The Effect of Standard Compression Adjuvant with a Tailored Exercise Training Program on Health-Related Quality of Life Outcomes in Treating Adults with Venous Leg Ulcer: A Randomized Controlled Trial.

Exercise training adjuvant to standard compression is considered to improve calf muscle pump dysfunction in venous leg ulcer (VLU) and subsequent healing. The objectives of this trial were to assess the effectiveness of a tailored exercise training intervention in addition to standard compression therapy on health-related quality of life and anticipating wound healing. Twenty-four VLU participants were recruited and randomly divided into 2 groups. The control group was prescribed conventional compression, and the intervention group received compression plus progressive tailored exercise training. The 14-item chronic venous disease quality of life questionnaire (CIVIQ-14) was used to assess improvement after treatment over time (0, 6, and 12 weeks). Intervention and control groups achieved wound closure for 11 (92%) and 7 (58%) patients. After adjusting for age, sex, and wound size at baseline, the exercise intervention group had 2 times the probability of complete wound healing in 12 weeks than those in the control group (risk ratio = 1.98, 95% CI= 1.01-3.72, P = .047). The primary outcome was the difference in CIVIQ-14 score in 3 dimensions and global index score per visit. The outcomes were evaluated by independent assessors. Demographic, comorbidities, and wound assessments were collected on enrollment. The overall adherence to exercise protocol was 71%. After adjusting age, sex, size of VLU, and CIVIQ score at baseline, the participants in the intervention group had the average global index scores and psychological scores increase at week 12 than those in the control group (21.2; 95% CI= 7.1-35.2, P = .005, and 13.5; 95% CI = 2.9-24.2, P = .044, respectively). Both groups showed similar improvement in the mean change in physical and pain scores within-group over time. Patients with combined conventional compression therapy with exercise training appeared to have a higher quality of life score in psychological and global scores than those with compression therapy alone.

Effects of physical activity on the severity of illness and mortality in COVID-19 patients: A systematic review and meta-analysis.

Purpose: This systematic review and meta-analysis investigated the association between Physical activity (PA) before Coronavirus Disease 2019 (COVID-19) infection and the severity of illness and mortality in COVID-19 patients. Methods: A comprehensive search was undertaken to identify retrospective and nonrandomized controlled trial studies comparing the severity and mortality of COVID-19 infection among COVID-19 patients who had previously reported their participation in PA with those who had not. The databases searched were PubMed, Cochrane Library, Scopus, Science Direct, EMBASE, OPENGREY.EU, and ClinicalTrials.gov. The risk of bias was assessed using the Newcastle-Ottawa Scale. A random-effects model was used for determining pairwise meta-analyses. The protocol was registered with PROSPERO (CRD42021262548). Results: Eighteen studies met the inclusion criteria (5 cross-sectional, 12 cohort, and 1 case-control studies). All 1 618 680 subjects were adults. PA significantly decreased the risk of death in COVID-19 patients (odds ratio [OR] 0.34; 95% confidence interval [CI], 0.19-0.62; p < 0.001) and the risk of severe outcomes (OR 0.60; 95% CI, 0.48-0.76; p < 0.001). Subgroup analysis showed that PA for ≥150 min/wk at a moderate intensity or ≥75 min/wk at a vigorous intensity reduced the risks of severity and mortality. Vigorous PA reduced mortality risk, whereas moderate to vigorous PA reduced the risks of severity and mortality. Conclusion: PA before infection might reduce severity and mortality in COVID-19 patients, especially PA ≥ 150 min/wk of moderate activity or ≥75 min/wk of vigorous activity. However, careful interpretations should be considered due to the difference in PA patterns and severity definitions among included studies. This finding implies that engaging in regular PA, even in different patterns, has beneficial effects on the severity and mortality of COVID-19 patients.

Upper limb exercise for arteriovenous fistula maturation in people requiring permanent haemodialysis access.

