Carbohydrate metabolism during exercise in females: effect of reduced fat availability

This study examined the effect of reduced plasma free fatty acid (FFA) availability on carbohydrate metabolism during exercise. Six untrained women cycled for 60 minutes at approximately 58% of maximum oxygen uptake after ingestion of a placebo (CON) or nicotinic acid (NA), 30 minutes before exercise (7.4 +/- 0.5 mg.kg(-1) body weight), and at 0 minutes (3.7 +/- 0.3 mg.kg(-1)) and 30 minutes (3.7 +/- 0.3 mg.kg(-1)) of exercise. Glucose kinetics were measured using a primed, continuous infusion of [6,6-(2)H] glucose. Plasma FFA (CON, 0.86 +/- 0.12; NA, 0.21 +/- 0.11 mmol.L(-1) at 60 minutes, P <.05) and glycerol (CON, 0.34 +/- 0.05; NA, 0.10 +/- 0.04 mmol.L(-1) at 60 minutes, P <.05) were suppressed throughout exercise. Mean respiratory exchange ratio (RER) during exercise was higher (P <.05) in NA (0.89 +/- 0.02) than CON (0.83 +/- 0.02). Plasma glucose and glucose production were similar between trials. Total glucose uptake during exercise was greater (P <.05) in NA (1,876 +/- 161 micromol.kg(-1)) than in CON (1,525 +/- 107 micromol.kg(-1)). Total fat oxidation was reduced (P <.05) by approximately 32% during exercise in NA. Total carbohydrate oxidized was approximately 42% greater (P <.05) in NA (412 +/- 40 mmol) than CON (290 +/- 37 mmol), of which, approximately 16% (20 +/- 10 mmol) could be attributed to glucose. Plasma insulin and glucagon were similar between trials. Catecholamines were higher (P <.05) during exercise in NA. In summary, during prolonged moderate exercise in untrained women, reduced FFA availability results in a compensatory increase in carbohydrate oxidation, which appears to be due predominantly to an increase in glycogen utilization, although there was a small, but significant, increase in whole body glucose uptake.     

Accelerated decline in hepatic glucose production during fasting in normal women compared with men

Plasma glucose values have been reported to be lower in women than in men after a 72-hour fast. However, a comparison of glucose kinetics in fasting men and women has not been described. Therefore, five normal men and five normal women underwent sequential 3-3H-glucose infusions after both a 14- and a 64-hour fast. Plasma glucose levels fell similarly during the fast in men (5.23 +/- 0.03 v 3.96 +/- 0.14 mmol/L, P less than .01) and women (4.84 +/- 0.14 v 3.65 +/- 0.25 mmol/L, P less than .01). The fall in plasma glucose was associated with a significantly greater fall in glucose appearance (Ra) in women compared with men (P less than .05). Ra fell 15.8% +/- 3.0% in men (2.11 +/- 0.24 to 1.79 +/- 0.24 mg.kg-1.min-1, P less than .01) and 24.6% +/- 1.4% in women (2.22 +/- 0.17 to 1.67 +/- 0.12 mg.kg-1.min-1, P less than .001). During the fast, plasma glycerol, free fatty acids (FFA), and beta-hydroxybutyrate levels rose significantly and plasma alanine fell significantly in both sexes. Plasma glycerol levels were significantly higher in women compared with men after fasting (0.16 +/- 0.01 v 0.11 +/- 0.02 mmol/L, P less than .05). In addition, the transition from ambulation to bed rest demonstrated unexpected sex-related differences in glucose homeostasis after the 64-hour fast. During the two-hour equilibration period required for glucose kinetic studies (subjects reclining), significant decrements in glucose, FFA, and lactate were observed in the 64-hour fasted women but not in the men.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of plasma fatty acid composition in endogenous glucose production in patients with type 2 diabetes mellitus

Hepatic insulin resistance and increased endogenous glucose production (EGP) are associated with increased plasma free fatty acids (FFA). However, the contribution of FFA composition to the regulation of EGP is not known. Six obese nondiabetic subjects and 6 patients with type 2 diabetes mellitus (DM2) were studied after an overnight and a 3-day fast. Plasma insulin concentrations after an overnight fast were similar in the DM2 and nondiabetic patients (88.8 +/- 26.4 v 57.6 +/- 12.6 pmol/L, not significant [NS]) despite increased plasma glucose (9.9 +/- 1.8 v 5.1 +/- 0.1 mmol/L, P <.01) and EGP (510.3 +/- 77.7 v 298.3 +/- 18.3 micromol x m(-2) x min(-1), P <.05) in the patients with DM2. Absolute rates of gluconeogenesis using the heavy water method were also increased in the patients with DM2 (346.8 +/- 74.9 v 198.8 +/- 16.4 micromol x m(-2). min(-1), P <.05). No differences were observed in plasma polyunsaturated fatty acids (PUFA) between the diabetic and nondiabetic subjects. However, total saturated fatty acid (SFA) concentrations (350 +/- 37.4 v 230.9 +/- 33.3 micromol/L, P <.02) were significantly increased in the diabetic subjects. Rates of EGP were correlated with total plasma FFA concentration (r =.71, P <.01) and the concentration of SFA (r =.71, P <.01), but not monounsaturated fatty acids or PUFA. Rates of gluconeogenesis were also correlated with plasma FFA (r =.64, P <.05) and SFA (r =.67, P <.05). We observed no relationship between EGP and either total FFA or fatty acid composition after a 3-day fast. We conclude that increases in EGP are associated with concentrations of plasma SFA after an overnight fast.     

