Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults

Circulating adiponectin is reduced in disorders associated with insulin resistance. This study was conducted to determine whether an exercise/diet intervention would alter adiponectin multimer distribution and adiponectin receptor expression in skeletal muscle. Impaired glucose-tolerant older (>60 yr) obese (BMI 30-40 kg/m(2)) men (n = 7) and women (n = 14) were randomly assigned to 12 wk of supervised aerobic exercise combined with either a hypocaloric (ExHypo, approximately 500 kcal reduction, n = 11) or eucaloric diet (ExEu, n = 10). Insulin sensitivity was determined by the euglycemic (5.0 mM) hyperinsulinemic (40 mU x m(-2) x min(-1)) clamp. Adiponectin multimers [high (HMW), middle (MMW), and low molecular weight (LMW)] were measured by nondenaturing Western blot analysis. Relative quantification of adiponectin receptor expression through RT-PCR was determined from skeletal muscle biopsy samples. Greater weight loss occurred in ExHypo compared with ExEu subjects (8.0 +/- 0.6 vs. 3.2 +/- 0.6%, P < 0.0001). Insulin sensitivity improved postintervention in both groups (ExHypo: 2.5 +/- 0.3 vs. 4.4 +/- 0.5 mg x kg FFM(-1) x min(-1), and ExEu: 2.9 +/- 0.4 vs. 4.1 +/- 0.4 mg x kg FFM(-1) x min(-1), P < 0.0001). Comparison of multimer isoforms revealed a decreased percentage in MMW relative to HMW and LMW (P < 0.03). The adiponectin SA ratio (HMW/total) was increased following both interventions (P < 0.05) and correlated with the percent change in insulin sensitivity (P < 0.03). Postintervention adiponectin receptor mRNA expression was also significantly increased (AdipoR1 P < 0.03, AdipoR2 P < 0.02). These data suggest that part of the improvement in insulin sensitivity following exercise and diet may be due to changes in the adiponectin oligomeric distribution and enhanced membrane receptor expression.     

Sex-specific influence of aging on exercising leg blood flow.

Our previous work suggests that healthy human aging is associated with sex-specific differences in leg vascular responses during large muscle mass exercise (2-legged cycling) (Proctor DN, Parker BA. Microcirculation 13: 315-327, 2006). The present study determined whether age x sex interactions in exercising leg hemodynamics persist during small muscle mass exercise that is not limited by cardiac output. Thirty-one young (20-30 yr; 15 men/16 women) and 31 older (60-79 yr; 13 men/18 women) healthy, normally active adults performed graded single-leg knee extensions to maximal exertion. Femoral artery blood velocity and diameter (Doppler ultrasound), heart rate (ECG), and beat-to-beat arterial blood pressure (mean arterial pressure, radial artery tonometry) were measured during each 3-min work rate (4.8 and 8 W/stage for women and men, respectively). The results (means +/- SE) were as follows. Despite reduced resting leg blood flow and vascular conductance, older men exhibited relatively preserved exercising leg hemodynamic responses. Older women, by contrast, exhibited attenuated hyperemic (young: 52 +/- 3 ml.min(-1).W(-1); vs. older: 40 +/- 4 ml.min(-1).W(-1); P = 0.02) and vasodilatory responses (young: 0.56 +/- 0.06 ml.min(-1).mmHg(-1).W(-1) vs. older: 0.37 +/- 0.04 ml.min(-1).mmHg(-1) W(-1); P < 0.01) to exercise compared with young women. Relative (percentage of maximal) work rate comparisons of all groups combined also revealed attenuated vasodilator responses in older women (P < 0.01 for age x sex x work rate interaction). These sex-specific age differences were not abolished by consideration of hemoglobin, quadriceps muscle, muscle recruitment, and mechanical influences on muscle perfusion. Collectively, these findings suggest that local factors contribute to the sex-specific effects of aging on exercising leg hemodynamics in healthy adults.     

Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity.

We evaluated plasma fatty acid availability and plasma and whole body fatty acid oxidation during exercise in five lean and five abdominally obese women (body mass index = 21 +/- 1 vs. 38 +/- 1 kg/m(2)), who were matched on aerobic fitness, to test the hypothesis that obesity alters the relative contribution of plasma and nonplasma fatty acids to total energy production during exercise. Subjects exercised on a recumbent cycle ergometer for 90 min at 54% of their peak oxygen consumption. Stable isotope tracer methods ([(13)C]palmitate) were used to measure fatty acid rate of appearance in plasma and the rate of plasma fatty acid oxidation, and indirect calorimetry was used to measure whole body substrate oxidation. During exercise, palmitate rate of appearance increased progressively and was similar in obese and lean groups between 60 and 90 min of exercise [3.9 +/- 0.4 vs. 4.0 +/- 0.3 micromol. kg fat free mass (FFM)(-1). min(-1)]. The rate of plasma fatty acid oxidation was also similar in obese and lean subjects (12.8 +/- 1.7 vs. 14.5 +/- 1.8 micromol. kg FFM(-1). min(-1); P = not significant). However, whole body fatty acid oxidation during exercise was 25% greater in obese than in lean subjects (21.9 +/- 1.2 vs. 17.5 +/- 1.6 micromol. kg FFM(-1). min(-1); P < 0.05). These results demonstrate that, although plasma fatty acid availability and oxidation are similar during exercise in lean and obese women, women with abdominal obesity use more fat as a fuel by oxidizing more nonplasma fatty acids.     