BACKGROUND: The failure of arteriovenous fistulas (AVF) to mature is a major problem in patients with kidney failure who require haemodialysis (HD). Preoperative planning is an important factor in increasing functional AVF. Upper limb exercise has been recommended to gain AVF maturation. Studies of pre- and post-operative upper limb exercises in patients with kidney failure patients have been reported; however, the optimal program for this population is unknown due to inconsistent results among these programs. OBJECTIVES: We aimed to determine if upper limb exercise would be beneficial for AVF maturation (prior to and post AVF creation) in patients with kidney failure and to improve AVF outcomes. This review also aimed to identify adverse events related to upper limb exercise. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 15 March 2022 through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov, and other resources (e.g. reference list, contacting relevant individuals, and grey literature). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs, comparing upper limb exercise training programs with no intervention or other control programs before or after AVF creation in patients with kidney failure. Outcome measures included time to mature, ultrasound and clinical maturation, venous diameter, blood flow in the inflow artery, dialysis efficacy indicator, vascular access function (functional AVF), vascular access complications, and adverse events. DATA COLLECTION AND ANALYSIS: Study selection and data extraction were taken by four independent authors. Bias assessment and quality assessment were undertaken independently by two authors. The effect estimate was analysed using risk ratio (RR) with 95% confidence intervals (CI) for dichotomous data, or mean difference (MD) or standardised mean difference (SMD) for continuous data. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Nine studies (579 participants) were included, and seven studies (519 participants) conducting post-operative exercise training could be meta-analysed. Three comparisons were undertaken: (i) isotonic exercise training versus no intervention; (ii) isometric versus isotonic exercise training; and (iii) isotonic (high volume) versus isotonic exercise training (low volume). Due to insufficient data, we could not analyse pre-operative exercise training. Overall, the risk of bias was low for selection and reporting bias, high for performance and attrition bias, and unclear for detection bias. Compared to no intervention, isotonic exercise training may make little or no difference to ultrasound maturation (2 studies, 263 participants: RR 1.09, 95% CI 0.94 to 1.25; I² = 0%; low certainty evidence), but may improve clinical maturation (2 studies, 263 participants: RR 1.14, 95% CI 1.02 to 1.27; I² = 0%; low certainty evidence). Compared to isotonic exercise training, isometric exercise training may improve both ultrasound maturation (3 studies, 160 participants: RR 1.56, 95% CI 1.21 to 2.00; I² = 22%; low certainty evidence) and clinical maturation (3 studies, 160 participants: RR 1.80, 95% CI 1.18 to 2.76; I² = 53%; low certainty evidence). Venous diameter (3 studies, 160 participants: MD 0.84 mm, 95% CI 0.45 to 1.23; I² = 0%; low certainty evidence) and blood flow in the inflow artery (3 studies, 160 participants: MD 140.62 mL/min, 95% CI 38.72 to 242.52; I² = 0%; low certainty evidence) may be greater with isometric exercise training. It is uncertain whether isometric exercise training reduces vascular access complications (2 studies, 110 participants: RR 2.54, 95% CI 0.38 to 17.08; I² = 47%; very low certainty evidence). It is uncertain whether high volume isotonic exercise training improves venous diameter (2 studies, 93 participants: MD 0.19 mm, 95% CI -0.75 to 1.13; I² = 34%; very low certainty evidence) or blood flow in the inflow artery (1 study, 15 participants: MD -287.70 mL/min, 95% CI -625.99 to 60.59; very low certainty evidence) compared to low volume isotonic exercise training. None of the included studies reported time to mature, dialysis efficacy indicator, vascular access function, or adverse events. AUTHORS' CONCLUSIONS: Our findings suggest that the current research evidence examining upper limb exercise programs is of low quality, attributable to variability in the type of interventions used and the overall low number of studies and participants.

Agreement between physical and ultrasound examination for arteriovenous fistula maturation diagnostics in Thai hemodialysis patients.

