Skeletal muscle uncoupling protein-3 restores upon intervention in the prediabetic and diabetic state: implications for diabetes pathogenesis?

AIM: Skeletal muscle uncoupling protein-3 (UCP3) is reduced in type 2 diabetes, and in the pre-diabetic condition of impaired glucose tolerance (IGT). Here we examined whether intervention programs known to improve insulin sensitivity are paralleled by an increase in skeletal muscle UCP3 protein levels. METHODS: Skeletal muscle UCP3 protein content was measured before and after one year of an exercise intervention in muscle biopsies of eight diabetic subjects. In addition, UCP3 was measured in IGT subjects before and after 1 year of following a lifestyle-intervention program or serving as control. RESULTS: In the diabetic patients a significant increase of approximately 75% in UCP3 protein was found after 1 year of exercise training (P < 0.05). In IGT subjects UCP3 protein increased in the intervention group (P = 0.02), while UCP3 remained unaltered in the control group (P = 0.64). CONCLUSION: Both, exercise training and a lifestyle-intervention program increase UCP3 protein content in skeletal muscle of subjects with reduced glycaemic control, indicating a restoration towards normal UCP3 levels. These data support the idea that UCP3 has a role in the aetiology of type 2 diabetes mellitus.     

UCP-3: regulation of genic expression on skeletal muscle and possible role on body weight control

Uncoupling proteins constitute a subgroup of mitochondrial carrier proteins that are located in the inner mitochondrial membrane. By dissipating proton gradients, they act to uncouple respiration from oxidative phosphorylation and convert fuel to heat. Four homologous UCP isoforms have been identified. UCP-1, the first UCP to be described, is found exclusively in brown adipose tissue, UCP-2 in several tissues, UCP-3 in human skeletal muscle and rat brown adipose tissue and skeletal muscle, whereas UCP-4 is expressed in the brain. Expression of UCP-3 in the skeletal muscle and the brown adipose tissue may place these tissues as important mediators for adaptative thermogenesis. However, the role of UCP-3 in energy expenditure and as a cause of obesity has been controversial. There are evidences that UCP-3 can be regulated by energy substrates as fatty acids and glucose, by entering the muscle and stimulating UCP-3 to increase energy expenditure. Our aim in this review was to describe and discuss the available information on UCP-3 regulation and its possible relation with body weight control.     

Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension

The effects of physical training on the formation of vasodilating and vasoconstricting compounds, as well as on related proteins important for vascular function, were examined in skeletal muscle of individuals with essential hypertension (n=10). Muscle microdialysis samples were obtained from subjects with hypertension before and after 16 weeks of physical training. Muscle dialysates were analyzed for thromboxane A(2), prostacyclin, nucleotides, and nitrite/nitrate. Protein levels of thromboxane synthase, prostacyclin synthase, cyclooxygenase 1 and 2, endothelial nitric oxide synthase (eNOS), cystathionine-γ-lyase, cytochrome P450 4A and 2C9, and the purinergic receptors P2X1 and P2Y2 were determined in skeletal muscle. The protein levels were compared with those of normotensive control subjects (n=12). Resting muscle dialysate thromboxane A(2) and prostacyclin concentrations were lower (P<0.05) after training compared with before training. Before training, dialysate thromboxane A(2) decreased with acute exercise, whereas after training, no changes were found. Before training, dialysate prostacyclin levels did not increase with acute exercise, whereas after training there was an 82% (P<0.05) increase from rest to exercise. The exercise-induced increase in ATP and ADP was markedly reduced after training (P<0.05). The amount of eNOS protein in the hypertensive subjects was 40% lower (P<0.05) than in the normotensive control subjects, whereas cystathionine-γ-lyase levels were 25% higher (P<0.05), potentially compensating for the lower eNOS level. We conclude that exercise training alters the balance between vasodilating and vasoconstricting compounds as evidenced by a decrease in the level of thromboxane, reduction in the exercise-induced increase in ATP and a greater exercise-induced increase in prostacyclin.     

Expression of <Emphasis Type="Italic">uncoupling protein-3</Emphasis> mRNA in rat skeletal muscle is acutely stimulated by thiazolidinediones: an exercise-like effect?

