Effects of Cumulative Head Impact Exposure in Adolescent Male Contact and Collision Sport Student Athletes.

OBJECTIVE: This prospective cohort study aimed to investigate the association between head impact exposure (HIE) and neuropsychological sequelae in high school football and ice hockey players over 1 year. SETTING: Community sample. PARTICIPANTS: A cohort of 52 adolescent American football and ice hockey players were enrolled in the study, with a final study sample of 35 included in analyses. DESIGN: The study followed a prospective cohort design, with participants undergoing neuropsychological screening and accelerometer-based measurement of HIE over 1 season. MAIN MEASURES: Changes in cognition, emotions, behavior, and reported symptoms were assessed using standardized neuropsychological tests and self-reported questionnaires. RESULTS: Cumulative HIE was not consistently associated with changes in cognition, emotions, behavior, or reported symptoms. However, it was linked to an isolated measure of processing speed, showing inconsistent results based on the type of HIE. History of previous concussion was associated with worsened verbal memory recognition (ImPACT Verbal Memory) but not on a more robust measure of verbal memory (California Verbal Learning Test [CVLT]). Reported attention-deficit/hyperactivity disorder history predicted improved neurocognitive change scores. No associations were found between reported history of anxiety/depression or headaches/migraines and neuropsychological change scores. CONCLUSION: Overall, our findings do not support the hypothesis that greater HIE is associated with an increase in neuropsychological sequelae over time in adolescent football and ice hockey players. The results align with the existing literature, indicating that HIE over 1 season of youth sports is not consistently associated with significant neuropsychological changes. However, the study is limited by a small sample size, attrition over time, and the absence of performance validity testing for neurocognitive measures. Future studies with larger and more diverse samples, longer follow-up, and integration of advanced imaging and biomarkers are needed to comprehensively understand the relationship between HIE and neurobehavioral outcomes. Findings can inform guidelines for safe youth participation in contact sports while promoting the associated health and psychosocial benefits.

Identification and Management of Thyroid Dysfunction Using At-Home Sample Collection and Telehealth Services: Retrospective Analysis of Real-World Data.

BACKGROUND: Programs aimed at modernizing thyroid care by pairing at-home sample collection methods with telehealth options may serve an important and emerging role in thyroid care. OBJECTIVE: The primary objective of this analysis was to evaluate telehealth use, demographics, and clinical characteristics of a cohort of consumer-initiated at-home laboratory thyroid test users who were also offered the option of follow-up telehealth consultations. METHODS: This was a retrospective analysis of real-world data from a deidentified consumer database of home-collected, mail-in thyroid tests used from March to May 2021 (N=8152). The mean age was 38.6 (range 18-85) years, and 86.6% (n=7061) of individuals identified as female. RESULTS: In total, 7% (n=587) of test takers fell into a thyroid dysfunction category (overt hypothyroidism: n=75, 0.9%; subclinical hypothyroidism: n=236, 2.9%; overt hyperthyroidism: n=5, 0.1%; and subclinical hyperthyroidism: n=271, 3.3%). Overall, 12% (n=984) of the overall sample opted into a telehealth consultation, with 91.8% (n=903) receiving a nontreatment telehealth consultation and 8.2% (n=81) receiving a treatment telemedicine consultation. Furthermore, 16% (n=96) of individuals with overt or subclinical thyroid dysfunction engaged in telehealth consultations. The majority of treatment consultations (59.3%, n=48) were conducted with people reporting a history of thyroid issues, with 55.6% (n=45) of people indicating wanting to discuss their current thyroid medication and 48% (n=39) receiving a prescription medication. CONCLUSIONS: The combination of at-home sample collection and telehealth is an innovative model for screening thyroid disorders, monitoring thyroid function, and increasing access to care, which can be implemented at a large scale and across a wide range of age groups.

Real-world evidence: Telemedicine for complicated cases of urinary tract infection.