INTRODUCTION: Physical examination (PE) is used to determine if arteriovenous fistula (AVF) meets criteria for first hemodialysis (HD) cannulation in chronic kidney disease (CKD) with HD patients. Three ultrasound (US) based criteria are adopted to investigate maturation: (i) Rule of Six: blood flow ⩾600 milliliters per minute (mL/min), vein diameter ⩾6 millimeters (mm), vein depth ⩽6 mm); (ii) Rule of Five: blood flow ⩾500 mL/min, vein diameter ⩾5 mm, vein depth ⩽6 mm; and (iii) Rule of Four: blood flow ⩾500 mL/min, vein diameter ⩾4 mm, vein depth ⩽6 mm. In Thai, no study determined optimal US criteria for predicting AVF maturation measured by PE before first cannulation. This study examined the significance of these US criteria on the physical AVF maturation in Thai. METHODS: Fifty CKD patients, operated brachiocephalic AVF, were enrolled and examined on the operative day and 6 weeks afterwards. PE was evaluated by an experienced vascular surgeon, and US measurements were obtained by an experienced US technologist. Matching mature number between US criteria and PE was computed using McNemar test. Agreement between US criteria and PE was measured using Kappa. Mature and immature discrimination were evaluated by the Receiver Operator Characteristics (ROC) curve and Youden index. RESULTS: Rule of Six and Rule of Five had higher non-mature matching number than Rule of Four (p < 0.001 both). Regarding Kappa statistics, Rule of Six and Rule of Five agreed with the PE (p < 0.01 both). The ROC curve of Rule of Six and Rule of Five were 0.75 and 0.74, respectively (p <0.01 both). Youden index (maturity and immaturity discriminating performance) of both rules was 0.5 and 0.47, respectively. CONCLUSION: Rule of Six and Rule of Five agreed with the PE, with the highest performance of the Rule of Six to predict first successful cannulation in Thai.

A randomized controlled trial of the effect of postoperative hand exercise training on arteriovenous fistula maturation in patients with chronic kidney disease.

OBJECTIVE: Immature arteriovenous fistula (AVF) is a critical problem in patients with chronic kidney disease (CKD) after creation. Exercise with 30% maximum voluntary contraction (MVC) encourages vascular functions in other populations. It is unknown which exercise type is superior on maturation in the CKD population. We compare effects of isometric (ISM) and isotonic (IST) hand exercise training, both at 30% MVC, on AVF maturation and grip strength in patients with CKD. METHODS: Fifty patients with CKD were randomized into the ISM program or IST program (25 per group). Each group performed exercise program at intensity of 30% MVC every day for 10 weeks. Cephalic vein (CV) and brachial artery diameters, brachial blood flows, and grip strength were measured at weeks 0, 2, 6, and 10 of the program. The number of patients meeting clinical and ultrasound maturation were evaluated at weeks 2, 6, and 10. RESULTS: At weeks 6 and 10 of the programs, the ISM group had greater CV diameters (week 6, 7.1 ± 1.2 vs 6.2 ± 1.0 mm; week 10, 7.1 ± 1.0 vs 6.2 ± 1.1 mm) than the IST group. Compared with the IST group, the ISM group had a higher number of patients meeting ultrasound maturation at weeks 2 (IST/ISM, 8/2), 6 (IST/ISM, 16/8), and 10 (IST/ISM, 21/12), and clinical maturation at week 10 (IST/ISM, 25/18). No adverse events were observed throughout the study. CONCLUSIONS: At 30% MVC, ISM is more effective at promoting increases in CV diameter and maturation than IST. Both exercise types are feasible and safe for patients with CKD after AVF creation.

Effectiveness of combined conventional treatment with a tailored exercise training program on wound healing in patients with venous leg ulcer: A randomized controlled trial.

INTRODUCTION: Venous leg ulcer (VLU) is a therapeutic challenge. The mainstay of care is compression therapy and wound care. Exercise is also recommended for facilitating wound healing. This study aimed to determine whether adding tailored exercise training to conventional treatment would be superior on wound healing, ankle mobility, calf muscle function, and functional ability compared to those with the conventional treatment alone. METHODS: A randomized controlled trial, single-blinded was conducted. VLU patients were randomized to the conventional treatment plus tailored exercise training (intervention group) and the conventional treatment alone (control group) (12/group). The conventional treatment contained foam dressing and short-stretch bandage, while the tailored exercise training consisted of stretching, resistive, and aerobic exercise sessions (3-day/week, for 12-week). Primary outcomes included healing rate and wound size parameters. Secondary outcomes were ankle range of motion (ROM), calf circumference, calf muscle endurance and strength, and functional ability. All outcomes were assessed at baseline, 6-, and 12-week intervention. RESULTS: The intervention group had a higher trend of healing rate after 12-week training than those in the control group, but this trend was not significantly different (92% versus 58%, p = 0.06). After training, the intervention group had significantly decreased wound size. The intervention group had significantly higher ankle ROM and dorsiflexor muscle strength after 6- and 12-week training than those in the control group. CONCLUSION: Adding the tailored exercise training incorporated with the conventional treatment may provide a greater tendency on wound healing and have the potential to improve ankle mobility than the conventional treatment alone. TRIAL REGISTRATION NUMBER: TCTR20170405002.