Decline in insulin action with age in endurance-trained humans.

We tested the hypothesis that regular endurance exercise prevents the age-related decline in insulin action typically observed in healthy, sedentary adults. An index of whole body insulin sensitivity (ISI), obtained from minimal model analysis of insulin and glucose concentrations during a frequently sampled intravenous glucose tolerance test, was determined in 126 healthy adults: 25 young [27 +/- 1 (SE) yr; 13 men/12 women] and 43 older (59 +/- 1 yr; 20/13) sedentary and 25 young (29 +/- 1 yr; 12/13) and 33 older (60 +/- 1 yr; 20/13) endurance trained. ISI values were lower in the older vs. young adults in both sedentary (-53%; 3.9 +/- 0.3 vs. 7.0 +/- 0.7 x10(-4) x min(-1) x microU(-1) x ml(-1); P < 0.01) and endurance-trained (-36%; 7.9 +/- 0.6 vs. 12.4 +/- 1.0 x 10(-4) min(-1) x microU(-1) x ml(-1); P < 0.01) groups, but the value was 72-102% higher in the trained subjects at either age (P < 0.01). In subgroup analysis of sedentary and endurance-trained adults with similar body fat levels (n = 62), the age-related reduction in ISI persisted only in the endurance-trained subjects (12.9 +/- 1.9 vs. 8.7 +/- 1.2 x 10(-4) x min(-1) x microU(-1) x ml(-1); P < 0.01). The results of the present study suggest that habitual endurance exercise does not prevent the age-associated decline insulin action. Moreover, the age-related reduction in ISI in endurance-trained adults appears to be independent of adiposity.     

Age-related decline in RMR in physically active men: relation to exercise volume and energy intake

We tested the hypothesis that resting metabolic rate (RMR) declines with age in physically active men (endurance exercise > or =3 times/wk) and that this decline is related to weekly exercise volume (h/wk) and/or daily energy intake. Accordingly, we studied 137 healthy adult men who had been weight stable for > or =6 mo: 32 young [26 +/- 1 (SE) yr] and 34 older (62 +/- 1 yr) sedentary males (internal controls); and 39 young (27 +/- 1 yr) and 32 older (63 +/- 2 yr) physically active males (regular endurance exercise). RMR was measured by indirect calorimetry (ventilated hood system) after an overnight fast and approximately 24 h after exercise. Because RMR is related to fat-free mass (FFM; r = 0.76, P < 0.001, current study), FFM was covaried to adjust RMR (RMR(adj)). RMR(adj) was lower with age in both the sedentary (72.0 +/- 2.0 vs. 64.0 +/- 1.3 kcal/h, P < 0.01) and the physically active (76.6 +/- 1.1 vs. 67.9 +/- 1.2 kcal/h, P < 0.01) males. In the physically active men, RMR(adj) was related to both exercise volume (no. of h/wk, regardless of intensity; r = 0.56, P < 0.001) and estimated energy intake (r = 0.58, P < 0.001). Consistent with these relations, RMR(adj) was not significantly different in subgroups of young and older physically active men matched either for exercise volume (h/wk; n = 11 each) or estimated energy intake (kcal/day; n = 6 each). These results indicate that 1) RMR, per unit FFM, declines with age in highly physically active men; and 2) this decline is related to age-associated reductions in exercise volume and energy intake and does not occur in men who maintain exercise volume and/or energy intake at a level similar to that of young physically active men.     

Determinants of fat oxidation during exercise in healthy men and women: a cross-sectional study.

