Long-term prognosis after acute myocardial infarction in patients with a history of arterial hypertension. TRACE study group.

AIMS: The objective of the study was to investigate the influence of a history of arterial hypertension on long-term prognosis after an acute myocardial infarction in a representative population, and secondly to assess the impact on prognosis of left ventricular systolic function in hypertensives after acute myocardial infarction. METHODS: A retrospective analysis of survival data on 6676 patients with acute myocardial infarction screened for entry into the TRAndolapril Cardiac Evaluation (TRACE) study. Follow-up time was 4-6 years. RESULTS: One thousand five hundred and seven (23%) of the patients had a history of arterial hypertension. During the time of observation 763 (50.6%) hypertensives and 2253 (43.7%) normotensives died, corresponding to a risk ratio for death in hypertensives of 1.23 (1.13-1.33, P < 0.0001). In a multivariate analysis considering 12 other major risk factors after myocardial infarction, the risk ratio for death in hypertensives was 1.14 (1.04-1.24). There was a significant interaction between hypertension and age. Thus, hypertension only increased risk in patients aged 65 years or less (P < 0.001). No interaction with left ventricular systolic function was found. CONCLUSION: A history of arterial hypertension is a moderate risk factor for mortality after an acute myocardial infarction in patients aged 65 years or less. This excess risk is present at all levels of left ventricular systolic function.

Glucose homeostasis during exercise in humans with a liver or kidney transplant.

To investigate the role of liver nerve activity on hepatic glucose production during exercise, liver-transplant subjects (LTX, n = 7, 25-62 yr, 4-18 mo postoperative) cycled for 40 min, 20 min at 52 +/- 3% (SE) maximal O2 consumption (VO2max) and 20 min at 83 +/- 1% VO2max, respectively. Kidney-transplant (KTX) and healthy control subjects (C) matched for sex and age exercised at the same %VO2max as LTX. VO2max was lower in both LTX (1.59 +/- 0.12 l/min) and KTX (1.59 +/- 0.07) than in C (2.60 +/- 0.26). At rest plasma renin and insulin were higher and plasma adrenocorticotropic hormone and cortisol lower in transplant corticosteroid-treated subjects compared with C. In LTX, hepatic glucose production (Ra) increased from 11.9 +/- 0.9 (rest) to 17.6 +/- 1.8 and 25.5 +/- 1.8 mumol.min-1.kg-1 at 52 and 82% VO2max, respectively. Peripheral glucose uptake was similar to Ra, and glucose remained at basal postabsorptive levels. During exercise the Ra increase as well as norepinephrine, insulin, and growth hormone responses were similar in LTX compared with both KTX and C. The increase in epinephrine was smaller in LTX than in C, the only group showing an increase in cortisol. The increase in plasma renin activity during exercise was attenuated in KTX compared with LTX and C. During exercise blood lactate rose more and plasma glycerol and free fatty acid levels were lower in LTX and KTX compared with C.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of training on interaction between insulin and exercise in human muscle.

Exercise adds to the effect of maximal insulin on whole body glucose uptake. Training increases contraction-induced glucose transport measured in vitro but not glucose utilization in human muscle exercising during normoinsulinemia. We studied whether exercise adds to the effect of maximal insulin in human muscle and whether trained (T) and untrained (UT) muscle differ. Six healthy men [23 +/- 0.4 (SE) yr] trained one leg for 10 wk, 6 days/wk, 30 min/day at 70% of one-legged maximal O2 uptake while keeping the other leg sedentary. At 16 h after the last training bout, both femoral veins and a radial artery were catheterized and 150-min hyperinsulinemic (480 mU.min-1.m-2) euglycemic clamp was performed. During the final 30 min, subjects performed two-legged bicycling at 76 +/- 0.3% of maximal heart rate. During exercise, blood flow (597 +/- 45 vs. 572 +/- 37 ml.min-1.kg-1), O2 uptake (74 +/- 6 vs. 68 +/- 6 ml O2.min-1.kg-1), and carbohydrate oxidation (88 +/- 10 vs. 81 +/- 7 mg.min-1.kg-1) increased similarly (P > 0.05) in T and UT legs, respectively. Arteriovenous glucose difference decreased (P < 0.05) during exercise but tended to remain higher in T (0.47 +/- 0.04) than in UT (0.41 +/- 0.05 mol/l) (P < 0.1). Glucose uptake increased with exercise, the increase being higher in T than in UT (change: 28 +/- 5 vs. 23 +/- 5 mg.min-1.kg-1; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma levels of parathyroid hormone, vitamin D, calcitonin, and calcium in association with endurance exercise.