A systematic review with meta-analysis of the effects of arm exercise training programs on arteriovenous fistula maturation among people with chronic kidney disease.

This study systematically reviewed the evidence and quantified the effectiveness of arm exercise training programs, before and after arteriovenous fistula (AVF) operation on AVF maturation, among people with chronic kidney disease. Scopus, CINAHL, PubMed, Science Direct, Cochrane Library, and reference lists were searched. Experimental studies that investigated the effect of arm exercise before and post-operation on AVF maturations were included. Screened and extracted data were administered by two independent reviewers. Seven studies with preoperative exercise were included in a systematic review, while five studies were analyzed in a meta-analysis. Preoperative exercise significantly increased vessel diameters and grip strength after training. Postoperative exercise had higher clinical and ultrasonographic (US) maturation rates and arterial blood flow than controls (risk ratio [RR], 1.44; 95% confidence interval [CI], 1.23-1.69; RR, 1.27; 95% CI, 1.02-1.57; weight mean difference, 166.03; 95% CI, 27.58-304.49, respectively). Subgroup analysis showed that isometric exercise training promoted clinical and US maturations (RR, 2.40; 95% CI, 1.51-3.82; RR, 1.53; 95% CI, 1.02-2.30, respectively), whereas isotonic exercise promoted clinical maturation (RR, 1.18; 95% CI, 1.03-1.34). Grip strength had a greater trend in the intervention group than controls (standardized mean difference, 0.59; 95% CI, -0.06 to 1.25). In conclusion, arm exercise training improves vascular function, which is essential before surgery. The meta-analysis suggested that arm exercise training promotes AVF clinical and US maturations after surgery. Subgroup analysis suggested that isometric-arm exercise training may have a larger effect on AVF maturation. However, more studies are needed to draw a solid conclusion.

Effects of Inspiratory Muscle Training and Early Mobilization on Weaning of Mechanical Ventilation: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To compare the effectiveness and rank order of physical therapy interventions, including conventional physical therapy (CPT), inspiratory muscle training (IMT), and early mobilization (EM) on mechanical ventilation (MV) duration and weaning duration. DATA SOURCES: PubMed, The Cochrane Library, Scopus, and CINAHL complete electronic databases were searched through August 2019. STUDY SELECTION: Randomized controlled trials (RCTs) investigating the effect of IMT, EM, or CPT on MV duration and the weaning duration in patients with MV were included. Studies that were determined to meet the eligibility criteria by 2 independent authors were included. A total of 6498 relevant studies were identified in the search, and 18 RCTs (934 participants) were included in the final analysis. DATA EXTRACTION: Data were extracted independently by 2 authors and assessed the study quality by the Cochrane risk-of-bias tool. The primary outcomes were MV duration and weaning duration. DATA SYNTHESIS: Various interventions of physical therapy were identified in the eligible studies, including IMT, IMT+CPT, EM, EM+CPT, and CPT. The data analysis demonstrated that compared with CPT, IMT+CPT significantly reduced the weaning duration (mean difference; 95% confidence interval) (-2.60; -4.76 to -0.45) and EM significantly reduced the MV duration (-2.01; -3.81 to -0.22). IMT+CPT and EM had the highest effectiveness in reducing the weaning duration and MV duration, respectively. CONCLUSION: IMT or EM should be recommended for improving the weaning outcomes in mechanically ventilated patients. However, an interpretation with caution is required due to the heterogeneity.

Rosmarinic acid improves hypertension and skeletal muscle glucose transport in angiotensin II-treated rats.