The aim of the present study was to establish fat oxidation rates over a range of exercise intensities in a large group of healthy men and women. It was hypothesised that exercise intensity is of primary importance to the regulation of fat oxidation and that gender, body composition, physical activity level, and training status are secondary and can explain part of the observed interindividual variation. For this purpose, 300 healthy men and women (157 men and 143 women) performed an incremental exercise test to exhaustion on a treadmill [adapted from a previous protocol (Achten J, Venables MC, and Jeukendrup AE. Metabolism 52: 747-752, 2003)]. Substrate oxidation was determined using indirect calorimetry. For each individual, maximal fat oxidation (MFO) and the intensity at which MFO occurred (Fat(max)) were determined. On average, MFO was 7.8 +/- 0.13 mg.kg fat-free mass (FFM)(-1).min(-1) and occurred at 48.3 +/- 0.9% maximal oxygen uptake (Vo(2 max)), equivalent to 61.5 +/- 0.6% maximal heart rate. MFO (7.4 +/- 0.2 vs. 8.3 +/- 0.2 mg.kg.FFM(-1).min(-1); P < 0.01) and Fat(max) (45 +/- 1 vs. 52 +/- 1% Vo(2 max); P < 0.01) were significantly lower in men compared with women. When corrected for FFM, MFO was predicted by physical activity (self-reported physical activity level), Vo(2 max), and gender (R(2) = 0.12) but not with fat mass. Men compared with women had lower rates of fat oxidation and an earlier shift to using carbohydrate as the dominant fuel. Physical activity, Vo(2 max), and gender explained only 12% of the interindividual variation in MFO during exercise, whereas body fatness was not a predictor. The interindividual variation in fat oxidation remains largely unexplained.     

Whole body leucine flux in HIV-infected patients treated with or without protease inhibitors

The present study was carried out to assess the effects of protease inhibitor (PI) therapy on basal whole body protein metabolism and its response to acute amino acid-glucose infusion in 14 human immunodeficiency virus (HIV)-infected patients. Patients treated with PIs (PI+, 7 patients) or without PIs (PI-, 7 patients) were studied after an overnight fast during a 180-min basal period followed by a 140-min period of amino acid-glucose infusion. Protein metabolism was investigated by a primed constant infusion of l-[1-(13)C]leucine. Dual-energy X-ray absorptiometry for determination of fat-free mass (FFM) and body fat mass measured body composition. In the postabsorptive state, whole body leucine balance was 2.5 times (P < 0.05) less negative in the PI+ than in the PI- group. In HIV-infected patients treated with PIs, the oxidative leucine disposal during an acute amino acid-glucose infusion was lower (0.58 +/- 0.09 vs. 0.81 +/- 0.07 micromol x kg FFM(-1) x min(-1) using plasma [(13)C]leucine enrichment, P = 0.06; or 0.70 +/- 0.10 vs. 0.99 +/- 0.08 micromol x kg FFM(-1) x min(-1) using plasma [(13)C]ketoisocaproic acid enrichment, P = 0.04 in PI+ and PI- groups, respectively) than in patients treated without PIs. Consequently, whole body nonoxidative leucine disposal (an index of protein synthesis) and leucine balance (0.50 +/- 0.10 vs. 0.18 +/- 0.06 micromol x kg FFM x (-1) x min(-1) in PI+ and PI- groups respectively, P < 0.05) were significantly improved during amino acid-glucose infusion in patients treated with PIs. However, whereas the response of whole body protein anabolism to an amino acid-glucose infusion was increased in HIV-infected patients treated with PIs, any improvement in lean body mass was detected.     

Oxidation rate of exogenous carbohydrate during exercise is higher in boys than in men.

To determine whether the relative utilization of exogenous carbohydrate (CHO(exo)) differs between children and adults, substrate utilization during 60 min of cycling at 70% peak O(2) uptake was studied in 12 pre- and early pubertal boys (9.8 +/- 0.1 yr) and 10 men (22.1 +/- 0.5 yr) on two occasions. Subjects consumed either a placebo or a (13)C-enriched 6% CHO(exo) beverage (total volume per trial: 24 ml/kg). Substrate utilization was calculated for the final 30 min of exercise. During both trials, total fat oxidation was higher (5.4 +/- 0.5 vs. 3.0 +/- 0.4 mg x kg(-1) x min(-1), P < 0.001) and total CHO oxidation lower (27.4 +/- 1.5 vs. 34.8 +/- 1.2 mg x kg(-1) x min(-1), P < 0.001) in boys than in men, respectively. During the CHO(exo) trial, CHO(exo) oxidation was higher (P < 0.001) in boys (8.8 +/- 0.5 mg x kg(-1) x min(-1)) than in men (6.2 +/- 0.5 mg x kg(-1) x min(-1)) and provided a greater (P < 0.001) relative proportion of total energy in boys (21.8 +/- 1.4%) than in men (14.6 +/- 0.9%). These results suggest that, although endogenous CHO utilization during exercise is lower, the relative oxidation of ingested CHO is considerably higher in boys than in men. The greater reliance on CHO(exo) in boys may be important in preserving endogenous fuels and may be related to pubertal status.     