Telemedicine programs for the treatment of urinary tract infections (UTIs) offer an opportunity to reduce burdens on patients and providers. However, these programs are typically restricted to patients with uncomplicated UTIs. This real-world analysis evaluated treatment and resolution rates in a large-scale, national UTI telemedicine program inclusive of patients with uncomplicated and complicated UTIs. We conducted a retrospective analysis of data obtained from a commercially available telemedicine program for the treatment of UTIs among adult women in the US between 2017 and 2021 (n = 51,474). The primary outcomes were the number of women who presented with symptoms of uncomplicated UTI, complicated UTI, and vaginal infection; prescription use and antibiotic type; symptom resolution within seven days after appointment; and treatment failure or relapse. Most patients reported frequent urination (94.4%), urgency (94.5%), and dysuria (97.6%). Those with uncomplicated UTI symptoms represented the majority of patients (61.6%); however, a substantial number of patients (36.5%) also reported at least one symptom associated with a complicated UTI. One-fifth of patients (19.2%) reported at least one co-occurring symptom of vaginal infection or sexually transmitted infection. Across all treated patients, 94.0% received recommended antibiotics according to the clinical protocol. Of the treated patients who provided follow-up data (n = 3,521), 89.7% reported seven-day symptom resolution. Symptom resolution rates were similar between patients with uncomplicated UTI symptoms (90.8%) and complicated UTI symptoms (87.9%), and symptom resolution among all treated patients (89.7%) was similar to reports for in-person standard of care. These findings suggest that large-scale telemedicine programs for the treatment of UTIs can be effective in the treatment of complicated UTIs.

At-home sample collection is an effective strategy for diagnosis and management of symptomatic and asymptomatic SARS-CoV-2 carriers.

BACKGROUND: Diagnostic testing accessibility and asymptomatic transmission of SARS-CoV-2 present major challenges for curbing and preventing community prevalence of COVID-19. At-home sample collection for molecular testing provides a convenient and effective solution for disease containment and prevention. METHODS: This is a retrospective, cross-sectional, case-control study. Our primary aim was to determine the prevalence and relative risk of SARS-CoV-2 among asymptomatic versus symptomatic individuals using at-home sample collection kits for diagnosis. Participants included adults from across the United States who completed a COVID-19 Home Collection kit between May 2020 and September 2021. Main measurements included self-reported symptoms and at-home self-collected anterior nasal swab RT-PCR test results for SARS-CoV-2. RESULTS: Data from 282,831 individuals were included in this analysis. The overall SARS-CoV-2 prevalence of at-home test takers was low compared to national averages during this period (3.28% vs. 7.68%). Those reporting no symptoms were at lower risk of positive test results compared to those with symptoms (risk ratio: 0.080, 95% CI, 0.078-0.082). However, of all positive SARS-CoV-2 tests, 48.75% were from individuals reporting no symptoms at the time of testing. CONCLUSIONS: We conclude that at-home sample collection is a viable option and potentially important strategy for improving access to testing, detecting asymptomatic cases, and curbing preventable transmission of COVID-19.

Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes.

Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with (n = 18) and without (n = 17) diabetes. Similarly, in vivo mitochondrial oxidative phosphorylation capacity measured in the gastrocnemius muscle via 31P-MRS indicated an impairment in the rate of ADP depletion with rest (27 ± 6 s [diabetes], 21 ± 7 s [control subjects]; P = 0.008) and oxidative phosphorylation (P = 0.046) in type 2 diabetes after isometric calf exercise compared with control subjects. Importantly, the in vivo impairment in oxidative capacity resolved with oxygen supplementation in adults with diabetes (ADP depletion rate 5.0 s faster, P = 0.012; oxidative phosphorylation 0.046 ± 0.079 mmol/L/s faster, P = 0.027). Multiple in vivo mitochondrial measures related to HbA1c These data suggest that oxygen availability is rate limiting for in vivo mitochondrial oxidative exercise recovery measured with 31P-MRS in individuals with uncomplicated diabetes. Targeting muscle oxygenation could improve exercise function in type 2 diabetes.

Acute vitamin C improves cardiac function, not exercise capacity, in adults with type 2 diabetes.

BACKGROUND: People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. METHODS: Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m2) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m2) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO2peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. RESULTS: Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E' (P < 0.01), but did not change RH (P = 0.92), or VO2peak (P = 0.33) in any participants. CONCLUSION: Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets.Trial registration NCT00786019. Prospectively registered May 2008.

Dissociation of local and global skeletal muscle oxygen transport metrics in type 2 diabetes.