Effect of growth hormone (GH) on glycerol and free fatty acid metabolism during exhaustive exercise in GH-deficient adults

GH is an important regulator of fat metabolism at rest, but it is not known whether it regulates fat metabolism during exercise. To determine whether physiologic concentrations of GH influence fat metabolism during exercise, we randomized 16 GH-deficient adults, receiving long-term (mean duration, 5 yr) GH replacement, to either continue GH (n = 8) or receive identical placebo (n = 8) for a 3-month period. Metabolic studies, at rest, during and following exhaustive exercise were carried out at baseline and at the end of the 3 months. The rate of appearance of glycerol (glycerol Ra, an index of lipolysis) and free fatty acids (FFA, FFA Ra) and the rate of disappearance of FFA (FFA Rd) in the plasma were measured using infusions of (2)H(5)-glycerol and 1-(13)C-palmitic acid. Changes in body composition were assessed using dual-energy x-ray absorptiometry scanning and anthropometric measurements. In the baseline studies, exercise resulted in an increase in plasma glycerol and FFA concentrations, glycerol Ra, FFA Ra, and FFA Rd (P < 0.001). Three months of GH withdrawal resulted in reductions in plasma glycerol and FFA, glycerol Ra, FFA Ra, and FFA Rd at rest (P < 0.05 vs. baseline) and during exercise (P < 0.05 vs. baseline and vs. GH treated). Lean body mass decreased after 3 months of GH withdrawal, but total body fat, trunk fat, waist circumference, and the sum of skinfold thicknesses increased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). Fasting insulin and homeostasis model assessment of insulin resistance decreased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). In summary, GH withdrawal for 3 months resulted in reductions in release of glycerol and FFA into the circulation and uptake of FFA into the tissues during intense exercise. These changes were accompanied by reduced lean body mass and increased total body and trunk fat. Further studies are required to determine whether reduced mobilization of fat during exercise contributes to reduced exercise capacity and increased body fat in GH-deficient adults.     

Lipolysis and lipid oxidation in weight-losing cancer patients and healthy subjects

Increased lipolysis has been suggested as one of the possible mechanisms underlying cancer cachexia. The study aim was to assess whether lipolysis is increased in weight-losing cancer patients, considering their differences in food intake and body composition. Sixteen healthy subjects and 18 cancer patients with different tumor types and a weight loss of at least 5% in the previous 6 months were included in the study. Food intake was recorded for 4 days. After an overnight fast, [1,1,2,3,3-2H5]glycerol was infused to determine the rate of appearance (Ra) of glycerol as a measure of whole-body lipolysis, and [1-13C]palmitic acid was infused to determine the Ra of palmitate as a measure of adipocyte fatty acid release. Palmitate oxidation was determined by measuring 13CO2 enrichment in breath samples, and body composition was measured by bioelectrical impedance analysis. After adjustment for energy intake, whole-body lipolysis was significantly higher in cancer patients versus healthy subjects (6.46 +/- 0.63 and 4.67 +/- 0.46 micromol/kg +/- min, respectively, P < .05). The difference in adipocyte fatty acid release did not reach statistical significance. The rate of palmitate oxidation was also significantly higher in patients than in healthy subjects (1.15 +/- 0.10 and 0.93 +/- 0.07 )micromol/kg x min, respectively, P < .05). No differences in body composition were observed between groups. In conclusion, whole-body lipolysis (as measured by the Ra of glycerol) and palmitate oxidation were elevated in weight-losing cancer patients, but fatty acid release was not significantly different.     

Long- and medium-chain fatty acid oxidation is increased in exercise-trained human skeletal muscle

The purpose of this study was to test the hypothesis that skeletal muscle fatty acid oxidation is enhanced by increased entry into the mitochondria with exercise training. Muscle was obtained from young ( approximately 24 years) sedentary (n = 13) and endurance-trained (n = 10) volunteers and oxidation studied by measuring (14)CO(2) production from labeled medium-chain (MCFA) or long-chain (LCFA) fatty acids in muscle homogenate preparations. LCFA (palmitate) oxidation was (P <.05) approximately 34% higher in the trained than sedentary subjects (26.9 +/- 3.0 v 17.8 +/- 1.3 nmol CO(2)/g x h). MCFA (octanoate) oxidation was also about 26% higher (P <.05) in the trained subjects (21.7 +/- 2.1 v 16.1 +/- 2.0 nmol CO(2)/g x h). To examine the roles of carnitine-mediated transport and mitochondrial content, we also measured carnitine palmitoyltransferase I (CPT1), carnitine octanoyl transferase (COT), and citrate synthase (CS) activities. CPT1 and CS activity were significantly (P <.05) higher (approximately 25%) in the endurance-trained subjects; there was no difference in COT activity. These data suggest that adaptations at the level of CPT1 and processes distal to this step may contribute to increases in LCFA or MFCA oxidation with exercise training. In contrast, carnitine-mediated transport (COT) does not appear to contribute to an enhancement in MCFA oxidation with exercise training.     