Metabolic response to carbohydrate ingestion during exercise in males and females

The present study investigated potential sex-related differences in the metabolic response to carbohydrate (CHO) ingestion during exercise. Moderately endurance-trained men and women (n = 8 for each sex) performed 2 h of cycling at approximately 67% Vo(2 max) with water (WAT) or CHO ingestion (1.5 g of glucose/min). Substrate oxidation and kinetics were quantified during exercise using indirect calorimetry and stable isotope techniques ([(13)C]glucose ingestion, [6,6-(2)H(2)]glucose, and [(2)H(5)]glycerol infusion). In both sexes, CHO ingestion significantly increased the rates of appearance (R(a)) and disappearance (R(d)) of glucose during exercise compared with WAT ingestion [males: WAT, approximately 28-29 micromol x kg lean body mass (LBM)(-1) x min(-1); CHO, approximately 53 micromol x kg LBM(-1) x min(-1); females: WAT, approximately 28-29 micromol x kg LBM(-1) x min(-1); CHO, approximately 61 micromol x kg LBM(-1) x min(-1); main effect of trial, P < 0.05]. The contribution of plasma glucose oxidation to the energy yield was significantly increased with CHO ingestion in both sexes (from approximately 10% to approximately 20% of energy expenditure; main effect of trial, P < 0.05). Liver-derived glucose oxidation was reduced, although the rate of muscle glycogen oxidation was unaffected with CHO ingestion (males: WAT, 108 +/- 12 micromol x kg LBM(-1) x min(-1); CHO, 108 +/- 11 micromol x kg LBM(-1) x min(-1); females: WAT, 89 +/- 10 micromol x kg LBM(-1) x min(-1); CHO, 93 +/- 11 micromol x kg LBM(-1) x min(-1)). CHO ingestion reduced fat oxidation and lipolytic rate (R(a) glycerol) to a similar extent in both sexes. Finally, ingested CHO was oxidized at similar rates in men and women during exercise (peak rates of 0.70 +/- 0.08 and 0.65 +/- 0.06 g/min, respectively). The present investigation suggests that the metabolic response to CHO ingestion during exercise is largely similar in men and women.     

Gender differences in glucose kinetics and substrate oxidation during exercise near the lactate threshold.

The purpose of this investigation was to determine plasma glucose kinetics and substrate oxidation in men and women during exercise relative to the lactate threshold (LT). Subjects cycled for 25 min at 70 and 90% of O(2) uptake (VO(2)) at LT (70 and 90% LT, respectively). Plasma glucose appearance (R(a)) and disappearance (R(d)) were determined with a primed constant infusion of [6,6-(2)H]glucose. There were no significant differences in glucose R(a) between men [22.6 +/- 1.9 and 39.9 +/- 3.9 micromol x kg fat-free mass (FFM)(-1) x min(-1) for 70 and 90% LT, respectively] and women (22.3 +/- 2.7 and 33.9 +/- 5.7 micromol x kg FFM(-1) x min(-1) for 70 and 90% LT, respectively). Similarly, there were no significant differences in glucose R(d) between men (21.2 +/- 1.9 and 38.1 +/- 3.7 micromol x kg FFM(-1) x min(-1) for 70 and 90% LT, respectively) and women (21.3 +/- 2.8 and 33.3 +/- 5.6 micromol x kg FFM(-1) x min(-1) for 70 and 90% LT, respectively). Although there were no differences between genders in the relative contribution of carbohydrate (CHO) to total energy expenditure, the relative contribution of muscle glycogen to total CHO oxidation (75.8 +/- 3.2 and 64.2 +/- 8.0% for men and women, respectively, at 70% LT and 75.1 +/- 2.6 and 60.1 +/- 11.2% for men and women, respectively, at 90% LT) was lower in women. Consequently, the relative contribution of blood glucose to total CHO oxidation was significantly higher in women. These results indicate that although plasma glucose R(a) and R(d) are similar in men and women, the relative contribution of muscle glycogen and blood glucose is significantly different in women during moderate-intensity exercise relative to LT.     

Epinephrine infusion during moderate intensity exercise increases glucose production and uptake

The glucoregulatory response to intense exercise [IE, >80% maximum O(2) uptake (VO(2 max))] comprises a marked increment in glucose production (R(a)) and a lesser increment in glucose uptake (R(d)), resulting in hyperglycemia. The R(a) correlates with plasma catecholamines but not with the glucagon-to-insulin (IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able to markedly stimulate R(a), this would support an important role for the catecholamines' response in IE. Seven fit male subjects (26 +/- 2 yr, body mass index 23 +/- 0.5 kg/m(2), VO(2 max) 65 +/- 5 ml x kg(-1) x min(-1)) underwent 40 min of postabsorptive cycle ergometer exercise (145 +/- 14 W) once without [control (CON)] and once with Epi infusion [EPI (0.1 microg x kg(-1) x min(-1))] from 30 to 40 min. Epi levels reached 9.4 +/- 0.8 nM (20x rest, 10x CON). R(a) increased approximately 70% to 3.75 +/- 0.53 in CON but to 8.57 +/- 0.58 mg x kg(-1) x min(-1) in EPI (P < 0.001). Increments in R(a) and Epi correlated (r(2) = 0.923, P 相似文献   

Effects of gender on exercise-induced growth hormone release.