Nine male marathon runners were investigated during habitual training (week 0), after 3 weeks of training break (week 3), and after 2 weeks (week 5) and 4 weeks (week 7) of retraining. Maximal oxygen uptake, body fat (BF), and plasma levels of 25(OH)D3, 1,25(OH)2D3, parathyroid hormone (PTH), calcitonin (CT), albumin, and albumin-corrected calcium were determined throughout weeks 0-7. The maximal oxygen uptake decreased after training break and increased during retraining (P = 0.002). BF did not change significantly. Plasma 1,25(OH)2D3 was elevated after training break and decreased after 2 and 4 weeks of retraining [week 0: 44.0 +/- 3.7 (SEM) pg x 1(-1); week 3: 52.4 +/- 6.0 pg x 1(-1); week 5: 42.0 +/- 2.8 pg x 1(-1); week 7: 36.9 +/- 2.3 pg x 1(-1); P = 0.03]. Plasma 25(OH)D3 did not change significantly. Plasma PTH increased throughout the training break and retraining (week 0: 1.36 +/- 0.25 pmol x 1(-1); week 3: 2.02 +/- 0.43 pmol x 1(-1); week 5: 2.23 +/- 0.60 pmol x 1(-1); week 7: 2.63 +/- 0.34 pmol x 1(-1); P = 0.03). Albumin-corrected calcium values were transiently decreased during retraining (week 3: 2.77 +/- 0.08 mM; week 5: 2.47 +/- 0.05 mM; week 7: 2.66 +/- 0.07 mM; P = 0.01). Plasma CT did not change during training break, but was transiently decreased during retraining (week 0: 9.97 +/- 0.39 pmol x 1(-1); week 3: 9.91 +/- 0.37 pmol x 1(-1); week 5: 8.19 +/- 0.50 pmol x 1(-1); week 7: 9.02 +/- 0.45 pmol x 1(-1); P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of training and detraining on dose-response relationship between glucose and insulin secretion.

UNLABELLED: We studied the effect of training and detraining on the dose-response relationship between plasma glucose and beta-cell secretion in seven trained young men using sequential hyperglycemic clamp technique (7, 11, and 20 mM). Experiments were performed in the habitual state 15 h after last training session (T) as well as after 5 days of detraining (DT). Results were compared to data from seven untrained subjects (UT). Glucose-stimulated insulin, proinsulin, and C-peptide levels were lower in T than in UT. They increased during detraining but not to levels seen in UT. Furthermore, in T and DT, but not in UT, increases in C-peptide and proinsulin leveled off with increasing glucose concentrations. Estimated by C-peptide-to-insulin ratios, clearance of endogenous insulin was not influenced by T. Glucose uptake in tissue was the same in T, DT, and UT during clamps, despite lower insulin levels in T and DT. Differences between groups in counterregulatory hormones, fat metabolites, alanine, or electrolytes did not account for these findings. Oxygen consumption was higher in the basal state in T and DT compared with UT but increased similarly in all groups in response to glucose. CONCLUSIONS: regular physical activity causes an adaptive decrease in glucose-mediated beta-cell secretion in humans. The training-induced decrease in glucose-stimulated insulin secretion is accurately matched to increased insulin action, keeping glucose disposal constant at any given plasma glucose concentration. Finally, training increases basal metabolic rate but does not influence glucose-induced thermogenesis or clearance of endogenous insulin.

Effects of acute exercise and detraining on insulin action in trained men.