BACKGROUND: Rosmarinic acid (RA) is a natural pure compound from herbs belonging to the Lamiaceae family, such as rosemary, sage, basil, and mint. The antioxidant, angiotensin-converting enzyme inhibitory, and vasodilatory effects of RA have been revealed. Angiotensin II (ANG II) is a potent agent that generates hypertension and oxidative stress. Hypertension and skeletal muscle insulin resistance are strongly related. The aim of this study was to evaluate the effects of acute and chronic RA treatment on blood pressure and skeletal muscle glucose transport in ANG II-induced hypertensive rats. METHODS: Eight-week-old male Sprague Dawley rats were separated into SHAM and ANG II-infused (250 ng/kg/min) groups. ANG II rats were treated with or without acute or chronic RA at 10, 20, or 40 mg/kg. At the end of the experiment, body weight, liver and heart weights, oral glucose tolerance, skeletal muscle glucose transport activity, and signaling proteins were evaluated. RESULTS: Both acute and chronic RA treatment decreased systolic, diastolic, and mean arterial blood pressure. Only acute RA at 40 mg/kg resulted in a reduction of fasting plasma glucose levels and an induction of skeletal muscle glucose transport activity. These effects might involve increased ERK activity in skeletal muscle. Meanwhile, chronic RA treatment with 10, 20, and 40 mg/kg prevented ANG II-induced hyperglycemia. CONCLUSIONS: Both acute and chronic RA treatment attenuated ANG II-induced cardiometabolic abnormalities in rats. Therefore, RA would be an alternative strategy for improving skeletal muscle glucose transport and protecting against ANG II-induced hypertension and hyperglycemia.

Current prevalence of intestinal parasitic infections and their impact on hematological and nutritional status among Karen hill tribe children in Omkoi District, Chiang Mai Province, Thailand.

Intestinal parasitic infection represents a substantial problem for children living in rural or limited resources areas and significantly relates to anemia and nutritional status. This study aimed to determine the current prevalence of intestinal parasitic infections among school-age children of Karen hill tribe population in Omkoi District, Chiang Mai Province, Thailand and assess the impact of intestinal parasitic infection on hematological and nutritional status in those children. A total of 375 Karen hill tribe children, 6-14 years of age, in Omkoi District were randomly selected to participate in this study. Stool samples were collected and examined for intestinal parasitic infection through formalin-ether concentration method. Blood samples were collected for hematological and iron analysis. The overall prevalence of intestinal parasitic infection was 47.7% (179/375), with single infections (29.3%) and polyparatism (18.4%). The most common pathogenic parasite was Trichuris trichiura (16.0%), followed by Ascaris lumbricoides (13%) and Giardia lamblia (3.5%). In addition, non-pathogenic amoeba, Entamoeba coli was observed with a high prevalence rate (31.2%). Anemia and eosinophilia prevalence were 6.40% (24/375) and 74.7% (280/375), respectively. Eosinophilia was significantly more prevalent in children with intestinal parasitic infection compared to uninfected children. Among 249 children, 13.7% were iron deficiency, 9.6% were thalassemia and hemoglobinophathy and 8% were G-6-PD deficiency. A high prevalence infection rate was significantly associated with eosinophilia, but independently related to anemia and iron deficiency. Intestinal parasitic infections are endemic in school-age children of Karen hill tribe population in Omkoi District. These data highlight the need for an integrated approach to control transmission of intestinal parasites and improve the health and sanitation status of Karen hill tribe children in Thailand.

Angiotensin II induces differential insulin action in rat skeletal muscle.

Angiotensin II (ANGII) is reportedly involved in the development of skeletal muscle insulin resistance. The present investigation evaluated the effects of two ANGII doses on the phenotypic characteristics of insulin resistance syndrome and insulin action and signaling in rat skeletal muscle. Male Sprague-Dawley rats were infused with either saline (SHAM) or ANGII at a commonly used pressor dose (100 ng/kg/min; ANGII-100) or a higher pressor dose (500 ng/kg/min; ANGII-500) via osmotic minipumps for 14 days. We demonstrated that ANGII-100-infused rats exhibited the phenotypic features of non-obese insulin resistance syndrome, including hypertension, impaired glucose tolerance and insulin resistance of glucose uptake in the soleus muscle, whereas ANGII-500-treated rats exhibited diabetes-like symptoms, such as post-prandial hyperglycemia, impaired insulin secretion and hypertriglyceridemia. At the cellular level, insulin-stimulated glucose uptake in the soleus muscle of the ANGII-100 group was 33% lower (P < 0.05) than that in the SHAM group and was associated with increased insulin-stimulated IRS-1 Ser307 and decreased Akt Ser473 and AS160 Thr642 phosphorylation and GLUT-4 expression. However, ANGII-500 infusion did not induce skeletal muscle insulin resistance or impair insulin signaling elements as initially anticipated. Moreover, we found that insulin-stimulated glucose uptake in the ANGII-500 group was accompanied by the enhanced expression of ACE2 and MasR proteins, which are the key elements in the non-classical pathway of the renin-angiotensin system. Collectively, this study demonstrates for the first time that chronic infusion with these two pressor doses of ANGII induced differential metabolic responses at both the systemic and skeletal muscle levels.