Aims/hypothesis We examined whether thiazolidinediones (TZDs) acutely affect uncoupling protein-3 (UCP-3) expression in skeletal muscle and plasma NEFA in Sprague-Dawley rats.Methods Expression of UCP-3 mRNA in hindlimb muscles and plasma NEFA were measured after a single intraperitoneal injection of TZDs in healthy male rats.Results Independent of which TZD was injected (50 µmol/kg), UCP-3 expression in gastrocnemius muscle was distinctly increased after 6 h (increase vs vehicle-injected control: pioglitazone, 10.3±3.2-fold, p=0.03; rosiglitazone, 8.7±1.2-fold, p=0.001; RWJ241947, 9.5±2.7-fold, p=0.03). This was accompanied by elevated plasma NEFA (control 158±13 µmol/l; pioglitazone, 281±40 µmol/l, p=0.03; rosiglitazone, 276±27 µmol/l, p=0.005; RWJ241947, 398±51 µmol/l, p=0.004). The increase in plasma NEFA could in part have mediated TZD-induced UCP-3 expression, but increased UCP-3 mRNA was also found in isolated muscle after 2 h of TZD exposure in vitro (25 µmol/l pioglitazone, 1.7±0.3-fold, p=0.046), suggesting that TZDs act directly and independently of NEFA on skeletal muscle.Conclusions/interpretation In healthy rats, a single dose of TZDs rapidly increases UCP-3 mRNA in skeletal muscle and plasma NEFA. This effect resembles the acute response to a bout of exercise.     

Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men

We studied the acute effects of a single, sc GH dose on exercise performance and metabolism during bicycling. Seven highly trained men [age, 26 +/- 1 yr (mean +/- SEM); weight, 77 +/- 3 kg; maximal oxygen uptake, 65 +/- 1 ml O(2).min(-1).kg(-1)] performed 90 min of bicycling 4 h after receiving 7.5 IU (2.5 mg) GH or placebo in a randomized, double-blinded, cross-over design trial. A standardized pre-exercise meal was given 2 h before exercise. Blood was sampled at rest and during exercise and analyzed for GH, IGF-I, glucose, lactate, insulin, glycerol, and nonesterified fatty acids (NEFA). In the placebo trial, all subjects completed the exercise protocol without any difficulties. In contrast, two subjects were not able to complete the exercise protocol in the GH trial, and one subject barely managed to complete the protocol. In addition, GH administration resulted in exaggerated increases in plasma lactate concentrations during exercise (P < 0.0001). The combined lipolytic effect of GH and exercise, evidenced by increased plasma glycerol and serum NEFA concentrations, was 3-fold greater than the effect of exercise alone (P < 0.0001), but this increased substrate availability did not result in increased whole body fat oxidation (indirect calorimetry). Plasma glucose was, on average, 9% higher during exercise after GH administration compared with placebo (P < 0.0001). We conclude that a single, relevant GH dose causes exaggerated increases in plasma lactate and glycerol as well as serum NEFA during 90 min of subsequent bicycling at moderate to high intensity. The exaggerated increase in plasma lactate may be associated with substantially decreased exercise performance.     

Effect of thyroid hormone on uncoupling protein-3 mRNA expression in rat heart and skeletal muscle.

Thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) stimulate UCP-3 expression in skeletal muscle. We examined whether thyroid hormone-induced changes in uncoupling protein (UCP)-3 mRNA expression are related to directs effects of T3 or reflect secondary effects of the hormone through stimulation of renin-angiotensin or beta-adrenergic systems. Hyperthyroidism was produced by three injections of 100 microg T3/100 g body weight on alternate days with or without concomitant treatment with either captopril (an angiotensin-converting enzyme [ACE] inhibitor), propranolol (a beta-blocker) or clenbuterol (a beta2-agonist). The relative abundance of UCP-3 mRNA was measured in ventricular myocardium and skeletal muscle (gastrocnemius and soleus). T3 resulted in a significant increase in the relative abundance of UCP-3 in heart and skeletal muscle (p < 0.05), and the effect was not altered by captopril or propanolol; the inhibitors alone had no effect of UCP-3 mRNA content. There was no synergistic or additive effect of T3 and clenbuterol on UCP-3 mRNA expression in skeletal muscle. Increased UCP-3 mRNA levels were associated with increased UCP-3 protein expression in skeletal muscle. We conclude that the effect of T3 on UCP-3 expression in cardiac and skeletal muscle is not dependent on either angiotensin II or the beta-adrenergic system and probably reflects a direct action of the hormone on UCP-3 gene expression.     

