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Purpose: Acute cold exposure (ACE) stimulates metabolism but data evaluating inflammatory and lipid biomarkers related to cardiovascular disease in response to ACE are lacking. Therefore, we investigated the relationship between ACE and inflammatory and lipid biomarkers. Methods: Twenty subjects underwent 30 min of ACE with blood drawn: 1) pre-ACE (baseline), 2) at 30 min ACE, and 3) 2 h post-ACE. Plasma was analyzed for 10 cytokines (monocyte chemoattractant protein1 (CCL2), interleukin (IL)-1?, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-?), interferon-gamma (INF?)), 9 acute phase proteins (ferritin, fibrinogen, procalcitonin, serum amyloid A, serum amyloid P, tissue plasminogen, C-reactive protein, haptoglobin, ?-2-macroglobin), and 5 lipid biomarkers (triglycerides, nonesterified fatty acids (NEFA), low- and high-density lipoprotein (LDL, HDL), and total cholesterol). Heart rate, whole body oxygen consumption (VO2), energy expenditure (EE), shivering sensations, and pain were measured prior and during ACE. Results: ACE increased heart rate by 11%, shivering sensations by 4-fold, pain by 2-fold, VO2 by 50%, and EE by 52%. IL-1? increased after 30 min ACE by 24% (p=0.048) and 2 h post ACE by 65% (p=0.01). Alpha-2-macroglobin increased after 30 min ACE by 16% (p=0.005) and returned to baseline levels 2 h post-ACE. HDL increased at 2 h post-ACE by 15% (p=0.034). Sex differences were noted between IL-2, IL-6, IL-8, ferritin, ?-2-macroglobin and HDL. Conclusions: These findings indicate ACE increases EE and modifies inflammation, the acute phase response, and lipid metabolism.

Determine whether a salivary biomarker of physical fatigue, referred to as the fatigue biomarker index (FBI), can discriminate a control group from a sleep deprived group when saliva is collected under controlled conditions. The study expands on previous work examining changes in the composition of saliva during periods of prolonged exercise.Thirty (30) young adults (14 Control [CON]; 16 Sleep Deprived [SDEP]) were monitored for mood state (Profile of Mood States [POMS]), cognitive performance (Stroop Color-Conflict Tests), and salivary biomarkers of physical fatigue over a 48-h period with sampling at 3-h intervals. Trials lasted from 06:00 on day 1 (time = -3 h) to 09:00 on day 3 (time = 48 h). Levels of salivary biomarkers were calculated from liquid chromatography-mass spectrometry (LC-MS) data. Statistical comparisons were made using Wilcoxon rank sum tests with a Bonferroni correction to limit type 1 error. Receiver-operator characteristic (ROC) analysis was used to evaluate the ability of the various parameters to distinguish the SDEP population from the CON population.Longitudinal analysis demonstrated significant between-group differences in all three parameters. ROC analysis demonstrated that cognitive performance tests and salivary biomarkers of physical fatigue distinguish the SDEP population from the CON population.A previously identified salivary biomarker of physical fatigue may provide an alternative method for discriminating sleep deprived from rested individuals. The salivary biomarker of physical fatigue holds promise as an objective measure of sleep deprivation, perhaps eventually removing the reliance on self-reported sleep diaries and/or repeated polysomnographs for longitudinal tracking of sleep quality and/or diagnosis of sleep disorders.