Excessive fluoride consumption increases haematological alteration in subjects with iron deficiency, thalassaemia, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Excessive fluoride consumption leads to accelerated red blood cell death and anaemia. Whether that increases the haematological alteration in subjects with haematological disorders (iron deficiency, thalassaemia, and G-6-PD deficiency) is still unclear. The fluoride in serum and urine and haematological parameters of students at Mae Tuen School (fluoride endemic area) were analysed and compared to those of students at Baan Yang Poa and Baan Mai Schools (control areas). Iron deficiency, thalassaemia, and G-6-PD deficiency were also diagnosed in these students. The students at Mae Tuen School had significantly (P < 0.001) higher levels of mean fluoride in the serum and urine than those in control areas. In both control and fluoride endemic areas, students with haematological disorders had significantly lower levels of Hb, Hct, MCV, MCH, and MCHC than those without haematological disorders. Moreover, the lowest levels of Hb, MCH, and MCHC were observed in the students with haematological disorders who live in the fluoride endemic area. Thus, the excessive fluoride consumption increased haematological alteration in subjects with iron deficiency, thalassaemia, and G-6-PD deficiency and that may increase the risk of anaemia in these subjects.

Effects of manual percussion during postural drainage on lung volumes and metabolic status in healthy subjects.

OBJECTIVE: The aim of this study was to evaluate the influence of manual percussion during three different positions of postural drainage (PD) on lung volumes and metabolic status. METHODS: Twenty six healthy volunteers (13 women and 13 men), with a mean age of 20.15 ± 1.17 years, participated. They were randomized into three standard positions of PD (upper, middle, or lower lobes) and given manual percussion at a frequency of 240 times per minute for 5 min. Lung volumes, including tidal volume (TV), inspiratory reserve volume (IRV), expiratory reserve volume (ERV) and vital capacity (VC); and metabolic status, such as oxygen consumption (VO2), carbon dioxide (VCO2), respiratory rate (RR), and minute ventilation (VE) were evaluated. RESULTS: The lung volumes showed no statistical difference in VC or IRV from percussion during PD in all positions, except for the lower lobe, where increased TV and decreased ERV were found when compared to PD alone. Furthermore, percussion during PD of the upper and middle lobes did not affect RR or VE, when compared to PD alone. In addition, percussion during PD of the middle and lower lobes increased VO2 and VCO2 significantly, when compared to PD alone, but it did not influence PD of the upper lobe. CONCLUSION: This study indicated that up to 5 min of manual percussion on PD of the upper and middle lobes is safe mostly for lung volumes, RR, and VE, but it should be given with care in PD conditions of the lower lobe.

The lipid peroxidation end-product and oxidant 4-hydroxynonenal induces insulin resistance in rat slow-twitch skeletal muscle.

CONTEXT: The lipid peroxidation end-product and oxidant 4-hydroxynonenal (4-HNE) impairs cell function. However, the impact of 4-HNE on the glucose transport system in mammalian slow-twitch skeletal muscle is not known. OBJECTIVE: We assessed the effects of 4-HNE on insulin signalling and glucose transport activity in slow-twitch muscle by incubating soleus strips from lean Zucker rats with 4-HNE (50 µM) in the absence or presence of insulin (5 mU/ml) for up to 6 hr. RESULTS: Insulin-stimulated glucose transport activity was significantly (p<0.05) decreased by 4-HNE at 2 hr. AS160 Thr(642) phosphorylation was decreased at 2 hr, whereas Akt Ser473 phosphorylation and IRS-1 protein expression were not substantially changed until 4 hr. IRS-2 protein expression was slightly decreased only at 6 hr. CONCLUSIONS: The lipid peroxidation end-product and oxidant 4-HNE induces insulin resistance of glucose transport activity in rat slow-twitch skeletal muscle, initially associated with impaired phosphorylation of AS160.