Regulation of glucose kinetics during intense exercise in humans: effects of alpha- and beta-adrenergic blockade

This study examined the effect of combined alpha- and beta-adrenergic blockade on glucose kinetics during intense exercise. Six endurance-trained men exercised for 20 minutes at approximately 78% of their peak oxygen consumption (Vo(2)) following ingestion of a placebo (CON) or combined alpha- (prazosin hydrochloride) and beta- (timolol maleate) adrenoceptor antagonists (BLK). Plasma glucose increased during exercise in CON (0 minutes: 5.5 +/- 0.1; 20 minutes: 6.5 +/- 0.3 mmol. L(-1), P <.05). In BLK, the exercise-induced increase in plasma glucose was abolished (0 minutes: 5.7 +/- 0.3; 20 minutes: 5.7 +/- 0.1 mmol. L(-1)). Glucose kinetics were measured using a primed, continuous infusion of [6,6-(2)H] glucose. Glucose production was not different between trials; on average these values were 25.3 +/- 3.9 and 30.9 +/- 4.4 micromol. kg(-1). min(-1) in CON and BLK, respectively. Glucose uptake during exercise was greater (P <.05) in BLK (30.6 +/- 4.6 micromol. kg(-1). min(-1)) compared with CON (18.4 +/- 2.5 micromol. kg(-1). min(-1)). In BLK, plasma insulin and catecholamines were higher (P <.05), while plasma glucagon was unchanged from CON. Free fatty acids (FFA) and glycerol were lower (P <.05) in BLK. These findings demonstrate that adrenergic blockade during intense exercise results in a blunted plasma glucose response that is due to enhanced glucose uptake, with no significant change in glucose production.     

Alcohol and postexercise metabolic responses in type 2 diabetes.

The objective was to investigate the impact of the combination of exercise and alcohol on the metabolic response in nonfasting and fasting type 2 diabetic subjects. In part 1, 12 untrained middle-aged type 2 diabetic subjects participated on 3 test days. On each day, they ingested a light meal (1,824 kJ) containing 48 energy percent (E%) carbohydrate, 38 E% fat, and 14 E% protein. The meal was followed by either (A) rest or (B) 30 minutes of exercise (40% of maximum O2 consumption [VO2max]) or (C) taken with alcohol (0.4 g/kg body weight) followed by 30 minutes of exercise (40% of VO2max). In part 2, 11 untrained middle-aged type 2 diabetic subjects participated on 4 test days without a meal. The subjects were either (A) resting, (B) drinking alcohol (0.4 g/kg body weight), (C) exercising 30 minutes (40% of VO2max), or (D) drinking alcohol (0.4 g/kg body weight) and exercising 30 minutes (40% of VO2max). On each test day, regular blood samples were drawn for 4 hours for analysis of glucose, insulin, lactate, triglycerides, nonesterified fatty acid (NEFA), and ethanol. Comparing exercise and rest following a light meal (part 1, no change (7%) occurred in the plasma glucose response area (642 +/- 119 v 724 +/- 109 mmol x L(-1) x 240 min, NS). However, it was significantly reduced (by 27%) in response to exercise and alcohol (509 +/- 98 v 724 +/- 109 mmol x L(-1) x 240 min; P = .03). Similar serum insulin response areas were obtained. After exercise and alcohol, plasma lactate increased compared with the resting state (2.2 +/- 0.2 v 1.6 +/- 0.1 mmol x L(-1), P = .004) and with exercise alone (2.2 +/- 0.2 v 1.8 +/- 0.2 mmol x L(-1), P = .04). Serum NEFAs were significantly reduced by exercise and alcohol compared with the resting state (0.50 +/- 0.04 v 0.65 +/- 0.06 mmol x L(-1), P = .008) and with exercise alone (0.50 +/- 0.04 v 0.61 +/- 0.05 mmol x L(-1), P = .02). Similar serum triglycerides were found. During the fasting state (part 2), similar plasma glucose response areas were obtained in the four situations. The insulin response area to exercise and alcohol increased significantly compared with the resting state (3,325 +/- 744 v 882 +/- 295 pmol x L(-1) x 240 min, P = .02) and with exercise alone (3,325 +/- 744 v 1,328 +/- 422 pmol x L(-1) x 240 min, P = .007). No difference was found compared with alcohol alone. Plasma lactate was higher after alcohol intake versus the resting state (1.9 +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .003), as well as after exercise and alcohol (1.9 +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .01). After exercise and alcohol serum NEFAs were significantly reduced compared with the resting state (0.43 +/- 0.02 v 0.64 +/- 0.02 mmol x L(-1), P < .001), alcohol alone (0.43 +/- 0.02 v 0.51 +/- 0.02 mmol x L(-1), P < .001), and exercise alone (0.43 +/- 0.02 v 0.64 +/- 0.02 mmol x L(-1), P < .001). Serum triglycerides were similar in the four situations. We conclude that moderate exercise with or without moderate alcohol intake does not cause acute hypoglycemia either after a light meal or in the fasting state in untrained overweight type 2 diabetic subjects.     