We examined gender differences in growth hormone (GH) secretion during rest and exercise. Eighteen subjects (9 women and 9 men) were tested on two occasions each [resting condition (R) and exercise condition (Ex)]. Blood was sampled at 10-min intervals from 0600 to 1200 and was assayed for GH by chemiluminescence. At R, women had a 3.69-fold greater mean calculated mass of GH secreted per burst compared with men (5.4 +/- 1.0 vs. 1.7 +/- 0.4 microg/l, respectively) and higher basal (interpulse) GH secretion rates, which resulted in greater GH production rates and serum GH area under the curve (AUC; 1,107 +/- 194 vs. 595 +/- 146 microg x l(-1) x min, women vs. men; P = 0.04). Compared with R, Ex resulted in greater mean mass of GH secreted per burst, greater mean GH secretory burst amplitude, and greater GH AUC (1,196 +/- 211 vs. 506 +/- 90 microg x l(-1) x min, Ex vs. R, respectively; P < 0.001). During Ex, women attained maximal serum GH concentrations significantly earlier than men (24 vs. 32 min after initiation of Ex, respectively; P = 0.004). Despite this temporal disparity, both genders had similar maximal serum GH concentrations. The change in AUC (adjusted for unequal baselines) was similar for men and women (593 +/- 201 vs. 811 +/- 268 microg x l(-1) x min), but there were significant gender-by-condition interactive effects on GH secretory burst mass, pulsatile GH production rate, and maximal serum GH concentration. We conclude that, although women exhibit greater absolute GH secretion rates than men both at rest and during exercise, exercise evokes a similar incremental GH response in men and women. Thus the magnitude of the incremental secretory GH response is not gender dependent.     

Regulation of middle cerebral artery blood velocity during dynamic exercise in humans: influence of aging.

Although cerebral autoregulation (CA) appears well maintained during mild to moderate intensity dynamic exercise in young subjects, it is presently unclear how aging influences the regulation of cerebral blood flow during physical activity. Therefore, to address this question, middle cerebral artery blood velocity (MCAV), mean arterial pressure (MAP), and the partial pressure of arterial carbon dioxide (Pa(CO(2))) were assessed at rest and during steady-state cycling at 30% and 50% heart rate reserve (HRR) in 9 young (24 +/- 3 yr; mean +/- SD) and 10 older middle-aged (57 +/- 7 yr) subjects. Transfer function analysis between changes in MAP and mean MCAV (MCAV(mean)) in the low-frequency (LF) range were used to assess dynamic CA. No age-group differences were found in Pa(CO(2)) at rest or during cycling. Exercise-induced increases in MAP were greater in older subjects, while changes in MCAV(mean) were similar between groups. The cerebral vascular conductance index (MCAV(mean)/MAP) was not different at rest (young 0.66 +/- 0.04 cm x s(-1) x mmHg(-1) vs. older 0.67 +/- 0.03 cm x s(-1) x mmHg(-1); mean +/- SE) or during 30% HRR cycling between groups but was reduced in older subjects during 50% HRR cycling (young 0.67 +/- 0.03 cm x s(-1) x mmHg(-1) vs. older 0.56 +/- 0.02 cm x s(-1) x mmHg(-1); P < 0.05). LF transfer function gain and phase between MAP and MCAV(mean) was not different between groups at rest (LF gain: young 0.95 +/- 0.05 cm x s(-1) x mmHg(-1) vs. older 0.88 +/- 0.06 cm x s(-1) x mmHg(-1); P > 0.05) or during exercise (LF gain: young 0.80 +/- 0.05 cm x s(-1) x mmHg(-1) vs. older 0.72 +/- 0.07 cm x s(-1) x mmHg(-1) at 50% HRR; P > 0.05). We conclude that despite greater increases in MAP, the regulation of MCAV(mean) is well maintained during dynamic exercise in healthy older middle-aged subjects.     

Oxygen uptake kinetics during treadmill running in boys and men.