Seven endurance-trained subjects [maximal O2 consumption (VO2max) 64 +/- 1 (SE) ml.min-1.kg-1] underwent sequential hyperinsulinemic euglycemic clamps on three occasions: 1) in the "habitual state" 15 h after the last training bout (C), 2) after 60 min of bicycle exercise at 72 +/- 3% of VO2max performed in the habitual state (E), and 3) 5 days after the last ordinary training session (detrained, DT). Sensitivity for insulin-mediated whole-body glucose uptake was not affected by acute exercise [insulin concentrations eliciting 50% of maximal insulin-mediated glucose uptake being 44 +/- 2 (C) vs. 46 +/- 3 (E) microU/ml] but was decreased after detraining (54 +/- 2 microU/ml, P less than 0.05) to levels comparable to those found in untrained subjects [Am. J. Physiol. 254 (Endocrinol. Metab. 17): E248-E259, 1988]. Near-maximal insulin-mediated glucose uptake (responsiveness) was higher than in untrained subjects and not influenced by acute exercise or detraining [13.4 +/- 1.2 (C), 12.2 +/- 0.9 (E), and 12.2 +/- 0.3 (DT) mg.min-1.kg-1]. Calculated by indirect calorimetry, the glucose-to-glycogen conversion was not influenced by E but was reduced during detraining (P less than 0.05) yet remained higher than previously found in untrained subjects (P less than 0.05). However, only on E days did muscle glycogen increase during insulin infusion. Glycogen synthase activity was increased on E and decreased on DT compared with C days.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of training on the dose-response relationship for insulin action in men.

Seven endurance-trained subjects [maximal O2 consumption (VO2max) 64 +/- 1 (SE) ml.min-1.kg-1] were subjected to three sequential hyperinsulinemic euglycemic clamps 15 h after having performed their last training session (T). Results were compared with findings in seven untrained subjects (VO2max 44 +/- 2 ml.min-1.kg-1) studied both at rest (UT) and after 60 min of bicycle exercise at 150 W (UT-ex). In T and UT-ex compared with UT, sensitivity for insulin-mediated whole-body glucose uptake was higher [insulin concentrations eliciting half-maximal glucose uptake being 44 +/- 2 (T) and 43 +/- 4 (UT-ex) vs. 52 +/- 3 microU/ml (UT), P less than 0.05] and responsiveness was higher [13.4 +/- 1.2 (T) and 10.9 +/- 0.7 (UT-ex) vs. 9.5 +/- 0.7 mg.min-1.kg-1 (UT), P less than 0.05]. Furthermore, responsiveness was higher (P less than 0.05) in T than in UT-ex. Insulin-stimulated O2 uptake and maximal glucose oxidation rate were higher in T than in UT and UT-ex. Insulin-stimulated conversion or glucose to glycogen and muscle glycogen synthase was higher in T than in UT and UT-ex. However, glycogen storage in vastus lateralis muscle was found only in UT-ex. No change in any glucoregulatory hormone or metabolite could explain the increased insulin action in trained subjects. It is concluded that physical training induces an adaptive increase in insulin responsiveness of whole-body glucose uptake, which does not reflect increased glycogen deposition in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of hepatic glucose production in running rats studied by glucose infusion.

The importance of metabolic feedback regulation vs. feedforward regulation of hepatic glucose production (HGP) during exercise was investigated in rats by infusing glucose intravenously from the onset of running. Glucose infusion equaled the average exercise-induced increase from basal to steady state in HGP found in saline-infused control rats. Rats were studied at two work loads, running at 21 (series I) or 18 m/min (series II) for 35 min. Glucose turnover was measured by means of an intravenous [3H]glucose infusion. HGP was suppressed by glucose infusion corresponding to the infused amount of glucose in both series, except for late in exercise in series I, where HGP plus infused glucose tended to exceed HGP in saline-infused rats (P less than 0.10). Muscle glycogenolysis and fat metabolism were similar in both groups in the two series. Plasma glucose was never elevated, whereas insulin was, in glucose- vs. saline-infused rats of both series. Plasma catecholamines were lower in glucose- compared with saline-infused rats in series II. In conclusion, HGP is very sensitive to metabolic feedback inhibition at low exercise intensities. Feedforward control of HGP may play a role at higher work loads (series I). Exogenously supplied glucose, in moderate amounts, may replace HGP specifically without concomitant changes in mobilization of other substrates.

Role of metabolic feedback regulation in glucose production of running rats.