Effects of hypoosmolality on whole-body lipolysis in man

Changes in extracellular osmolality, and thus in the cellular hydration state, appear to directly influence cell metabolism. The metabolic changes associated with cell swelling are inhibition of glycogenolysis, glycolysis, and proteolysis. Recent studies in our laboratory demonstrated diminished whole-body protein breakdown in humans during an acute hypoosmolar state. Because of the close interrelationship between carbohydrate and fat metabolism, we speculated that adipose tissue lipolysis and fatty acid oxidation are regulated by changes in extracellular osmolality. Therefore, we investigated the effect of artificially induced hypoosmolality on whole-body lipolysis and fat oxidation in seven healthy young men. Hypoosmolality was induced by intravenous administration of desmopressin, liberal ingestion of water, and infusion of hypotonic (0.45%) saline solution. Lipolysis was assessed by a stable-isotope method (2-[13C]-glycerol infusion). The glycerol rate of appearance (Ra), reflecting whole-body lipolysis, was higher under hypoosmolar compared with isoosmolar conditions (2.35+/-0.40 v 1.68+/-0.21 micromol/kg/min, P=.03). This was even more pronounced when lipolysis was suppressed during hyperinsulinemia and euglycemic clamping (0.90+/-0.08 v 0.61+/-0.03 micromol/kg/min, P=.002). However, plasma free fatty acid (FFA), glycerol, ketone body, insulin, and glucagon concentrations and carbohydrate and lipid oxidation measured by indirect calorimetry were not significantly altered by hypoosmolality. Plasma norepinephrine concentrations were lower under hypoosmolar conditions (P<.01 v control). In conclusion, hypoosmolality in vivo results in increased whole-body lipolysis, which is not due to changes in major lipolysis regulating hormones.     

Exogenous insulin replacement in type 2 diabetes reverses excessive hepatic glucose release,but not excessive renal glucose release and impaired free fatty acid clearance

In type 2 diabetes renal and hepatic glucose release are increased and free fatty acids (FFA) clearance is reduced. Restoration of normoglycemia by exogenous insulin replacement normalizes overall glucose release and plasma FFA concentrations. However, it is unclear to what extent normalization of overall glucose release is due to suppression of hepatic (HGR) and renal glucose release (RGR) and whether the abnormal FFA clearance is improved. We therefore determined overall, renal, and hepatic glucose release, as well as systemic FFA release and clearance by tracer techniques in type 2 diabetic subjects with (DM(+)) and without (DM(-)) physiologic overnight insulin infusion and in nondiabetic volunteers (NV). Insulin infusion normalized plasma glucose (5.3 +/- 0.1 v 5.2 +/- 0.1 mmol/L in NV) and overall glucose release (10.1 +/- 0.7 v 10.6 +/- 0.4 micromol x kg(-1) x min(-1) in NV), (both P >.9). Values in DM(-) were 9.1 +/- 0.6 mmol/L and 14.6 +/- 0.8 micromol x kg(-1) x min(-1), respectively (both P <.001 v DM(+) and NV). The correction of overall glucose release in DM(+) was due to suppression of HGR to rates below normal (6.11 +/- 0.53 v 8.67 +/- 0.44 micromol x kg(-1) x min(-1) in NV, P <.03). RGR remained increased (3.91 +/- 0.38 v 1.90 +/- 0.28 micromol x kg(-1) x min(-1) in NV, P <.002) and was similar to DM(-) (3.97 +/- 0.33 micromol x kg(-1) x min(-1), P >.9). Insulin infusion also normalized plasma FFA levels (450 +/- 45 v 476 +/- 42 in NV, P >.9 and v613 +/- 33 micromol/L in DM(-), P <.04). This was due to suppression of FFA release to below normal (4.04 +/- 0.45 v 5.25 +/- 0.25 micromol x kg(-1) x min(-1) in NV, P <.04). Plasma FFA clearance remained reduced (7.2 +/- 1.0 v 11.4 +/- 1.2 mL x kg(-1) x min(-1) in NV, P <.04) and was similar to DM(-) (7.3 +/- 0.5 mL x kg(-1) x min(-1), P >.9). We conclude that in contrast to the excessive HGR, excessive RGR and impaired FFA clearance are not corrected by acute exogenous insulin replacement.     

Effects of moderate and high glycemic index meals on metabolism and exercise performance.