The purpose of this study was to compare the kinetics of the oxygen uptake (VO(2)) response of boys to men during treadmill running using a three-phase exponential modeling procedure. Eight boys (11-12 yr) and eight men (21-36 yr) completed an incremental treadmill test to determine lactate threshold (LT) and maximum VO(2). Subsequently, the subjects exercised for 6 min at two different running speeds corresponding to 80% of VO(2) at LT (moderate exercise) and 50% of the difference between VO(2) at LT and maximum VO(2) (heavy exercise). For moderate exercise, the time constant for the primary response was not significantly different between boys [10.2 +/- 1.0 (SE) s] and men (14.7 +/- 2.8 s). The gain of the primary response was significantly greater in boys than men (239.1 +/- 7.5 vs. 167.7 +/- 5.4 ml. kg(-1). km(-1); P < 0.05). For heavy exercise, the VO(2) on-kinetics were significantly faster in boys than men (primary response time constant = 14.9 +/- 1.1 vs. 19.0 +/- 1.6 s; P < 0.05), and the primary gain was significantly greater in boys than men (209.8 +/- 4.3 vs. 167.2 +/- 4.6 ml. kg(-1). km(-1); P < 0.05). The amplitude of the VO(2) slow component was significantly smaller in boys than men (19 +/- 19 vs. 289 +/- 40 ml/min; P < 0.05). The VO(2) responses at the onset of moderate and heavy treadmill exercise are different between boys and men, with a tendency for boys to have faster on-kinetics and a greater initial increase in VO(2) for a given increase in running speed.     

Regulation of endogenous glucose production after a mixed meal in type 2 diabetes

The extent and time course of suppression of endogenous glucose production (EGP) in type 2 diabetes after a mixed meal have been determined using a new tracer methodology. Groups of age-, sex-, and weight-matched normal controls (n = 8) and diet-controlled type 2 diabetic subjects (n = 8) were studied after ingesting a standard mixed meal (550 kcal; 67% carbohydrate, 19% fat, 14% protein). There was an early insulin increment in both groups such that, by 20 min, plasma insulin levels were 266 +/- 54 and 190 +/- 53 pmol/l, respectively. EGP was similar basally [2.55 +/- 0.12 mg x kg(-1) x min(-1) in control subjects vs. 2.92 +/- 0.16 mg x kg(-1) x min(-1) in the patients (P = 0.09)]. After glucose ingestion, EGP declined rapidly in both groups to approximately 50% of basal within 30 min of the meal. Despite the initial rapid decrease, the EGP was significantly greater in the diabetic group at 60 min (1.75 +/- 0.12 vs. 1.05 +/- 0.14 mg x kg(-1) x min(-1); P < 0.01) and did not reach nadir until 210 min (0.96 +/- 0.17 mg x kg(-1) x min(-1)). Between 60 and 240 min, EGP was 47% higher in the diabetic group (0.89 +/- 0.09 vs. 1.31 +/- 0.13 mg x kg(-1) x min(-1), P < 0.02). These data quantitate the initial rapid suppression of EGP after a mixed meal in type 2 diabetes and the contribution of continuing excess glucose production to subsequent hyperglycemia.     

Increased insulin receptor signaling and glycogen synthase activity contribute to the synergistic effect of exercise on insulin action.

The purpose of this study was to determine the factors contributing to the ability of exercise to enhance insulin-stimulated glucose disposal. Sixteen insulin-resistant nondiabetic and seven Type 2 diabetic subjects underwent two hyperinsulinemic (40 mU x m-2 x min-1) clamps, once without and once with concomitant exercise at 70% peak O2 consumption. Exercise was begun at the start of insulin infusion and was performed for 30 min. Biopsies of the vastus lateralis were performed before and after 30 min of insulin infusion (immediately after cessation of exercise). Exercise synergistically increased insulin-stimulated glucose disposal in nondiabetic [from 4.6 +/- 0.4 to 9.5 +/- 0.8 mg x kg fat-free mass (FFM)-1x min-1] and diabetic subjects (from 4.3 +/- 1.0 to 7.9 +/- 0.7 mg. kg FFM-1x min-1) subjects. The rate of glucose disposal also was significantly greater in each group after cessation of exercise. Exercise enhanced insulin-stimulated increases in glycogen synthase fractional velocity in control (from 0.07 +/- 0.02 to 0.22 +/- 0.05, P < 0.05) and diabetic (from 0.08 +/- 0.03 to 0.15 +/- 0.03, P < 0.01) subjects. Exercise also enhanced insulin-stimulated glucose storage (glycogen synthesis) in nondiabetic (2.9 +/- 0.9 vs. 4.9 +/- 1.1 mg x kg FFM-1x min-1) and diabetic (1.7 +/- 0.5 vs. 4.2 +/- 0.8 mg x kg FFM-1. min-1) subjects. Increased glucose storage accounted for the increase in whole body glucose disposal when exercise was performed during insulin stimulation in both groups; effects of exercise were correlated with enhancement of glucose disposal and glucose storage (r = 0.93, P < 0.001). Exercise synergistically enhanced insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity (P < 0.05) and Akt Ser473 phosphorylation (P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects. The data indicate that exercise, performed in conjunction with insulin infusion, synergistically increases insulin-stimulated glucose disposal compared with insulin alone. In nondiabetic and diabetic subjects, increased glycogen synthase activation is likely to be involved, in part, in this effect. In nondiabetic, but not diabetic, subjects, exercise-induced enhancement of insulin stimulation of the phosphatidylinositol 3-kinase pathway is also likely to be involved in the exercise-induced synergistic enhancement of glucose disposal.     