Hepatic glucose production (Ra) was studied in phlorizin (P)- and saline (C)-infused rats running for 35 min at 21 m/min in the postabsorptive state (series I) or 18 m/min in the fed state (series II). Phlorizin-induced increase in glucose clearance would increase or not affect Ra, depending on whether metabolic feedback mechanisms or central command from central nervous system (CNS), respectively, regulate Ra during exercise. Initial exercise-induced increases in Ra were similar in P and C rats of both series, although glucose clearance was higher and plasma glucose lower, however not hypoglycemic, in P rats. After 5 min of exercise, Ra remained similar in P and C rats in series I, whereas in series II, Ra increased almost twice as much in P compared with C rats. In both series muscle glycogenolysis and lipolysis were higher in P than in C rats. The results suggest a central command regulation of Ra from CNS motor centers and that this primary setting may be modulated by metabolic feedback mechanisms. Hypoglycemia is not needed to activate metabolic feedback. A variety of substrates rather than glucose specifically is mobilized by metabolic feedback mechanisms associated with decreased glucose availability.

Stimulatory role for endogenous opioid peptides on postexercise insulin secretion in rats.

Endogenous opioid peptides (EOP) and prior exercise may modulate the stimulatory effect of glucose on insulin secretion. To gain insights into these relationships, we studied male Wistar rats (187-245 g) during sustained hyperglycemia by use of the glucose clamp technique. Four groups of sedentary fed rats (n = 8/group) either ran (Ex) at 24 m/min, 0% grade, or rested (R) for 40 min. Thirty minutes after Ex or R, arterial blood glucose was elevated to and maintained at 11 mM for 2 h by a variable glucose infusion. At the start of Ex or R rats had saline (Sal) or naloxone (Nal, an opioid antagonist) intravenous infusions for 160 min (40 min Ex + 30 min R + 90 min of a 120-min glucose clamp). Steady-state glucose infusion rates (SSGIR) were approximately 55 mg.kg-1.min-1 at the start of the clamp and declined significantly over the 2nd h to approximately 45 mg.kg-1.min-1. No significant differences existed in SSGIR between groups. R-Sal and Ex-Sal groups did not differ in their insulin response to hyperglycemia. In contrast, when all groups were compared at the end of the Nal or Sal infusion, Ex-Nal had the lowest insulin concentration (749 +/- 174 pmol/l), whereas the R-Nal group had the highest (1,581 +/- 216 pmol/l, P less than 0.05). These data suggest a stimulatory role for EOP on insulin secretion that is expressed after a prior stress (Ex). Thus one function of exercise-induced activation of EOP may be to regulate insulin secretion in the immediate postexercise period.

Postexercise dose-response relationship between plasma glucose and insulin secretion.

To investigate whether exertion changes beta-cell reactivity to glucose stimulation and to characterize the beta-cell response to glucose in humans, we performed four sequential 90-min hyperglycemic clamps (7, 11, 20, and 35 mM). Concentrations of hormones and metabolites involved in glucoregulation were measured. Metabolic rate and substrate utilization were studied by indirect calorimetry. Studies were performed without prior exercise, as well as 2 and 48 h after 60 min of bicycle exercise at 150 W. We found 1) a progressive increase in insulin concentrations reaching 1,092 +/- 135 microU/ml with increasing glucose levels, 2) linear relationships between glucose concentrations and concentrations of C-peptide (r = 0.931 +/- 0.008) and proinsulin (r = 0.952 +/- 0.009),3) increased glucose oxidation with increasing glucose uptake, 4) increased plasma norepinephrine, O2 uptake, and beta-hydroxybutyrate at greater than or equal to 20 mM glucose, and 5) no change in beta-cell response or glucose-induced thermogenesis after one bout of exercise despite no compensating changes in plasma concentrations of hormones or metabolites. We conclude that the beta-cell has a very large secretory potential. Secretion of the beta-cell increases linearly with prolonged, graded hyperglycemia. The processing of proinsulin is unchanged during prolonged beta-cell stimulation. In addition, hyperglycemia and sympathetic nervous activity induced by hyperinsulinemia enhance metabolic rate and ketone body production. Finally, a single bout of exercise does not influence either the beta-cell response to intravenous glucose or glucose-induced thermogenesis.

Effect of physical exercise on sensitivity and responsiveness to insulin in humans.