The purpose of this study was to determine whether pre-exercise ingestion of meals with moderate and high glycemic indexes (GI) affects glucose availability during exercise and exercise performance time. Six male volunteers (22 +/- 1 years; 80.4 +/- 3.7 kg; VO(2peak), 54.3 +/- 1.2 ml. kg(-1). min(-1)) ingested 75 g of carbohydrate in the form of 2 different breakfast cereals, rolled oats (moderate GI, approximately 61; MOD-GI) or puffed rice (high GI, approximately 82; HI-GI), combined with 300 mL of water; or water alone (control). The trials were randomized, and the meals were ingested 45 minutes before the subjects performed cycling exercise (60% VO(2peak)) to exhaustion. Venous blood samples were drawn to measure glucose, free fatty acids (FFAs), glycerol, insulin (INS), epinephrine (EPI) and norepinephrine (NE) concentrations. A muscle biopsy specimen was obtained from the vastus lateralis before the meal and immediately after exercise for glycogen determination. Before exercise, both test meals elicited significant (P <.05) hyperglycemia and hyperinsulinemia compared with control. The glycemic response was higher (P <.05) at the start of exercise after the HI-GI meal than after the control. During exercise, plasma glucose levels were higher (P <.05) at 60 (5.2 +/- 0.1, 4.2 +/- 0.2, and 4.6 +/- 0.1 mmol. L(-1)) and 90 (4.8 +/- 0.1, 4.1 +/- 0.1, and 4.3 +/- 0.1 mmol. L(-1)) minutes after the MOD-GI meal than after either the HI-GI or control. Total carbohydrate oxidation was greater (P <.05) during the MOD-GI trial than in control and was directly correlated with exercise performance time (r =.95, P <.0001). Pre-exercise plasma FFA levels were suppressed (P <.05) 30 and 45 minutes after ingestion of the HI-GI meal and 45 minutes after the MOD-GI meal compared with control. At 30, 60, and 120 minutes of exercise, FFAs remained suppressed (P <.05) for both test meals compared with control. At exhaustion, plasma glucose, INS, FFA, glycerol, EPI, and NE levels and muscle glycogen use were not different for all trials. Exercise time was prolonged (P <.05) after the MOD-GI meal compared with control, but the HI-GI trial was not different from control (MOD-GI, 165 +/- 11; HI-GI, 141 +/- 8; control, 134 +/- 13 minutes). Thus, in contrast to the HI-GI meal or control, the MOD-GI breakfast cereal ingested 45 minutes before exercise enhanced performance time, maintained euglycemia for a longer period during exercise, and resulted in greater total carbohydrate oxidation during the exercise bout. We conclude that a MOD-GI meal provides a significant performance and metabolic advantage when consumed 45 minutes before exercise.     

Effects of obesity phenotype on fat metabolism in obese men during endurance exercise

OBJECTIVE: The effects of obesity phenotype on fat metabolism during endurance exercise are unclear. This study aimed to investigate in obese men whether body fat distribution would influence plasma fat availability and oxidation during endurance exercise. DESIGN: Fourteen sedentary men (body mass index (BMI) > 25 kg/m2) were divided into two groups by visceral fat (VF) area: VF obese (VF-Ob) (n = 7, age; 52.0 +/- 2.5 (s.e.) years) and abdominal subcutaneous fat obese (SF-Ob) (n = 7, age; 57.3 +/- 2.8 (s.e.) years). All participants performed stationary cycling exercise for 60 min at 50% of peak oxygen uptake.Measurements:Blood and respiratory gas samples were taken for analysis of hormone, metabolite and substrate oxidation in each participant at rest and during exercise. RESULTS: There is a significant group x time interaction in the plasma concentration of free fatty acid (FFA) (P < 0.05) and glycerol (P < 0.05) during the exercise bout. In addition, total plasma concentration of FFA (area under the curve) was 59.2% higher in VF-Ob compared with SF-Ob men during endurance exercise (1.99 +/- 0.24 and 1.25 +/- 0.13 mEq/l/min, respectively; P < 0.05). Total plasma concentration of glycerol (area under the curve) was 102.3% higher in VF-Ob than SF-Ob men during the exercise (69.6 +/- 12.5 and 34.4 +/- 5.1 mg/dl/min, respectively; P < 0.05). However, fat oxidation was not different throughout the exercise between VF-Ob and SF-Ob men (176.5 +/- 25.7 and 183.0 +/- 12.8 kcal/60 min, respectively). CONCLUSION: During moderate endurance exercise, plasma fat availability may be higher in men with VF obesity compared to men with SF obesity. However, total fat oxidation is similar between obesity phenotype.     

Effects of different lipid substrates on glucose metabolism in normal postabsorptive humans.