Decreased maximal heart rate with aging is related to reduced {beta}-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate.

A decrease in maximal exercise heart rate (HR(max)) is a key contributor to reductions in aerobic exercise capacity with aging. However, the mechanisms involved are incompletely understood. We sought to gain insight into the respective roles of intrinsic heart rate (HR(int)) and chronotropic beta-adrenergic responsiveness in the reductions in HR(max) with aging in healthy adults. HR(max) (Balke treadmill protocol to exhaustion), HR(int) (HR during acute ganglionic blockade with intravenous trimethaphan), and chronotropic beta-adrenergic responsiveness (increase in HR with incremental intravenous infusion of isoproterenol during ganglionic blockade) were determined in 15 older (65 +/- 5 yr) and 15 young (25 +/- 4 yr) healthy men. In the older men, HR(max) was lower (162 +/- 9 vs. 191 +/- 11 beats/min, P < 0.0001) and was associated with a lower HR(int) (58 +/- 7 vs. 83 +/- 9 beats/min, P < 0.0001) and chronotropic beta-adrenergic responsiveness (0.094 +/- 0.036 vs. 0.154 +/- 0.045 DeltaHR/[isoproterenol]: P < 0.0001). Both HR(int) (r = 0.87, P < 0.0001) and chronotropic beta-adrenergic responsiveness (r = 0.61, P < 0.0001) were positively related to HR(max). Accounting for the effects of HR(int) and chronotropic beta-adrenergic responsiveness reduced the age-related difference in HR(max) by 83%, rendering it statistically nonsignificant (P = 0.2). Maximal oxygen consumption was lower in the older men (34.9 +/- 8.1 vs. 48.6 +/- 6.7 ml x kg(-1) x min(-1), P < 0.0001) and was positively related to HR(max) (r = 0.62, P < 0.0001), HR(int) (r = 0.51, P = 0.002), and chronotropic beta-adrenergic responsiveness (r = 0.47, P = 0.005). Our findings indicate that, together, reductions in HR(int) and chronotropic responsiveness to beta-adrenergic stimulation largely explain decreases in HR(max) with aging, with the reduction in HR(int) playing by far the greatest role.     

Effects of beta-adrenergic receptor stimulation and blockade on substrate metabolism during submaximal exercise

We used beta-adrenergic receptor stimulation and blockade as a tool to study substrate metabolism during exercise. Eight moderately trained subjects cycled for 60 min at 45% of VO(2 peak) 1) during a control trial (CON); 2) while epinephrine was intravenously infused at 0.015 microg. kg(-1) x min(-1) (beta-STIM); 3) after ingesting 80 mg of propranolol (beta-BLOCK); and 4) combining beta-BLOCK with intravenous infusion of Intralipid-heparin to restore plasma fatty acid (FFA) levels (beta-BLOCK+LIPID). beta-BLOCK suppressed lipolysis (i.e., glycerol rate of appearance) and fat oxidation while elevating carbohydrate oxidation above CON (135 +/- 11 vs. 113 +/- 10 micromol x kg(-1) x min(-1); P < 0.05) primarily by increasing rate of disappearance (R(d)) of glucose (36 +/- 2 vs. 22 +/- 2 micromol x kg(-1) x min(-1); P < 0.05). Plasma FFA restoration (beta-BLOCK+LIPID) attenuated the increase in R(d) glucose by more than one-half (28 +/- 3 micromol x kg(-1) x min(-1); P < 0.05), suggesting that part of the compensatory increase in muscle glucose uptake is due to reduced energy from fatty acids. On the other hand, beta-STIM markedly increased glycogen oxidation and reduced glucose clearance and fat oxidation despite elevating plasma FFA. Therefore, reduced plasma FFA availability with beta-BLOCK increased R(d) glucose, whereas beta-STIM increased glycogen oxidation, which reduced fat oxidation and glucose clearance. In summary, compared with control exercise at 45% VO(2 peak) (CON), both beta-BLOCK and beta-STIM reduced fat and increased carbohydrate oxidation, albeit through different mechanisms.     