The effect of acute physical exercise on insulin sensitivity and responsiveness of glucose uptake and hepatic glucose production was studied. Seven untrained men were subjected to four sequential euglycemic hyperinsulinemic clamps after rest (R), immediately after exercise (E), as well as 48 h after 60 min of 150 W ergometer exercise (ER). Insulin-mediated glucose uptake was higher on E and ER days compared with R days. Apparent Km decreased after exercise (52 +/- 3 R vs. 43 +/- 4 E and 40 +/- 3 ER microU/ml, means +/- SE) and Vmax increased (9.5 +/- 0.8 R vs. 10.9 +/- 0.7 E and 10.7 +/- 0.8 ER mg.min-1.kg-1). Glucose oxidation increased with the increasing insulin infusion rate, and maximal glucose oxidation rate was lower on E days compared with R days. The maximal conversion rate of glucose to glycogen was higher on E and ER days (8.0 +/- 0.3 and 7.2 +/- 0.2, respectively) than on R days (5.7 +/- 0.6 mg.min-1 kg-1). Muscle glycogen synthase I activity was higher immediately after exercise and remained higher for the next 48 h. No change in any glucoregulatory hormone or metabolite could explain the increased insulin action seen after exercise. In additional experiments (n = 3), no remaining effect existed 5 days after exercise. Both insulin and exercise suppressed the pancreatic secretion of insulin and proinsulin. The conclusions drawn are that prolonged moderate exercise increases insulin action on glucose uptake in humans by reducing apparent Km and increasing Vmax. This effect lasts 48 h but not 5 days. The increased insulin action may be related to an exercise-induced increase in glycogen synthase activity.

Glucose turnover in 48-hour-fasted running rats.

In fed rats, hyperglycemia develops during exercise. This contrasts with the view based on studies of fasted human and dog that euglycemia is maintained in exercise and glucose production (Ra) controlled by feedback mechanisms. Forty-eight-hour-fasted rats (F) were compared to fed rats (C) and overnight food-restricted (FR) rats. [3-3H]- and [U-14C] glucose were infused and blood and tissue sampled. During running (21 m/min, 0% grade) Ra increased most in C and least in F and only in F did Ra not significantly exceed glucose disappearance. Plasma glucose increased more in C (3.3 mmol/l) than in FR (1.6 mmol/l) and only modestly (0.6 mmol/l) and transiently in F. Resting liver glycogen and exercise glycogenolysis were highest in C and similar in FR and F. Resting muscle glycogen and exercise glycogenolysis were highest in C and lowest in F. During running, lactate production and gluconeogenesis were higher in FR than in F. At least in rats, responses of production and plasma concentration of glucose to exercise depend on size of liver and muscle glycogen stores; glucose production matches increase in clearance better in fasted than in fed states. Probably glucose production is stimulated by "feedforward" mechanisms and "feedback" mechanisms are added if plasma glucose decreases.

Carbohydrate metabolism in fructose-fed and food-restricted running rats.

In chronically catheterized rats hepatic glycogen was increased by fructose (approximately 10 g/kg) gavage (FF rats) or lowered by overnight food restriction (FR rats). [3-3H]- and [U-14C]glucose were infused before, during, and after treadmill running. During exercise the increase in glucose production (Ra) was always directly related to work intensity and faster than the increase in glucose disappearance, resulting in increased plasma glucose levels. At identical work-loads the increase in Ra and plasma glucose as well as liver glycogen breakdown were higher in FF and control (C) rats than in FR rats. Breakdown of muscle glycogen was less in FF than in C rats. Incorporation of [14C]glucose in glycogen at rest and mobilization of label during exercise partly explained that 14C estimates of carbohydrate metabolism disagreed with chemical measurements. In some muscles glycogen depletion was not accompanied by loss of 14C and 3H, indicating futile cycling of glucose. In FR rats a postexercise increase in liver glycogen was seen with 14C/3H similar to that of plasma glucose, indicating direct synthesis from glucose. In conclusion, in exercising rats the increase in glucose production is subjected to feedforward regulation and depends on the liver glycogen concentration. Endogenous glucose may be incorporated in glycogen in working muscle and may be used directly for liver glycogen synthesis rather than after conversion to trioses. Fructose ingestion may diminish muscular glycogen breakdown. The [14C]glucose infusion technique for determination of muscular glycogenolysis is of doubtful value in rats.