We investigated the effects on glucose metabolism of the infusion of either long-chain triglycerides (LCT), a mixture of long-chain and medium-chain triglycerides (MCT/LCT), D-beta-hydroxybutyrate (D-beta-OHB), or saline in normal postabsorptive subjects. Plasma insulin, C-peptide, and glucagon concentrations were unchanged in all groups. LCT and MCT/LCT infusions increased levels of plasma free fatty acids (FFA) compared with those of the saline group, whereas D-beta-OHB decreased them. Plasma ketone body concentrations were higher during the D-beta-OHB and triglyceride infusions than during the saline test. Glucose concentrations and appearance (Ra) and disappearance (Rd) rates were not modified during saline infusion. Glucose levels decreased only in the D-beta-OHB and MCT/LCT groups (P < .05), whereas they were unchanged during LCT infusion. Glucose Ra decreased slightly by 15% to 17% in LCT, MCT/LCT, and D-beta-OHB groups (P < .05 v saline). Glucose Rd decreased by 14% to 16% in each lipid-infusion group (P < .05 v saline). Glucose clearance rates decreased by 14% only in the LCT group (P < .001). Glucose oxidation rates did not change significantly during the lipid substrate infusions compared with saline infusion. In conclusion, (1) the effects of fatty acids on glucose metabolism appear to depend on the fatty acid chain length, since only LCT infusion significantly impaired glucose utilization; and (2) in subjects with normal endocrine pancreas function, we found no adverse effects of a short-term increase in lipid substrate availability on glucose production rate and concentration.     

Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene expression in untrained but not trained humans

In rodents, acute exercise increases skeletal muscle uncoupling protein (UCP) gene expression and is associated with elevations in serum nonesterified fatty acids (NEFA). To test whether contractions increase UCP mRNA levels in humans, vastus lateralis biopsies were obtained 1 hour postexercise from untrained and trained subjects and analyzed for UCP-2 and UCP-3 long (UCP-3(L)) and short (UCP-3(S)) isoforms. The acute exercise bout (graded cycling protocol; 65% to 85% relative VO(2)max) induced significant (P <.01) elevations in serum NEFA in both untrained and trained subjects, but the increase in untrained subjects was significantly (P <.05) greater (60% v 30%). Ribonuclease protection assay demonstrated that basal levels of all UCP isoforms measured were similar between the 2 groups. However, acute exercise induced a significant increase (P <.02) in both UCP-3(L) and UCP-3(S), but not UCP-2 mRNA levels in untrained, but not trained subjects. Correlation analysis did not show a significant relationship between exercise-induced changes in NEFA and UCP-3 levels. These results demonstrate that acute endurance exercise increases UCP-3 gene expression only in untrained skeletal muscle, but this effect does not seem to be tightly linked to the exercise-induced fluctuations in serum NEFA levels.     

No difference in the lipolytic response to beta-adrenoceptor stimulation in situ but a delayed increase in adipose tissue blood flow in moderately obese compared with lean men in the postexercise period

This study was undertaken to determine the effect of previous exercise on adipose tissue responsiveness to beta-adrenoceptor stimulation and on adipose tissue blood flow (ATBF). Eight lean and 8 obese men (body mass index [BMI], 23.6 +/- 2.1 [SD] v 29.0 +/- 1.9 kg x m(-2)) were investigated with abdominal subcutaneous microdialysis and 133Xe clearance. A stepwise isoprenaline infusion (10(-8), 10(-7), and 10(-6) mol x L(-1)) was administered in situ in the microdialysis catheter before and 2 hours after a submaximal exercise bout (90 minutes of cycling at 55% of maximal O2 uptake). No differences in the response (increase in interstitial glycerol v preinfusion level) to isoprenaline infusions were found between the 2 groups. In both groups, there was no difference in the response to postexercise versus preexercise infusion. When the vasodilating agent hydralazine (0.125 g x L(-1)) was infused into the microdialysis catheter to control for the vascular effects of isoprenaline, an interaction effect between exercise and isoprenaline dose was found. Analyses showed an attenuated response to the high isoprenaline dose after exercise (lean, 251 +/- 42 [SE] micromol x L(-1); obese, 288 +/- 77 micromol x L(-1)) versus before exercise (lean, 352 +/- 62 micromol x L(-1), P = .045 v after; obese, 380 +/- 94 micromol x L(-1), P = .021 v after), indicating a desensitization of lipolysis to beta-adrenoceptor stimulation. ATBF and arterial plasma glycerol increased after exercise in both groups, but the increase was delayed in obese subjects. Arterial plasma insulin was higher in the obese versus lean subjects at all times, and decreased during recovery in both groups. In conclusion, abdominal subcutaneous adipose tissue responsiveness to beta-stimulation is not enhanced postexercise in lean and obese men, whereas previous exercise increases ATBF. Furthermore, the data suggest slower lipid mobilization postexercise and resistance to the antilipolytic effect of insulin in the obese.     

During exercise in the cold increased availability of plasma nonesterified fatty acids does not affect the pattern of substrate oxidation