We examined the effect of exercise on postprandial hypertriglyceridemia (PHTG) and insulin resistance in individuals with metabolic syndrome. Subjects were 10 hypertriglyceridemic men with insulin resistance [age = 35.0 ± 1.8 yr, body weight = 90.7 ± 3.3 kg, fasting triglyceride (TG) = 2.6 ± 0.4 mmol/l, peak oxygen consumption (V̇o2peak) = 36.0 ± 1.3 ml−1·kg−1·min−1, and homeostatic model assessment of insulin resistance (HOMA-IR)= 3.1 ± 0.3]. Each participant performed a control trial (Ctr; no exercise) and three exercise trials at 60% of their V̇o2peakfor 30 min (30 min-Ex), 45 min (45 min-Ex) and 60 min (60 min-Ex). All subjects had a fat meal in each trial. In the exercise trials, the subject jogged on a treadmill for a designated duration of 12 h before ingestion of a fat meal. Blood samples were taken at 0 h (before the meal) and at 2, 4, 6, and 8 h after the meal. The plasma TG, area score under TG concentration curve over an 8-h period (TG AUC) after the meal, and HOMA-IR were analyzed. The TG AUC scores in both the 45 min-Ex and 60 min-Ex were 31 and 33% lower, respectively, than Ctr ( P < 0.02). There were no significant differences in TG AUC scores between the 30 min-Ex and the Ctr ( P > 0.05). There were no trial differences in the fasting plasma glucose concentration ( P > 0.05). HOMA-IR values in the 30 min-Ex, 45 min-Ex, and 60 min-Ex trials were lower than the Ctr ( P < 0.03), but no significant differences were found in HOMA-IR among the exercise trials. The results suggest that for physically inactive individuals with metabolic syndrome, exercising at moderate intensity for 45 min effectively attenuates PHTG while exercise for 30 min is sufficient to improve insulin action.

The restorative capacities of a high carbohydrate-protein (CHO-PRO) beverage containing electrolytes and a traditional 6% carbohydrate-electrolyte sports beverage (SB) were assessed after glycogen-depleting exercise. Postexercise ingestion of the CHO-PRO beverage, in comparison with the SB, resulted in a 55% greater time to exhaustion during a subsequent exercise bout at 85% maximum oxygen consumption (VO(2)max). The greater recovery after the intake of the CHO-PRO beverage could be because of a greater rate of muscle glycogen storage. Therefore, a second study was designed to investigate the effects of after exercise CHO-PRO and SB supplements on muscle glycogen restoration. Eight endurance-trained cyclists (VO(2)max = 62.1 +/- 2.2 ml.kg(-1) body wt.min(-1)) performed 2 trials consisting of a 2-hour glycogen-depletion ride at 65-75% VO(2)max. Carbohydrate-protein (355 ml; approximately 0.8 g carbohydrate (CHO).kg(-1) body wt and approximately 0.2 g protein.kg(-1) body wt) or SB (355 ml; approximately 0.3 g CHO.kg(-1) body wt) was provided immediately and 2 hours after exercise. Trials were randomized and separated by 7-15 days. Ingestion of the CHO-PRO beverage resulted in a 17% greater plasma glucose response, a 92% greater insulin response, and a 128% greater storage of muscle glycogen (159 +/- 18 and 69 +/- 32 micromol.g(-1) dry weight for CHO-PRO and SB, respectively) compared with the SB (p < 0.05). These findings indicate that the rate of recovery is coupled with the rate of muscle glycogen replenishment and suggest that recovery supplements should be consumed to optimize muscle glycogen synthesis as well as fluid replacement.

The nonapeptide bradykinin (BK) has been implicated as the mediator of the beneficial effect of angiotensin-converting enzyme inhibitors on insulin-stimulated glucose transport in insulin-resistant skeletal muscle. In the present study, the effects of chronic in vivo BK treatment of obese Zucker ( fa/ fa) rats, a model of glucose intolerance and severe insulin resistance, on whole body glucose tolerance and skeletal muscle glucose transport activity stimulated by insulin or contractions were investigated. BK was administered subcutaneously (twice daily at 40 μg/kg body wt) for 14 consecutive days. Compared with a saline-treated obese group, the BK-treated obese animals had significantly ( P < 0.05) lower fasting plasma levels of insulin (20%) and free fatty acids (26%), whereas plasma glucose was not different. During a 1 g/kg body wt oral glucose tolerance test, the glucose and insulin responses [incremental areas under the curve (AUC)] were 21 and 29% lower, respectively, in the BK-treated obese group. The glucose-insulin index, the product of the glucose and insulin AUCs and an indirect index of in vivo insulin action, was 52% lower in the BK-treated obese group compared with the obese control group. Moreover, 2-deoxyglucose uptake in the isolated epitrochlearis muscle stimulated by a maximally effective dose of insulin (2 mU/ml) was 52% greater in the BK-treated obese group. Contraction-stimulated (10 tetani) 2-deoxyglucose uptake was also enhanced by 35% as a result of the BK treatment. In conclusion, these findings indicate that in the severely insulin-resistant obese Zucker rat, chronic in vivo treatment with BK can significantly improve whole body glucose tolerance, possibly as a result of the enhanced insulin-stimulated skeletal muscle glucose transport activity observed in these animals.

Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese Zucker (fa/fa) rat—an animal model of muscle insulin resistance—was used to test whether acute (100 mg/kg body wt for 1 h) and chronic (5–100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant α-lipoic acid (ALA) could improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and glucose oxidation were determined in the isolated epitrochlearis muscles in the absence or presence of insulin (13.3 nmol/1). Severe insulin resistance of 2-DG uptake, glycogen synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/−) rats. Acute and chronic treatments (30 mgkg−1 · day−1, a maximally effective dose) with ALA significantly (P < 0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was associated with a significantly greater (21%) in vivo muscle glycogen concentration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15–17%) plasma levels of insulin and free fatty acids. No significant effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase and citrate synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhances the capacity of the insulinstimulatable glucose transport system and of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle.

Background This study's purpose investigated the impact of different macronutrient distributions and varying caloric intakes along with regular exercise for metabolic and physiological changes related to weight loss. Methods One hundred forty-one sedentary, obese women (38.7 ± 8.0 yrs, 163.3 ± 6.9 cm, 93.2 ± 16.5 kg, 35.0 ± 6.2 kg•m-2, 44.8 ± 4.2% fat) were randomized to either no diet + no exercise control group (CON) a no diet + exercise control (ND), or one of four diet + exercise groups (high-energy diet [HED], very low carbohydrate, high protein diet [VLCHP], low carbohydrate, moderate protein diet [LCMP] and high carbohydrate, low protein [HCLP]) in addition to beginning a 3x•week-1 supervised resistance training program. After 0, 1, 10 and 14 weeks, all participants completed testing sessions which included anthropometric, body composition, energy expenditure, fasting blood samples, aerobic and muscular fitness assessments. Data were analyzed using repeated measures ANOVA with an alpha of 0.05 with LSD post-hoc analysis when appropriate. Results All dieting groups exhibited adequate compliance to their prescribed diet regimen as energy and macronutrient amounts and distributions were close to prescribed amounts. Those groups that followed a diet and exercise program reported significantly greater anthropometric (waist circumference and body mass) and body composition via DXA (fat mass and % fat) changes. Caloric restriction initially reduced energy expenditure, but successfully returned to baseline values after 10 weeks of dieting and exercising. Significant fitness improvements (aerobic capacity and maximal strength) occurred in all exercising groups. No significant changes occurred in lipid panel constituents, but serum insulin and HOMA-IR values decreased in the VLCHP group. Significant reductions in serum leptin occurred in all caloric restriction + exercise groups after 14 weeks, which were unchanged in other non-diet/non-exercise groups. Conclusions Overall and over the entire test period, all diet groups which restricted their caloric intake and exercised experienced similar responses to each other. Regular exercise and modest caloric restriction successfully promoted anthropometric and body composition improvements along with various markers of muscular fitness. Significant increases in relative energy expenditure and reductions in circulating leptin were found in response to all exercise and diet groups. Macronutrient distribution may impact circulating levels of insulin and overall ability to improve strength levels in obese women who follow regular exercise.

Insulin-stimulated muscle glucose uptake is inversely associated with the muscle glycogen concentration. To investigate whether this association is a cause and effect relationship, we compared insulin-stimulated muscle glucose uptake in noncontracted and postcontracted muscle of GSL3-transgenic and wild-type mice. GSL3-transgenic mice overexpress a constitutively active form of glycogen synthase, which results in an abundant storage of muscle glycogen. Muscle contraction was elicited by in situ electrical stimulation of the sciatic nerve. Right gastrocnemii from GSL3-transgenic and wild-type mice were subjected to 30 min of electrical stimulation followed by hindlimb perfusion of both hindlimbs. Thirty minutes of contraction significantly reduced muscle glycogen concentration in wild-type (49%) and transgenic (27%) mice, although transgenic mice retained 168.8 ± 20.5 μmol/g glycogen compared with 17.7 ± 2.6 μmol/g glycogen for wild-type mice. Muscle of transgenic and wild-type mice demonstrated similar pre- (3.6 ± 0.3 and 3.9 ± 0.6 μmol·g-1·h-1 for transgenic and wild-type, respectively) and postcontraction (7.9 ± 0.4 and 7.0 ± 0.4 μmol·g-1·h-1 for transgenic and wild-type, respectively) insulin-stimulated glucose uptakes. However, the [14C]glucose incorporated into glycogen was greater in noncontracted (151%) and postcontracted (157%) transgenic muscle vs. muscle of corresponding wild-type mice. These results indicate that glycogen synthase activity is not rate limiting for insulin-stimulated glucose uptake in skeletal muscle and that the inverse relationship between muscle glycogen and insulin-stimulated glucose uptake is an association, not a cause and effect relationship.