Sex differences in left ventricular function and beta-receptor responsiveness following prolonged strenuous exercise.

Sex differences in neuroendocrine and metabolic responses to prolonged strenuous exercise (PSE) have been well documented. The aim of this investigation was to examine sex differences in left ventricular function and cardiac beta-receptor responsiveness following a single bout of PSE. Nine male and eight female triathletes were examined during three separate sessions: before, immediately after, and 24 h following a half-ironman triathlon using dobutamine stress echocardiography. Steady-state graded infusions of dobutamine were used to assess beta-receptor responsiveness. Slopes calculated from linear regressions between dobutamine doses and changes in heart rate and contractility for each participant were used as an index of beta-receptor responsiveness. Despite no change in preload, fractional area change decreased from baseline after the race in both men and women, with a greater decrease in men [men: 54.1% (SD 2.1) to 50.7% (SD 3.4) vs. women: 55.4% (SD 2.7) to 53.3% (SD 2.5); P < 0.05]. The amount of dobutamine necessary to increase heart rate by 25 beats/min [men: 29.6 microg x kg(-1) x min(-1) (SD 6.6) to 42.7 microg x kg(-1) x min(-1) (SD 12.9) vs. women: 23.5 microg x kg(-1) x min(-1) (SD 4.0) to 30.0 microg x kg(-1) x min(-1) (SD 7.8); P < 0.05] and contractility by 10 mmHg/cm2 [men: 20.9 microg x kg(-1) x min(-1) (SD 5.1) to 37.0 microg x kg(-1) x min(-1) (SD 11.5) vs. women: 22.6 microg x kg(-1) x min(-1) (SD 6.4) to 30.7 microg x kg(-1) x min(-1) (SD 7.2); P < 0.05] was greater in both men and women postrace. However, the amount of dobutamine required to induce these changes was greater in men, reflecting larger beta-receptor alterations in male triathletes following PSE relative to women. These data suggest that following an acute bout of PSE, male triathletes demonstrate an attenuated chronotropic and inotropic response to beta-adrenergic stimulation compared with female triathletes.     

Autoregulation of glucose production in men with a glycerol load during rest and exercise

Related to hepatic autoregulation we evaluated hypotheses that 1) glucose production would be altered as a result of a glycerol load, 2) decreased glucose recycling rate (Rr) would result from increased glycerol uptake, and 3) the absolute rate of gluconeogenesis (GNG) from glycerol would be positively correlated to glycerol rate of disappearance (R(d)) during a glycerol load. For these purposes, glucose and glycerol kinetics were determined in eight men during rest and during 90 min of leg cycle ergometry at 45 and 65% of peak O2 consumption (.VO2 (peak)). Trials were conducted after an overnight fast, with exercise commencing 12 h after the last meal. Subjects received a continuous infusion of [6,6-(2)H(2)]glucose, [1-(13)C]glucose, and [1,1,2,3,3-(2)H(5)]glycerol without (CON) or with an additional 1,000 mg (rest: 20 mg/min; exercise: 40 mg/min) of [2-(13)C]- or unlabeled glycerol added to the infusate (GLY). Infusion of glycerol dampened glucose Rr, calculated as the difference between [6,6-(2)H(2)]- and [1-(13)C]glucose rates of appearance (R(a)), at rest [0.35 +/- 0.12 (CON) vs. 0.12 +/- 0.10 mg. kg(-1). min(-1) (GLY), P < 0.05] and during exercise at both intensities [45%: 0.63 +/- 0.14 (CON) vs. 0.04 +/- 0.12 (GLY); 65%: 0.73 +/- 0.14 (CON) vs. 0.04 +/- 0.17 mg. kg(-1). min(-1) (GLY), P < 0.05]. Glucose R(a) and oxidation were not affected by glycerol infusion at rest or during exercise. Throughout rest and both exercise intensities, glycerol R(d) was greater in GLY vs. CON conditions (rest: 0.30 +/- 0.04 vs. 0.58 +/- 0.04; 45%: 0.57 +/- 0.07 vs. 1.19 +/- 0.04; 65%: 0.73 +/- 0.06 vs. 1.27 +/- 0.05 mg. kg(-1). min(-1), CON vs. GLY, respectively). Differences in glycerol R(d) (DeltaR(d)) between protocols equaled the unlabeled glycerol infusion rate and correlated with plasma glycerol concentration (r = 0.97). We conclude that infusion of a glycerol load during rest and exercise at 45 and 65% of .VO2(peak) 1) does not affect glucose R(a) or R(d), 2) blocks glucose Rr, 3) increases whole body glycerol R(d) in a dose-dependent manner, and 4) results in gluconeogenic rates from glycerol equivalent to CON glucose recycling rates.