AIMS: Exercise capacity is impaired in type 2 diabetes, and this impairment predicts excess morbidity and mortality. This defect appears to involve excess skeletal muscle deoxygenation, but the underlying mechanisms remain unclear. We hypothesized that reduced blood flow, reduced local recruitment of blood volume/hematocrit, or both contribute to excess skeletal muscle deoxygenation in type 2 diabetes. METHODS: In patients with (n=23) and without (n=18) type 2 diabetes, we recorded maximal reactive hyperemic leg blood flow, peak oxygen utilization during cycling ergometer exercise (VO2peak), and near-infrared spectroscopy-derived measures of exercise-induced changes in skeletal muscle oxygenation and blood volume/hematocrit. RESULTS: We observed a significant increase (p<0.05) in skeletal muscle deoxygenation in type 2 diabetes despite similar blood flow and recruitment of local blood volume/hematocrit. Within the control group skeletal muscle deoxygenation, local recruitment of microvascular blood volume/hematocrit, blood flow, and VO2peak are all mutually correlated. None of these correlations were preserved in type 2 diabetes. CONCLUSIONS: These results suggest that in type 2 diabetes 1) skeletal muscle oxygenation is impaired, 2) this impairment may occur independently of bulk blood flow or local recruitment of blood volume/hematocrit, and 3) local and global metrics of oxygen transport are dissociated.

Sex differences in the effects of type 2 diabetes on exercise performance.

PURPOSE: People with uncomplicated type 2 diabetes (T2D) have impaired peak exercise performance compared with that of their nondiabetic counterparts. This impairment may represent the earliest indication of cardiovascular (CV) abnormalities in T2D. Women with T2D are known to have worse CV outcomes than those in men with T2D. We hypothesized that women with diabetes have a greater exercise impairment than that in men with diabetes compared with that in their nondiabetic counterparts. METHODS: We studied 15 women (premenopausal) and 14 men with T2D as well as their nondiabetic counterparts (22 women and 13 men). Exercise testing was performed. Additional outcomes included measurements of insulin sensitivity, endothelial function, blood flow, and resting cardiac function. RESULTS: Men and women with T2D but not controls had impaired insulin sensitivity. Women with T2D had a lower peak oxygen consumption (V˙O2peak) compared with that of nondiabetic women (24%, P < 0.05) than men with diabetes compared with that in nondiabetic men (16%, P < 0.05) (P value between groups < 0.05). The time constants (phase 2) of the V˙O2 kinetic response tended to be slower in men and women with T2D than those in nondiabetic controls (P = 0.08). There were no differences in resting ventricular function by Doppler echocardiography techniques between groups. Women with T2D had significantly lower flow-mediated dilation and blood flow responses to hyperemia than those in nondiabetic women (both P < 0.05), whereas men with T2D had lower flow-mediated dilation but not lower blood flow than those in nondiabetic men. CONCLUSIONS: Although both men and women with uncomplicated T2D had a lower V˙O2peak, the abnormality in women with T2D compared with that in nondiabetic women was greater than that seen in men. Because V˙O2peak has a strong inverse correlation with mortality, sex disparities observed in exercise capacity among people with T2D suggest a possible rationale for the increased CV morbidity and mortality observed in women compared with those observed in men with uncomplicated T2D.

Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease.

Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). This multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of GSK1278863 (an oral PHD inhibitor) in subjects with PAD. The study assessed two active treatment paradigms: single dosing and subchronic daily dosing (300 mg single dose and 15 mg daily for 14 days, respectively). Neither regimen improved exercise performance compared with placebo (change from baseline in the 6-minute walk test (6MWT; feet), (GSK1278863, placebo): single dose (-46, -44), p=0.96; repeat dose (9, 8), p=0.99; change in number of contractions to onset of claudication (goniometry): single dose (4, -1), p=0.053; repeat dose (-2, 1), p=0.08). A calf-muscle biopsy substudy showed no increases in mRNA or protein levels of HIF target genes. More subjects receiving GSK1278863 than placebo experienced adverse events, particularly following the 300 mg single dose. Thus, assessing the safety of GSK1278863 in this setting would require a larger population exposed to the agent for a longer duration. These data do not support a benefit of GSK1278863 in PAD using the regimens tested. CLINICALTRIALSGOV IDENTIFIER NCT01673555:

Effect of tirasemtiv, a selective activator of the fast skeletal muscle troponin complex, in patients with peripheral artery disease.