The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle.

The canonical renin-angiotensin system (RAS) involves the initial action of renin to cleave angiotensinogen to angiotensin I (ANG I), which is then converted to ANG II by the angiotensin converting enzyme (ACE). ANG II plays a critical role in numerous physiological functions, and RAS overactivity underlies many conditions of cardiovascular dysregulation. In addition, ANG II, by acting on both endothelial and myocellular AT1 receptors, can induce insulin resistance by increasing cellular oxidative stress, leading to impaired insulin signaling and insulin-stimulated glucose transport activity. This insulin resistance associated with RAS overactivity, when coupled with progressive ß-cell dysfunction, eventually leads to the development of type 2 diabetes. Interventions that target RAS overactivity, including ACE inhibitors, ANG II receptor blockers, and, most recently, renin inhibitors, are effective both in reducing hypertension and in improving whole-body and skeletal muscle insulin action, due at least in part to enhanced Akt-dependent insulin signaling and insulin-dependent glucose transport activity. ANG-(1-7), which is produced from ANG II by the action of ACE2 and acts via Mas receptors, can counterbalance the deleterious actions of the ACE/ANG II/AT1 receptor axis on the insulin-dependent glucose transport system in skeletal muscle. This beneficial effect of the ACE2/ANG-(1-7)/Mas receptor axis appears to depend on the activation of Akt. Collectively, these findings underscore the importance of RAS overactivity in the multifactorial etiology of insulin resistance in skeletal muscle, and provide support for interventions that target the RAS to ameliorate both cardiovascular dysfunctions and insulin resistance in skeletal muscle tissue.

Obesity-related alterations in cardiac lipid profile and nondipping blood pressure pattern during transition to diastolic dysfunction in male db/db mice.

Obesity and a nondipping circadian blood pressure (BP) pattern are associated with diastolic dysfunction. Ectopic lipid accumulation is increasingly recognized as an important metabolic abnormality contributing to diastolic dysfunction. However, little is known about the contribution of different lipids and the composition of lipid analytes to diastolic dysfunction. We have performed functional and structural studies and analyzed cardiac lipid profile at two time points during progression to diastolic dysfunction in a genetic model of obesity. Serial cardiac magnetic resonance imaging and telemetric measures of BP between 12 and 15 wk of age in obese male db/db mice indicated a nondipping circadian BP pattern and normal diastolic function at 12 wk that progressed to a deteriorating nondipping pattern and onset of diastolic dysfunction at 15 wk of age. Lipidomic analysis demonstrated elevated fatty acids and ceramides in db/db at 12 wk, but their levels were decreased at 15 wk, and this was accompanied by persistent mitochondrial ultrastructural abnormalities in concert with evidence of increased fatty acid oxidation and enhanced production of reactive oxygen species. Triacylglyceride and diacylglyceride levels were elevated at both 12 and 15 wk, but their composition changed to consist of more saturated and less unsaturated fatty acyl at 15 wk. An increase in the lipid droplets was apparent at both time points, and this was associated with increases in phosphatidycholine. In conclusion, a distinct pattern of myocardial lipid remodeling, accompanied by oxidative stress, is associated with the onset of diastolic dysfunction in obese, insulin-resistant db/db mice.

ANG-(1-7) reduces ANG II-induced insulin resistance by enhancing Akt phosphorylation via a Mas receptor-dependent mechanism in rat skeletal muscle.