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

OBJECTIVE: It has been reported that an increased availability of free fatty acids (NEFA) not only interferes with glucose utilization in insulin-dependent tissues, but may also result in an uncoupling effect of heart metabolism. We aimed therefore to investigate the effect of an increased availability of NEFA on gene expression of proteins involved in transmembrane fatty acid (FAT/CD36) and glucose (GLUT4) transport and of the uncoupling proteins UCP2 and 3 at the heart and skeletal muscle level. STUDY DESIGN: Euglycemic hyperinsulinemic clamp was performed after 24 h Intralipid(R) plus heparin or saline infusion in lean Zucker rats. Skeletal and heart muscle glucose utilization was calculated by 2-deoxy-[1-(3)H]-D-glucose technique. Quantification of FAT/CD36, GLUT4, UCP2 and UCP3 mRNAs was obtained by Northern blot analysis or RT-PCR. RESULTS: In Intralipid(R) plus heparin infused animals a significant decrease in insulin-mediated glucose uptake was observed both in the heart (22.62+/-2.04 vs 10.37+/-2.33 ng/mg/min; P<0.01) and in soleus muscle (13.46+/-1.53 vs 6.84+/-2.58 ng/mg/min; P<0.05). FAT/CD36 mRNA was significantly increased in skeletal muscle tissue (+117.4+/-16.3%, P<0.05), while no differences were found at the heart level in respect to saline infused rats. A clear decrease of GLUT4 mRNA was observed in both tissues. The 24 h infusion of fat emulsion resulted in a clear enhancement of UCP2 and UCP3 mRNA levels in the heart (99.5+/-15.3 and 80+/-4%) and in the skeletal muscle (291.5+/-24.7 and 146.9+/-12.7%). CONCLUSIONS: As a result of the increased availability of NEFA, FAT/CD36 gene expression increases in skeletal muscle, but not at the heart level. The augmented lipid fuel supply is responsible for the depression of insulin-mediated glucose transport and for the increase of UCP2 and 3 gene expression in both skeletal and heart muscle.     

Mitochondrial dysfunction in COPD patients with low body mass index.

Patients with chronic obstructive pulmonary disease (COPD) show abnormal adaptations of skeletal muscle redox status after exercise training. Increased skeletal muscle oxidative stress in COPD patients may prompt mitochondrial dysfunction. The present study explores the association between body composition and mitochondrial respiration in seven COPD patients with low body mass index (BMI(L)), eight COPD patients with normal body mass index (BMI(N)) and seven healthy controls. All of them underwent a vastus lateralis biopsy in which muscle structure, in vitro mitochondrial respiratory function, uncoupling protein 3 (UCP3) mRNA expression and glutathione levels in both isolated mitochondria and the whole muscle were determined. Mitochondrial respiratory function (assessed by acceptor control ratio (ACR)) was impaired in BMI(L) (2.2+/-0.6) compared with both BMI(N) (5.3+/-1.3) and controls (8.2+/-1.3). ACR significantly correlated with arterial oxygen tension and with muscle endurance but it showed a negative association with exercise-induced increase in blood lactate levels. UCP3 mRNA expression was reduced in BMI(L) patients. In conclusion, chronic obstructive pulmonary disease patients with low body mass index show electron transport chain dysfunction, which may contribute to low muscle endurance in the current subgroup of patients.     

