, resting lactate Ra rose from sea level values to 2.2 +/- 0.2 mg.kg-1.min-1. During exercise on acute exposure, lactate Ra rose to 18.6 +/- 2.9 mg.kg-1.min-1. Resting lactate Ra after acclimatization (1.77 +/- 0.25 mg.kg-1.min-1) was intermediate between sea level and acute exposure values. During exercise after acclimatization, lactate Ra (9.2 +/- 0.7 mg.kg-1.min-1) rose from resting values but was intermediate between sea level and acute exposure values. The increased exercise arterial lactate concentration response on arrival at high altitude and subsequent decrease with acclimatization are due to changes in blood lactate appearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of carbohydrate ingestion on metabolism during running and cycling.

The effects of carbohydrate or water ingestion on metabolism were investigated in seven male subjects during two running and two cycling trials lasting 60 min at individual lactate threshold using indirect calorimetry, U-14C-labeled tracer-derived measures of the rates of oxidation of plasma glucose, and direct determination of mixed muscle glycogen content from the vastus lateralis before and after exercise. Subjects ingested 8 ml/kg body mass of either a 6.4% carbohydrate-electrolyte solution (CHO) or water 10 min before exercise and an additional 2 ml/kg body mass of the same fluid after 20 and 40 min of exercise. Plasma glucose oxidation was greater with CHO than with water during both running (65 +/- 20 vs. 42 +/- 16 g/h; P < 0.01) and cycling (57 +/- 16 vs. 35 +/- 12 g/h; P < 0.01). Accordingly, the contribution from plasma glucose oxidation to total carbohydrate oxidation was greater during both running (33 +/- 4 vs. 23 +/- 3%; P < 0.01) and cycling (36 +/- 5 vs. 22 +/- 3%; P < 0.01) with CHO ingestion. However, muscle glycogen utilization was not reduced by the ingestion of CHO compared with water during either running (112 +/- 32 vs. 141 +/- 34 mmol/kg dry mass) or cycling (227 +/- 36 vs. 216 +/- 39 mmol/kg dry mass). We conclude that, compared with water, 1) the ingestion of carbohydrate during running and cycling enhanced the contribution of plasma glucose oxidation to total carbohydrate oxidation but 2) did not attenuate mixed muscle glycogen utilization during 1 h of continuous submaximal exercise at individual lactate threshold.     

Acute effects of wortmannin on insulin's hemodynamic and metabolic actions in vivo

Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, was systemically infused during a hyperinsulinemic euglycemic clamp to investigate its effects in vivo. Rats were infused under anesthesia with saline, 10 or 20 mU.min-1.kg-1 insulin, wortmannin (1 microg.min-1.kg-1)+saline, or wortmannin+insulin (10 mU.min-1.kg-1); wortmannin was present for 1 h before and throughout the 2-h clamp. Femoral blood flow (FBF), glucose infusion rate to maintain euglycemia (GIR), glucose appearance (Ra), glucose disappearance (Rd), capillary recruitment by 1-methylxanthine metabolism (MXD), hindleg glucose uptake (HLGU), liver, muscle, and aorta Akt phosphorylation (P-Akt/Akt), and plasma insulin concentrations were determined. Plasma insulin increased from 410+/-49 to 1,680+/-430 and 5,060+/-230 pM with 10 and 20 mU.min-1.kg-1 insulin, respectively. Insulin (10 and 20 mU.min-1.kg-1) increased FBF, MXD, GIR, Rd, and HLGU as well as liver, muscle, and aorta P-Akt/Akt and decreased Ra (all P<0.05). Wortmannin alone increased plasma insulin to 5,450+/-770 pM and increased Ra, Rd, HLGU, and muscle P-Akt/Akt without effect on blood glucose, FBF, MXD liver, or aorta P-Akt/Akt. Wortmannin blocked FBF, MXD, and liver P-Akt/Akt increases from 10 mU.min-1.kg-1 insulin. Comparison of wortmannin+10 mU.min-1.kg-1 insulin and 20 mU.min-1.kg-1 insulin alone (both at approximately 5,000 pM PI) showed that wortmannin fully blocked the changes in FBF and Ra and partly those of GIR, Ra, Rd, HLGU, and muscle P-AKT/Akt. In summary, wortmannin in vivo increases plasma insulin and fully inhibits insulin-mediated effects in liver and aorta and partially those of muscle, where the latter may result from inhibition of insulin-mediated increases in blood flow and capillary recruitment.