Tirasemtiv (CK-2017357), a novel small-molecule activator of the fast skeletal muscle troponin complex, slows the rate of calcium release from troponin, thus sensitizing fast skeletal muscle fibers to calcium. In preclinical studies, tirasemtiv increased muscle force and delayed the onset and reduced the extent of muscle fatigue during hypoxia in vitro and muscle ischemia in situ. This study evaluated the effect of single doses of tirasemtiv on measures of skeletal muscle function and fatigability in patients with stable calf claudication due to peripheral artery disease (PAD). Sixty-one patients with an ankle-brachial index ≤0.90 in the leg with claudication received single double-blind doses of tirasemtiv 375 mg and 750 mg and matching placebo in random order about 1 week apart. After 33 patients were treated, the 750 mg dose was decreased to 500 mg due to adverse events and these dose groups were combined for analysis. On each study day, bilateral heel-raise testing was performed before and at 3 and 6 hours after dosing; a 6-minute walk test was performed at 4 hours after dosing. Claudicating calf muscle performance was increased at the highest dose and plasma concentration of tirasemtiv; however, the 6-minute walk distance decreased with both the dose and plasma concentration of tirasemtiv, possibly due to dose-related adverse events, particularly dizziness, that could impede walking ability. In conclusion, the mechanism of fast skeletal muscle troponin activation improved muscle function but not 6-minute walking distance in patients with claudication due to PAD. CLINICALTRIALSGOV IDENTIFIER NCT01131013:

Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function.

CONTEXT: Cardiovascular disease is the major cause of death in adults with diabetes, yet little is specifically known about the effects of type 1 diabetes (T1D) on cardiovascular outcomes in youth. Although insulin resistance (IR) likely contributes to exercise and cardiovascular dysfunction in T2D, IR is not typically considered a contributor in T1D. OBJECTIVE: We hypothesized that cardiopulmonary fitness would be reduced in T1D youth in association with IR and cardiovascular dysfunction. DESIGN AND PARTICIPANTS: This cross-sectional study at an academic hospital included 12 T1D adolescents compared with 12 nondiabetic controls, similar in age, pubertal stage, activity level, and body mass index. OUTCOME MEASURES: Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, intramyocellular lipid by magnetic resonance spectroscopy, and body composition by dual-energy x-ray absorptiometry. RESULTS: T1D adolescents had significantly decreased VO(2)peak, peak work rate, and insulin sensitivity compared with nondiabetic adolescents. T1D youth also had reduced vascular reactivity and evidence of diastolic dysfunction and left ventricular hypertrophy. Despite their IR and reduced cardiovascular fitness, T1D youth had paradoxically normal intramyocellular lipid, waist to hip ratio, and serum lipids and high adiponectin levels. In multivariate analysis, IR primarily, and forearm blood flow secondarily, independently predicted VO(2)peak. CONCLUSIONS: T1D youth demonstrated IR, impaired functional exercise capacity and cardiovascular dysfunction. The phenotype of IR in T1D youth was unique, suggesting a pathophysiology that is different from T2D, yet may adversely affect long-term cardiovascular outcomes.

Women with type 2 diabetes perceive harder effort during exercise than nondiabetic women.

Regular exercise is a cornerstone of diabetes treatment; however, people with type 2 diabetes (T2D) are commonly sedentary. It is possible that a harder rate of perceived exertion (RPE) during exercise for those with T2D as compared with nondiabetics may be a barrier to physical activity. This study examined RPE (Borg scale, ordinal range 6-20) during submaximal exercise at identical absolute work rates to test the hypothesis that women with T2D demonstrate harder RPE during exercise than nondiabetic controls. In a prespecified analysis of existing data from equivalently sedentary women, RPE during submaximal exercise was compared among women with uncomplicated T2D (n = 13, mean body mass index (BMI) 34.2, mean hemoglobin A1c 9%), overweight controls (OC, n = 13, mean BMI 30.7), and normal-weight controls (NWC, n = 13, mean BMI 23.1). Subjects performed three 7 min, constant-load exercise tests at 20 W and 30 W. Mixed-effects general linear modeling was used to test for differences in mean RPE estimates among groups with and without adjustment for relative work intensity, age, habitual physical activity, or BMI. Subjects with T2D perceived harder effort during bicycling exercise than controls, as measured by RPE at 20 W and 30 W (p < 0.05 for T2D vs. OC and for T2D vs. NWC). Adjusting for relative work intensity eliminated significant group RPE differences at 30 W, but group RPE differences at 20 W remained significant. Harder perceived effort during exercise may be a barrier to physical activity for those with T2D.

Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity.