Mitochondrial biogenesis and angiogenesis in skeletal muscle of the elderly

The aim of this study was to test the hypotheses that 1) skeletal muscles of elderly subjects can adapt to a single endurance exercise bout and 2) endurance trained elderly subjects have higher expression/activity of oxidative and angiogenic proteins in skeletal muscle than untrained elderly people. To investigate this, lifelong endurance trained elderly (ET; n = 8) aged 71.3 ± 3.4 years and untrained elderly subjects (UT; n = 7) aged 71.3 ± 4 years, performed a cycling exercise bout at 75% VO_2max with vastus lateralis muscle biopsies obtained before (Pre), immediately after exercise (0h) and at 2 h of recovery. Capillarization was detected histochemically and oxidative enzyme activities were determined on isolated mitochondria. GLUT4, HKII, Cyt c and VEGF protein expression was measured on muscle lysates from Pre-biopsies, phosphorylation of AMPK and P38 on lysates from Pre and 0h biopsies, while PGC-1α, VEGF, HKII and TFAM mRNA content was determined at all time points. ET had ~ 40% higher PDH, CS, SDH, α-KG-DH and ATP synthase activities and 27% higher capillarization than UT, reflecting increased skeletal muscle oxidative capacity with lifelong endurance exercise training. In addition, acute exercise increased in UT PGC-1α mRNA 11-fold and VEGF mRNA 4-fold at 2 h of recovery, and AMPK phosphorylation ~ 5-fold immediately after exercise, relative to Pre, indicating an ability to adapt metabolically and angiogenically to endurance exercise. However, in ET PGC-1α mRNA only increased 5 fold and AMPK phosphorylation ~ 2-fold, while VEGF mRNA remained unchanged after the acute exercise bout. P38 increased similarly in ET and UT after exercise. In conclusion, the present findings suggest that lifelong endurance exercise training ensures an improved oxidative capacity of skeletal muscle, and that skeletal muscle of elderly subjects maintains the ability to respond to acute endurance exercise.     

Time course responses of serum GH, insulin, IGF-1, IGFBP1, and IGFBP3 concentrations after heavy resistance exercise in trained and untrained men

To investigate the effect of heavy resistance exercise on IGF-1 system, 19 healthy trained men and 15 healthy untrained men volunteered to participate in this study. The subjects were randomly divided into experimental and control groups. Subjects of experimental groups were forced to perform a heavy resistance exercise with the intensity of 70-80% of 1RM in selected movements. The blood samples were taken from all subjects four times; before (T1), immediately after (T2), 5 (T3), and 8 (T4) hours after exercise. Analysis of data showed that a session of heavy resistance exercise induced significant increase in GH at T2 (P < 0.05) and a significant decrease in insulin at T4 (P < 0.05) and a significant decrease in IGFBP3 at T4 (P < 0.05) in trained group. In untrained group, no significant change in any of the variables was observed. However, the procedure of response in variables was almost similar in two experimental groups. Although, the exercise did not appreciably affect IGF-1 levels, it decreased in all groups at length of time after exercise. In addition, the exercise did not have any notable effect on IGFBP1 levels over time. In conclusion, the findings of this study indicate that the intense resistance exercise can lead to changes in blood concentrations of IGF-1 system components which are observable in blood circulation over time and the amounts of changes depend on subjects' fitness levels and exercise variables.     

Effect of exercise training on the untrained limb exercise performance of men with angina pectoris

This study examined the exercise capacity of trained and untrained limbs in men with angina pectoris before and after 8 weeks of arm (n = 4) or leg (n = 7) physical training or a control (n = 4) period. Time to angina (mean ± standard deviation) increased 3.6 ± 2.7 minutes (p < 0.01) during trained limb and 1.6 ± 1.2 minutes (p < 0.01) during untrained limb exercise. Myocardial oxygen demand at angina estimated by the product of heart rate and systolic blood pressure did not change with training. At a constant subanginal work load, rate-pressure product × 10^?2 was reduced by 35 ± 22 (p < 0.001) during trained limb and by 18 ± 27 (p < 0.05) during untrained limb exercise. The decrease in rate-pressure product with both trained and untrained limbs was greatest in subjects with the highest rate-pressure product at angina before training. Control subjects showed no change in any exercise measurement.Exercise training increases the exercise capacity of untrained limbs in patients with angina pectoris by a generalized training effect not dependent on adaptations In trained skeletal muscle. The improvement for both trained and untrained limbs results from a reduced rate-pressure product at subanginal work loads rather than from an increase in myocardial oxygen delivery. Subjects with the highest pretraining coronary arterial oxygen supply at the onset of angina benefit most from physical training.     