The present study was conducted to determine the effect of chronic administration of the long-acting β2-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats ( fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin · kg−1· min−1) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.

Essential hypertension is associated with an increased incidence of insulin resistance of skeletal muscle glucose transport. The present study determined if celiprolol, an antihypertensive agent with selective beta1-adrenoceptor antagonist and additional beta2-agonistic properties, administered by gavage either acutely (3 hr) or chronically (14 d), had a direct effect on improving glucose tolerance and insulin-stimulated glucose transport activity (using 2-deoxyglucose (2-DG) uptake) in isolated epitrochlearis muscles of the insulin-resistant obese Zucker rat. The effects of a selective beta1-blocker, metoprolol, were also assessed. Acute administration of celiprolol, but not metoprolol, increased insulin-stimulated 2-DG uptake in muscle by 22% (p

We have shown previously that the combination of a long-acting, non-sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor (trandolapril) and the Ca2+ channel blocker verapamil improve insulin-stimulated glucose transport in skeletal muscle of the obese Zucker rat, a model of insulin resistance, hyperinsulinemia, and dyslipidemia. In the present study, we investigated the interactions of chronic treatment (28 days) with verapamil (20 mg/kg) and a short-acting, sulfhydryl-containing ACE inhibitor (captopril, 50 mg/kg) in combination on insulinemia, lipidemia, glucose tolerance, and insulin action on skeletal muscle glucose transport (2-deoxyglucose uptake in epitrochlearis) in lean and obese Zucker rats. In lean animals, verapamil alone and in combination with captopril actually increased (P < .05) plasma insulin, whereas in obese animals, verapamil alone worsened the hyperinsulinemia already present, and this effect was abolished by cotreatment with captopril. Captopril alone or in combination with verapamil reduced plasma free fatty acid (FFA) levels in obese rats, but not in lean rats. Captopril alone reduced the glucose-insulin index in obese animals given an oral glucose load, and this was associated with a significant increase in insulin-mediated muscle glucose transport. The greatest improvement in these responses was elicited in obese animals receiving combined captopril and verapamil treatment, and was associated with increases in muscle GLUT-4 glucose transporter protein and hexokinase and citrate synthase activities. In conclusion, these findings indicate that the short-acting, sulfhydryl-containing ACE inhibitor captopril can elicit beneficial metabolic effects on the hyperinsulinemia, dyslipidemia, glucose intolerance, and insulin resistance of muscle glucose transport of the obese Zucker rat. Moreover, there is a positive interactive effect on these pathophysiological parameters between captopril and verapamil in this animal model of insulin resistance.

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.

The potential role of neurotrophic factors in the decline of glucose transporter (GLUT-4) protein levels and citrate synthase (CS) activity was studied by comparing distally with proximally denervated juvenile rat soleus muscle. Severing of the tibial nerve produced distal (long stump) or proximal (short stump) denervation. GLUT-4 levels and CS activities were measured at 24-h intervals for up to 96 h after denervation. No differences were observed in GLUT-4 or CS activity between soleus muscles left with short or long nerve stumps at any time point. However, within just 24 h, denervation decreased (P < 0.05). GLUT-4 and CS (67.4 +/- 3.3 and 63.4 +/- 1.7% of innervated control values, respectively). Both parameters continued to decline up to 96 h (44.4 +/- 3.1 and 48.7 +/- 4.0%, respectively). There was a significant correlation between the GLUT-4 protein level and CS activity over this 96-h period of denervation (r = 0.653, P < 0.001). A similar response in the 24-h denervated soleus of adult rats was observed. In contrast, 24-h denervation of red gastrocnemius (type IIa fibers) left with a long nerve stump resulted in a prevention of the decline of GLUT-4 and CS seen in red gastrocnemius left with a short nerve stump in both juvenile and adult animals. These results suggest that unlike type IIa muscles, the decline in GLUT-4 level and CS activity in type I soleus muscle after denervation results from a lack of coordinated electrical activity but likely does not involve a neurotrophic agent. These results also support the hypothesis that there is coregulation of decreased expression of GLUT-4 protein and CS activity in this model of reduced neuromuscular activity.