Exercise in the cold was investigated to establish if the relative contribution of fat to energy expenditure is affected by the increased availability of circulating nonesterified fatty acids (NEFA). Seven men after an overnight fast cycled at approximately 70% of peak oxygen uptake for 60 minutes at an ambient temperature of 0.0 degrees C +/- 0.1 degrees C. Fifteen minutes prior to exercise and then throughout the exercise, subjects were infused with either heparin (heparin) or saline (control). Immediately before exercise NEFA concentration (control, 0.27 +/- 0.04 mmol. L(-1); heparin 1.09 +/- 0.13 mmol. l(-1)) was significantly higher (P <.05) in the heparin trial. Pre-exercise concentration of plasma triacylglycerol (TG), blood glycerol, glucose, oxygen consumption (VO(2)) and respiratory exchange ratio (RER) were not significantly different between heparin and control trials. During exercise, plasma NEFA and blood glycerol concentrations were significantly higher (P <.05) in the heparin trial, and levels of plasma TG and glucose were not different between trials. Over the exercise period rectal temperature, mean skin temperature, VO(2), RER, and heart rate (HR) were not different between the 2 trials. Gross energy expenditure of cycling (control, 3.3 +/- 0.1 MJ; heparin 3.3 +/- 0.1 MJ), the oxidation rates of fat (control, 0.67 +/- 0.05 g. min(-1); heparin, 0.71 +/- 0.06 g. min(-1)) and carbohydrate (CHO) (control, 1.68 +/- 0.04 g.min(-1); heparin, 1.62 +/- 0.17 g. min(-1)) and the proportion of energy derived from fat (control, 43 +/- 4%; heparin trial, 44 +/- 9%) and CHO (control, 57 +/- 4%; heparin trial, 56 +/- 4%) were not different between the 2 trials. These findings suggest that despite increased availability of plasma NEFA, the pattern of substrate oxidation during exercise in cold temperatures does not change. This implies that uncoupling between the availability and oxidation of plasma NEFA may be a mechanism involved in the reduced oxidation of fat seen during cold exposure. Further research is needed on the utilization of intramuscular TG and circulating plasma TG-rich lipoproteins in the cold.     

Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man

Significant, sexual dimorphisms exist in counterregulatory responses to commonly occurring stresses, such as hypoglycemia, fasting, and cognitive testing. The question of whether counterregulatory responses differ during exercise in healthy men and women remains controversial. The aim of this study was to determine whether a sexual dimorphism exists in neuroendocrine, metabolic, or cardiovascular responses to prolonged moderate exercise. Sixteen healthy (eight men and eight women) subjects matched for age (28+/-2 yr), body mass index (22+/-1 kg/m2), nutrient intake, and spectrum of physical fitness were studied in a randomized fashion during 90 min of exercise on a cycle ergometer at 80% of their anaerobic threshold (approximately 50% VO2 max). Respiratory quotient and oxygen consumption relative to body weight were identical in men and women. Glycemia was equated (5.3+/-0.2 mmol/L) during exercise via an exogenous glucose infusion. Gender had significant effects on counterregulatory responses during exercise. Arterialized epinephrine (1.05+/-0.2 vs. 0.45+/-0.04 nmol/L), norepinephrine (9.2+/-1.1 vs. 5.8+/-1.1 nmol/L), and pancreatic polypeptide (52+/-6 vs. 37+/-6 pmol/L) were significantly (P<0.01) increased in men compared to women, respectively. Plasma glucagon, cortisol, and GH levels responded similarly in men and women. Insulin values were higher at baseline in men and fell by a greater amount to reach similar levels during exercise compared to those in women. Endogenous glucose production, measured with [3-3H]glucose was similar in men and women. Carbohydrate oxidation was significantly increased in men relative to women (21.2+/-2 vs. 15.6+/-2 mg/kg fat free mass x min; P<0.05). Despite reduced sympathetic nervous system (SNS) drive, lipolytic responses were increased in women. Arterialized blood glycerol (215+/-30 vs. 140+/-20 micromol/L), beta-hydroxybutyrate (54+/-9 vs. 25+/-10 micromol/L), and plasma nonesterified fatty acids (720+/-56 vs. 469+/-103 micromol/L) were significantly (P<0.01) increased in women. In keeping with increased SNS activity, systolic blood pressure and mean arterial pressure were significantly increased (P<0.01) in men. In summary, this study demonstrates that a significant sexual dimorphism exists in neuroendocrine, metabolic, and cardiovascular counterregulatory responses to prolonged moderate exercise in man. We conclude that during exercise, men have increased autonomic nervous system (epinephrine, norepinephrine, pancreatic polypeptide), cardiovascular (systolic, mean arterial pressure) and certain metabolic (carbohydrate oxidation) counterregulatory responses, but that women have increased lipolytic (glycerol, nonesterified fatty acids) and ketogenic (beta-hydroxybutyrate) responses. Women may compensate for diminished SNS activity during exercise by increased lipolytic responses.     

Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy

Human immunodeficiency virus (HIV) lipodystrophy is associated with fat redistribution, dyslipidemia, and insulin resistance; however, the mechanism of insulin resistance remains unknown. We hypothesized that HIV-infected subjects with fat redistribution have increased rates of lipolysis and increased circulating free fatty acid (FFA) levels that contribute to insulin resistance. Anthrompometric and body composition data were obtained and a standard 75-g oral glucose tolerance test (OGTT) was performed on day 1 of the study. Stable isotope infusions of glycerol and palmitate were completed following an overnight fast to assess rates of lipolysis and FFA flux in HIV-infected men (n = 19) with and without fat redistribution and healthy controls (n = 8) on day 2. Total FFA levels after standard glucose challenge were increased among HIV-infected subjects and positively associated with abdominal visceral adipose tissue area. In contrast, fasting total FFA levels were inversely associated with subcutaneous fat area. Rates of basal lipolysis were significantly increased among HIV-infected subjects (rate of appearance [Ra] glycerol, 4.1 +/- 0.2 v 3.3 +/- 0.2 micromol/kg/min in controls; P =.02). Among HIV-infected subjects, use of stavudine (P =.006) and the rate of lipolysis (ie, Ra glycerol, P =.02) were strong positive predictors of insulin resistance as measured by insulin response to glucose challenge, controlling for effects of age, body mass index (BMI), waist-to-hip ratio (WHR), and protease inhibitor (PI) exposure. These data demonstrate increased rates of lipolysis and increased total FFA levels in HIV-infected subjects and suggest that increased lipolysis may contribute to insulin resistance in this patient population.     

Abnormalities of whole body protein turnover, muscle metabolism and levels of metabolic hormones in patients with chronic heart failure

OBJECTIVE: It is well known that chronic heart failure (CHF) is associated with insulin resistance and cachexia, but little is known about the underlying substrate metabolism. The present study was undertaken to identify disturbances of basal glucose, lipid and protein metabolism. DESIGN: We studied eight nondiabetic patients with CHF (ejection fraction 30 +/- 4%) and eight healthy controls. Protein metabolism (whole body and regional muscle fluxes) and total glucose turnover were isotopically assayed. Substrate oxidation were obtained by indirect calorimetry. The metabolic response to exercise was studied by bicycle ergometry exercise. RESULTS: Our data confirm that CHF patients have a decreased lean body mass. CHF patients are characterised by (i) decreased glucose oxidation [glucose oxidation (mg kg(-1) min(-1)): 1.25 +/- 0.09 (patients) vs. 1.55 +/- 0.09 (controls), P < 0.01] and muscle glucose uptake [a - v diff(glucose) (micromol L(-1)): -10 +/- 25 (patients) vs. 70 +/- 22 (controls), P < 0.01], (ii) elevated levels of free fatty acids (FFA) [FFA (mmol L(-1)): 0.72 +/- 0.05 (patients) vs. 0.48 +/- 0.03 (controls), P < 0.01] and 3-hydroxybutyrate and signs of elevated fat oxidation and muscle fat utilization [a - v diff(FFA) (mmol L(-1)): 0.12 +/- 0.02 (patients) vs. 0.05 +/- 0.01 (controls), P < 0.05] and (iii) elevated protein turnover and protein breakdown [phenylalanine flux (micromol kg(-1) h(-1)): 36.4 +/- 1.5 (patients) vs. 29.6 +/- 1.3 (controls), P < 0.01]. Patients had high circulating levels of noradrenaline, glucagon, and adiponectin, and low levels of ghrelin. We failed to observe any differences in metabolic responses between controls and patients during short-term exercise. CONCLUSIONS: In the basal fasting state patients with CHF are characterized by several metabolic abnormalities which may contribute to CHF pathophysiology and may provide a basis for targeted intervention.     

Weight reduction and the impaired plasma-derived free fatty acid oxidation in type 2 diabetic subjects

In a previous study the oxidation of plasma free fatty acids (FFA) under baseline conditions and during exercise was lower in type 2 diabetic subjects compared with weight-matched controls. The present study intended to investigate the effect of weight reduction (very low calorie diet) on plasma FFA oxidation in seven type 2 diabetic male subjects (body fat, 37.4 +/- 1.2%; age, 51.3 +/- 3.4 yr; plasma glucose, 7.45 +/- 0.48 mmol/L). Subjects underwent a 10-week diet period. Body composition and substrate utilization during rest and during bicycle exercise (50% of maximum aerobic capacity) were determined before and after the diet (during weight-stable conditions). FFA metabolism was studied by means of the tracer [U-(13)C]palmitate. Rates of oxidation of plasma FFA were corrected with an acetate recovery factor. Additionally, activities of mitochondrial enzymes and cytosolic fatty acid-binding protein were determined in biopsies from the vastus lateralis muscle before and after the diet. The very low calorie diet resulted in a weight loss of 15.3 kg (110.8 +/- 7.4 vs. 95.5 +/- 5.8 kg; P < 0.01). The basal rates of appearance and disappearance of FFA decreased as a result of diet. The rates of appearance and disappearance of FFA during exercise were not different before and after diet. The oxidation of plasma-derived fatty acids tended to decrease after diet during baseline conditions (P = 0.10), whereas the plasma FFA oxidation during exercise was not different before and after the diet (14.1 +/- 1.9 vs. 14.8 +/- 1.8 micromol/kg fat-free mass.min). Skeletal muscle cytosolic fatty acid-binding protein and the activities of muscle oxidative enzymes did not significantly change as a result of weight loss. In conclusion, considerable weight reduction did not significantly improve plasma-derived FFA oxidation under baseline conditions and during exercise, suggesting that this impairment reflects a primary defect leading to the development of type 2 diabetes mellitus rather than resulting from the type 2 diabetic state.