Cortisol and growth hormone responses to exercise at different times of day

Exercise of appropriate intensity is a potent stimulus for GH and cortisol secretion. Circadian and diurnal rhythms may modulate the GH and cortisol responses to exercise, but nutrition, sleep, prior exercise patterns, and body composition are potentially confounding factors. To determine the influence of the time of day on the GH and cortisol response to acute exercise, we studied 10 moderately trained young men (24.1 +/- 1.1 yr old; maximal oxygen consumption, 47.9 +/- 1.4 mL/kg.min; percent body fat, 13.2 +/- 0.6%). After a supervised night of sleep and a standard meal 12 h before exercise, subjects exercised at a constant velocity (to elicit an initial blood lactate concentration of approximately 2.5 mmol/L) on a treadmill for 30 min on 3 separate occasions, starting at 0700, 1900, and 2400 h. Blood samples were obtained at 5-min intervals for 1 h before and 5 h after the start of exercise; subjects were not allowed to sleep during this period. Subjects were also studied on 3 control days under identical conditions without exercise. There were no significant differences with time of day in the mean blood lactate and submaximal oxygen consumption values during exercise. The differences over time in serum GH and cortisol concentrations between the exercise day and the control day were determined with 95% confidence limits for each time of day. Exercise stimulated a significant increase in serum GH concentrations over control day values for approximately 105--145 min (P < 0.05) with no significant difference in the magnitude of this response by time of day. The increase in serum GH concentrations with exercise was followed by a transient suppression of GH release (for approximately 55--90 min; P < 0.05) after exercise at 0700 and 1900 h, but not at 2400 h. Although the duration of the increase in serum cortisol concentrations after exercise was similar (approximately 150--155 min; P < 0.05) at 0700, 1900, and 2400 h, the magnitude of this increase over control day levels was greatest at 2400 h. This difference was significant for approximately 130 min and approximately 40 min compared to exercise at 1900 and 0700 h, respectively (P < 0.05). The cortisol response to exercise at 0700 h was significantly greater than that at 1900 h for about 55 min (P < 0.05). A rebound suppression of cortisol release for about 50 min (P < 0.05) was observed after exercise at 2400 h, but not 0700 or 1900 h. Both baseline (before exercise) and peak cortisol concentrations were significantly higher at 0700 h than at 1900 or 2400 h (P < 0.01). We conclude that time of day does not alter the GH response to exercise; however, the exercise-induced cortisol response is modulated by time of day.     

Skeletal muscle PGF(2)(alpha) and PGE(2) in response to eccentric resistance exercise: influence of ibuprofen acetaminophen

PGs have been shown to modulate skeletal muscle protein metabolism as well as inflammation and pain. In nonskeletal muscle tissues, the over the counter analgesic drugs ibuprofen and acetaminophen function through suppression of PG synthesis. We previously reported that ibuprofen and acetaminophen inhibit the normal increase in skeletal muscle protein synthesis after high intensity eccentric resistance exercise. The current study examined skeletal muscle PG levels in the same subjects to further investigate the mechanisms of action of these drugs in exercised skeletal muscle. Twenty-four males (25 +/- 3 yr) were assigned to 3 groups that received the maximal over the counter dose of ibuprofen (1200 mg/d), acetaminophen (4000 mg/d), or a placebo after 10-14 sets of 10 eccentric repetitions at 120% of concentric 1 repetition maximum using the knee extensors. Preexercise and 24 h postexercise biopsies of the vastus lateralis revealed that the exercise-induced change in PGF(2alpha) in the placebo group (77%) was significantly different (P < 0.05) from those in the ibuprofen (-1%) and acetaminophen (-14%) groups. However, the exercise-induced change in PGE(2) in the placebo group (64%) was only significantly different (P < 0.05) from that in the acetaminophen group (-16%). The exercise-induced changes in PGF(2alpha) and PGE(2) were not different between the ibuprofen and acetaminophen groups. These results suggest that ibuprofen and acetaminophen have a comparable effect on suppressing the normal increase in PGF(2alpha) in human skeletal muscle after eccentric resistance exercise, which may profoundly influence the anabolic response of muscle to this form of exercise.     

Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet

OBJECTIVE: To test the hypothesis that consumption of a high-fat diet leads to an increase in UCP mRNA expression in human skeletal muscle. In a group of endurance athletes, with a range in fiber type distribution, we hypothesized that the effect of the high-fat diet on UCP2 and UCP3 mRNA expression is more pronounced in muscle fibers which are known to have a high capacity to shift from carbohydrate to fat oxidation (type IIA fibers). DESIGN: Ten healthy trained athletes (five males, five females) consumed a low-fat diet (17+/-0.9 en% of fat) and high-fat diet (41.4+/-1.4 en% fat) for 4 weeks, separated by a 4 week wash-out period. Muscle biopsies were collected at the end of both dietary periods. MEASUREMENTS: Using RT-PCR, levels of UCP2 and UCP3 mRNA expression were measured and the percentage of type I, IIA and IIB fibers were determined using the myofibrillar ATPase method in all subjects. RESULTS: UCP3L mRNA expression tended to be higher on the high-fat diet, an effect which reached significance when only males were considered (P=0.037). Furthermore, diet-induced change in mRNA expression of UCP3T (r: 0.66, P=0.037), UCP3L (r: 0.61, P=0.06) and UCP2 (r: 0.70, P=0.025), but not UCP3S, correlated significantly with percentage dietary fat on the high-fat diet. Plasma FFA levels were not different during the two diets. Finally, the percentage of type IIA fibers was positively correlated with the diet-induced change in mRNA expression for UCP2 (r: 0.7, P=0.03), UCP3L (r: 0.73, P=0.016) and UCP3T (r: 0.68, P=0.03) but not with UCP3S (r: 0.06, NS). CONCLUSION: UCP2 and UCP3 mRNAs are upregulated by a high-fat diet. This upregulation is more pronounced in humans with high proportions of type IIA fibers, suggesting a role for UCPs in lipid utilization.     

The impact of one session resistance exercise on plasma adiponectin and RBP4 concentration in trained and untrained healthy young men

We designed this study, to investigate the predicting effect of a single resistance exercise session on serum level of RBP4 and adiponectin in trained and untrained subjects and to evaluate whether regular training may affect the response of these adipokines to exercise. Thirty four healthy young male students including 19 trained and 15 untrained participated in this study; each group was then randomly assigned to intervention and control groups. The exercise session prolonged 120 minutes intensive resistance program at 70%-80% of 1RM. The blood samples were collected just before the start of training program and 4 hours post exercise to evaluate concentration of adiponectin, RBP4 and CRP as well as other metabolic markers. The serum level of adiponectin, RBP4 and CRP was not significantly different between trained and untrained groups at baseline. More over four hours post exercise adipokines concentration and CRP didn't differ between groups. Adjusted regression model showed, basal adiponectin (β=0.59, p=<0.001) and HDL cholesterol (β=0.28, p=0.09) were the main predictors of post exercise adiponectin concentration. In addition, the basic level of RBP4 appeared to be the only predictor of after exercise RBP4 concentration (β=0.46, p=0.02). Neither one session of high intensity resistance exercise nor long term training had predicting effect on post exercise adiponectin and RBP4 concentration in healthy young men. In the other hand, the beneficial effect of acute resistance exercise training may not be reflected by changes in adiponectin, RBP4 and CRP concentration in healthy young individual no matter they trained or untrained.     

Insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity is enhanced in human skeletal muscle after exercise

Exercise increases skeletal muscle insulin action but the underlying mechanisms mediating this are equivocal. In mouse skeletal muscle, prior exercise enhances insulin-stimulated insulin receptor substrate-2 (IRS-2) signaling (Diabetes 2002;51:479-83), but it is unknown if this also occurs in humans. Hyperinsulinemic-euglycemic clamps were performed on 7 untrained males at rest and immediately after 60 minutes of cycling exercise at approximately 75% Vo2peak. Muscle biopsies were obtained at basal, immediately after exercise, and at 30 and 120 minutes of hyperinsulinemia. Insulin infusion increased (P < .05) insulin receptor tyrosine phosphorylation similarly in both the rest and exercise trials. Under resting conditions, insulin infusion resulted in a small, but non-statistically significant increase in IRS-2-associated phosphatidylinositol 3 (PI 3)-kinase activity over basal levels. Exercise per se decreased (P < .05) IRS-2-associated PI 3-kinase activity. After exercise, insulin-stimulated IRS-2-associated PI 3-kinase activity tended to increase at 30 minutes and further increased (P < .05) at 120 minutes when compared with the resting trial. Insulin increased (P < .05) Akt Ser473 and GSK-3alpha/beta Ser21/Ser9 phosphorylation in both trials, with the response tending to be higher in the exercise trial. In conclusion, in the immediate period after an acute bout of exercise, insulin-stimulated IRS-2 signaling is enhanced in human skeletal muscle.     

Involvement of bradykinin in acute exercise-induced increase of glucose uptake and GLUT-4 translocation in skeletal muscle: studies in normal and diabetic humans and rats

Acute exercise induces glucose uptake in skeletal muscle in vivo, but the molecular mechanism of this phenomenon remains to be identified. In this study, we evaluated the involvement of bradykinin in exercise-induced glucose uptake in humans and rats. In human studies, plasma bradykinin concentrations increased significantly during an ergometer exercise (20 minutes) in 8 healthy normoglycemic subjects and 6 well-controlled type 2 diabetic patients (mean hemoglobin A1c [HbA1c], 6.4% +/- 0.6%), but not in 6 poorly controlled type 2 diabetics (mean HbA1c, 11.6% +/- 2.6%). In rat studies, plasma bradykinin concentrations also significantly increased after 1 hour of swimming in nondiabetic and mildly diabetic (streptozotocin [STZ] 45 mg/kg intravenously [IV]) rats, but not in rats with severe diabetes (STZ 65 mg/kg IV). Glucose influx (maximum velocity [Vmax]) and GLUT-4 translocation in skeletal muscle of nondiabetic rats significantly increased after 1 hour of swimming, but these increases were abrogated by subcutaneous infusion of bradykinin B2 receptor antagonist HOE-140 (400 microg x kg(-1) x d(-1)). Insulin-stimulated tyrosine phosphorylation and phosphatidylinositol (PI) 3-kinase activity in response to insulin injection (20 U/kg IV) in the portal vein were significantly attenuated in exercised rats pretreated with HOE-140 compared with saline-treated exercised rats. Our results suggest that plasma bradykinin concentrations increase in response to acute exercise and this increase is affected by blood glucose status in diabetic patients. Moreover, the exercise-induced increase in bradykinin may be involved in modulating exercise-induced glucose transport through an increase of GLUT-4 translocation, as well as enhancement of the insulin signal pathway, during the postexercise period in skeletal muscle, resulting in a decrease of blood glucose.     

Relationship between zinc intake, physical activity, and blood levels of high-density lipoprotein cholesterol in a healthy elderly population

We investigated the relationship between level of exercise, ingestion of zinc supplements, and serum high-density lipoprotein (HDL) cholesterol levels in 270 healthy men and women over age 60. After controlling for sex, alcohol intake, and body mass, there was a significant positive correlation between level of exercise and serum HDL cholesterol in the 180 subjects not taking supplemental zinc (r = 0.26, P = .005) but not for those subjects taking supplemental zinc (r = -0.18, P = .14). Multiple regression analysis showed a significant interaction of zinc intake and activity level on HDL cholesterol (P = .04). In 22 subjects who were ingesting greater than 15 mg of supplemental, elemental zinc daily, cessation of zinc supplements for 8 weeks was associated with a significant increase in HDL cholesterol levels (2.0 mg/dL; P = .04). The change in HDL after stopping zinc was positively correlated with the level of exercise of the subjects (r = .41, P = .05). Thus supplemental zinc ingestion appears to block the exercise-induced increase in serum HDL cholesterol in a healthy population.