α-Lipoic acid (ALA), a potent biological antioxidant, improves insulin action of skeletal muscle glucose transport and metabolism in both human and animal models of insulin resistance. In order to obtain further insight into the potential intracellular mechanisms for the action of ALA on insulin-stimulated glucose transport in skeletal muscle, we investigated the effects of direct incubation with ALA (2 mM) on 2-deoxyglucose (2-DG) uptake by epitrochlearis muscle from either insulin-sensitive lean (Fa/-) or insulinresistant obese ( fa fa ) Zucker rats. ALA stimulated 2-DG uptake in muscle of lean animals by 76%, whereas ALA stimulated 2-DG uptake by only 48% in muscle from obese animals. The stimulation of 2-DG uptake due to ALA was enhanced 30–55% in the presence of insulin. In contrast, ALA action on 2-DG uptake was not additive with the effects of electrically-stimulated muscle contractions in either insulin-sensitive or insulin-resistant muscle. Wortmannin (1 μM), an inhibitor of phosphotidylinositol-3-kinase, completely inhibited insulin action on 2-DG uptake, but inhibited ALA action by only 25%. Collectively, these results indicate that although a portion of ALA action on glucose transport in mammalian skeletal muscle is mediated via the insulin signal transduction pathway, the majority of the direct effect of ALA on skeletal muscle glucose transport is insulin-independent.

Voluntary wheel running for 4 or 8 wk was used to assess whether a volitional training stimulus would induce adaptations in the oxidative capacity [citrate synthase activity (CS)], glucose phosphorylation capacity [hexokinase activity (HK)], and glucose transporter protein level (GLUT-4) of rat respiratory muscles. Running distances averaged approximately 10–13 km/day over the final 5 wk of training. Peak oxygen consumption by the trained animals was 17% greater (P < 0.05) than by age-matched sedentary control animals after 8 wk. CS, HK, and GLUT-4 in soleus and plantaris muscles all increased because of exercise training. CS increased in the rectus abdominis (+17%), external oblique (+28%), and internal oblique (+17%) but not in the costal or crural diaphragm after 4 wk of training. However, after 8 wk, CS in the costal diaphragm was 39% greater than control but was unchanged in the crural diaphragm. Whereas HK was significantly greater than control in the costal diaphragm (+18%) and rectus abdominis (+54%) after 4 wk, 8 wk of running were required for increases in HK in the external oblique (+17%) and internal oblique (+14%). HK in the crural diaphragm was not significantly altered by the exercise training. GLUT-4 did not change significantly in any of the respiratory muscles studied. These results indicate that significant adaptations in the glucose phosphorylation capacity and oxidative capacity of both inspiratory and expiratory muscles can take place in response to voluntary exercise. However, this same stimulus is not sufficient to cause an adaptive response in GLUT-4 protein level in these respiratory muscles.

The benefits of exercise training in the prevention and treatment of insulin resistance, impaired glucose homeostasis, and NIDDM are strongly supported by current research. The actual mechanisms involved have not been completely identified but occur at the systemic, tissue, and cellular levels. The adaptations that are responsible for the prophylactic effects of exercise training, however, start to subside rapidly once training ceases and are completely lost within 1 to 2 weeks of detraining [4, 17, 37, 68, 161]. Thus, the benefits of exercise training must be renewed on a regular basis. In addition, many of the systemic and cellular adaptations that are responsible for an improved skeletal muscle insulin action occur in only those muscles involved in the training program [4, 28]. Therefore, exercise training programs that consist of various modes of exercise, and which require the use of a large muscle mass, such as swimming, power walking, and strength training, may be the most advantageous for the prevention and treatment of insulin resistance and associated diseases.