Plasma beta endorphin immunoreactivity: effects of sustained hyperglycemia with and without prior exercise.

Seven healthy untrained men were studied to determine if sustained hyperglycemia is a stimulus to enhanced plasma levels of beta endorphin (beta-EP) and if so whether prior exercise affects that enhancement. After an overnight fast hyperglycemic glucose clamps were performed on 3 separate days: after prior rest, 2 h after exercise, and 48 h after exercise. Subjects exercised on a bicycle ergometer for 1 h at 150 W (64% VO2 max). Plasma glucose concentration was elevated in 4 continuous sequential stages to 7, 11, 20 and 35 mM with each stage lasting 90 min. Plasma glucose concentrations did not differ for each subject across the three clamps. beta-EP immunoreactivity was measured in arterialized venous blood samples using a specific and sensitive radioimmunoassay. Resting beta-EP at basal glucose concentrations was 3.8 +/- 0.7 fmol X ml-1 (mean +/- se) and prior exercise either 2h (3.2 +/- 0.5 fmol X ml-1) or 48 h (4.3 +/- 0.7 fmol X ml-1) before a clamp study did not effect these levels, (p greater than 0.05). At no time during the 3 hyperglycemic clamps did plasma levels of beta-EP differ significantly from resting values. At the highest level of hyperglycemia (35 mM) beta-EP was 3.1 +/- 0.2, 4.9 +/- 0.6 and 4.8 +/- 0.7 fmol X ml-1 in the resting, 2h and 48 h post exercise clamp studies respectively. The significance of these data is that this lack of a response is in distinct contrast to elevations of this peptide found during hypoglycemic states. We conclude that sustained hyperglycemia is not a stimulus to enhanced secretion of beta-EP into plasma and this lack of a response is not effected by prior exercise.

Route of administration of pentobarbital affects activity of liver glycogen phosphorylase.

Liver phosphorylase a activity in intact animals is mostly determined during anesthesia. The aim of this study was to investigate the effect of administering pentobarbital by different routes on activity of liver phosphorylase a. Rats had chronically implanted venous catheters and received pentobarbital (5 mg/100 g body wt) either intraperitoneally, as a slow intravenous infusion, or as an intravenous or intracardial bolus. Times from administration of barbiturate to sampling of the liver were 10 min, 10 min, 85 +/- 32 s (mean +/- SE), and 53 +/- 10 s, respectively. Phosphorylase a activity in % of total phosphorylase activity was 40 +/- 2, 56 +/- 4, 82 +/- 3, and 92 +/- 2, respectively, all significantly different. Thus the route of administration of pentobarbital affects the phosphorylase a activity and should be considered when evaluating this activity. This fact can only be partially explained by differences in duration before the drug takes effect. It is proposed that intraperitoneal injection of pentobarbital may anesthetize hepatic sympathetic nerves or have a direct inhibiting effect on phosphorylase a activity.

Role of liver nerves and adrenal medulla in glucose turnover of running rats.

Sympathetic control of glucose turnover was studied in rats running 35 min at 21 m X min-1 on the level. The rats were surgically liver denervated, adrenodemedullated, or sham operated. Glucose turnover was measured by primed constant infusion of [3-3H]glucose. At rest, the three groups had identical turnover rates and concentrations of glucose in plasma. During running, glucose production always rose rapidly to steady levels. The increase was not influenced by liver denervation but was halved by adrenodemedullation. Similarly, hepatic glycogen depletion was identical in denervated and control rats but reduced after adrenodemedullation. Early in exercise, glucose uptake rose identically in all groups and, in adrenodemedullated rats, matched glucose production. Accordingly, plasma glucose concentration increased in liver-denervated and control rats but was constant in adrenodemedullated rats. Compensatory changes in hormone or substrate levels explaining the lack of effect of liver denervation were not found. In rats with intact adrenals, the plasma epinephrine concentration was increased after 2.5 min of running. It is concluded that, in rats carrying out exercise of moderate intensity and duration, hepatic glycogenolysis and glucose production are not influenced by the autonomic liver nerves but are enhanced by circulating epinephrine.

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.