The nonapeptide angiotensin II (ANG II) induces vasoconstriction via the ANG II type I receptor, while its splice product ANG-(1-7) elicits an antihypertensive effect via the Mas receptor. Although a critical role of ANG II in the etiology of skeletal muscle insulin resistance is well documented, the role of the ANG-(1-7)/Mas receptor axis in this context is poorly understood. Therefore, we determined whether ANG-(1-7) is effective in ameliorating the negative effects of ANG II on insulin-stimulated insulin signaling and glucose transport activity in isolated soleus muscle from normotensive lean Zucker rats. ANG II alone (500 nM for 2 h) decreased insulin-stimulated glucose transport activity by 45% (P < 0.05). In the presence of 500-1000 nM ANG-(1-7), insulin-stimulated glucose transport activity in muscle exposed to ANG II improved by ~30% (P < 0.05). Moreover, ANG-(1-7) treatment increased Akt Ser(473) phosphorylation (47%, P < 0.05) without an effect on glycogen synthase kinase-3ß Ser(9) phosphorylation. The dependence of ANG-(1-7) action on the Mas receptor was assessed using A779 peptide, a selective Mas receptor antagonist. The positive effects of ANG-(1-7) on insulin-stimulated glucose transport activity and Akt Ser(473) phosphorylation in soleus muscle were completely prevented in presence of 1000 nM A779. In conclusion, the present study demonstrates that ANG-(1-7), via a Mas receptor-dependent mechanism, can ameliorate the inhibitory effect of ANG II on glucose transport activity in mammalian skeletal muscle, associated with enhanced Akt phosphorylation. These results provide further evidence supporting the targeting of the renin-angiotensin system for interventions designed to reduce insulin resistance in skeletal muscle tissue.

Contribution of the serine kinase c-Jun N-terminal kinase (JNK) to oxidant-induced insulin resistance in isolated rat skeletal muscle.

The specific and direct contribution of the stress-activated serine kinase c-Jun N-terminal kinase (JNK) in the development of oxidative stress-induced insulin resistance of the glucose transport system in mammalian skeletal muscle is not fully understood. We assessed the specific role of JNK in the development of insulin resistance caused by in vitro exposure of rat soleus muscle to low levels (30-40 µM) of the oxidant hydrogen peroxide (H(2)O(2)) for up to 6 h. Oxidant exposure caused significant (p < 0.05) decreases in insulin-stimulated glucose transport activity (up to 42%) and Akt Ser(473) phosphorylation (up to 67%), and increased (up to 74%) phosphorylation (Thr(183)/Tyr(185)) of JNK1 and JNK2/3 isoforms. Importantly, insulin-stimulated glucose transport activity in the presence of H(2)O(2) was moderately improved with the selective JNK inhibitor SP600125. These results indicate that activation of the serine kinase JNK contributes, at least in part, to oxidative stress-induced insulin resistance in isolated mammalian skeletal muscle.

Improvements of insulin resistance in ovariectomized rats by a novel phytoestrogen from Curcuma comosa Roxb.

BACKGROUND: Curcuma comosa Roxb. (C. comosa) is an indigenous medicinal herb that has been used in Thailand as a dietary supplement to relieve postmenopausal symptoms. Recently, a novel phytoestrogen, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol or compound 049, has been isolated and no study thus far has investigated the role of C. comosa in preventing metabolic alterations occurring in estrogen-deprived state. The present study investigated the long-term effects (12 weeks) of C. comosa hexane extract and compound 049 on insulin resistance in prolonged estrogen-deprived rats. METHODS: Female Sprague-Dawley rats were ovariectomized (OVX) and treated with C. comosa hexane extract (125 mg, 250 mg, or 500 mg/kg body weight (BW)) and compound 049 (50 mg/kg BW) intraperitoneally three times per week for 12 weeks. Body weight, food intake, visceral fat weight, uterine weight, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity, and GLUT-4 protein expression were determined. RESULTS: Prolonged ovariectomy resulted in dyslipidemia, impaired glucose tolerance and insulin-stimulated skeletal muscle glucose transport, as compared to SHAM. Treatment with C. comosa hexane extract and compound 049, three times per week for 12 weeks, markedly reduced serum total cholesterol and low-density lipoprotein levels, improved insulin sensitivity and partially restored uterine weights in ovariectomized rats. In addition, compound 049 or high doses of C. comosa hexane extract enhanced insulin-mediated glucose uptake in skeletal muscle and increased muscle GLUT-4 protein levels. CONCLUSIONS: Treatment with C. comosa and its diarylheptanoid derivative improved glucose and lipid metabolism in estrogen-deprived rats, supporting the traditional use of this natural phytoestrogen as a strategy for relieving insulin resistance and its related metabolic defects in postmenopausal women.