CONTEXT: The incidence of pediatric type 2 diabetes (T2D) is rising, with unclear effects on the cardiovascular system. Cardiopulmonary fitness, a marker of morbidity and mortality, is abnormal in adults with T2D, yet the mechanisms are incompletely understood. OBJECTIVE: We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12-19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level. MAIN OUTCOME MEASURES: Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers. RESULTS: Adolescents with T2D had significantly decreased VO(2)peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO(2)kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO(2)peak. CONCLUSIONS: Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

Cardiac dysfunction during exercise in uncomplicated type 2 diabetes.

PURPOSE: Type 2 diabetes mellitus (T2DM) has been associated with reduced peak exercise capacity (VO(2peak)). The causes of this impairment are not clearly established, but evidence suggests that abnormalities in cardiac function play a significant role. We hypothesized that exercise would be associated with impaired cardiac function and hemodynamics in recently diagnosed T2DM, even in the absence of clinically evident cardiovascular complications. METHODS: After baseline normal echocardiography screening, 10 premenopausal women with uncomplicated T2DM (average duration of diagnosed T2DM, 3.6 yr) and 10 healthy nondiabetic women of similar age, weight, and activity levels performed a peak cardiopulmonary exercise test while instrumented with an indwelling pulmonary artery catheter for assessing cardiac function. On separate days, technetium-99m sestamibi (cardolite) imaging was performed to assess myocardial perfusion at rest and peak exercise in seven T2DM and seven control patients. RESULTS: Resting measures of cardiac hemodynamics were similar in T2DM and control subjects. Absolute VO(2peak) (mL x min(-1)) and peak cardiac output (L x min(-1)) tended to be lower in T2DM than in control subjects but did not reach statistical significance. However, pulmonary capillary wedge pressure (PCWP) rose significantly more during exercise in T2DM than in controls (148% vs 109% increase at peak exercise, P < 0.01). Normalized myocardial perfusion index was lower in persons with diabetes than in controls (11.0 +/- 3.5 x e(-9) vs 17.5 +/- 8.1 x e(-9), respectively, P < 0.05) and inversely related to peak exercise PCWP (R = -0.56, P < 0.05). CONCLUSIONS: Cardiac hemodynamics during graded exercise are altered in women with recently diagnosed T2DM as demonstrated by the disproportionate increase in PCWP at peak exercise compared with controls subjects. Cardiac abnormalities observed are potentially early signs of subclinical cardiac dysfunction associated with T2DM, which may precede the more greatly impaired cardiac function at rest and with exercise observed in longer established T2DM.

Heart rate recovery predicts mortality and cardiovascular events in patients with type 2 diabetes.

PURPOSE: Heart rate recovery (HRR) immediately after peak exercise has utility as a predictor of all-cause mortality. However, a prognostic role for HRR has not been specifically evaluated in patients with type 2 diabetes mellitus (T2DM), nor has an association between HRR and cardiovascular (CV) events been documented. This study investigated whether HRR is predictive of all-cause mortality, CV mortality, and CV events in asymptomatic patients with T2DM. METHODS: HRR in subjects with T2DM was obtained via chart review of peak exercise treadmill tests (N = 890) performed at entry into the Appropriate Blood Pressure Control in Diabetes trial. Survival analysis was used to test the association of 1- and 2-min HRR with all-cause mortality, CV mortality, and CV events during the follow-up period. RESULTS: Subjects were followed for a median of 5.0 yr. All-cause mortality and CV events were significantly greater among the lowest quintile (< 12 bpm) of 1-min HRR compared with the fourth (23-28 bpm) quintile. Similarly all-cause mortality and CV events were significantly greater among the lowest quintile (< 28 bpm) of 2-min HRR compared with the third quintile (37-42 bpm) quintile. After adjustment for traditional cardiac risk factors, attenuated 1- and 2-min HRR remained significantly associated with increased risk of CV events as compared with those without attenuation. CONCLUSIONS: HRR provides information beyond traditional CV risk factors that could aid in the clinical risk stratification of patients with T2DM. The results suggest that HRR results should be incorporated into standard diagnostic treadmill testing reports and target those patients with T2DM and attenuated HRR who can benefit from directed therapies.

Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes.

OBJECTIVE: People with type 2 diabetes have impaired exercise responses even in the absence of cardiovascular complications. One key factor associated with the exercise intolerance is abnormally slowed oxygen uptake (VO2) kinetics during submaximal exercise. The mechanisms of this delayed adaptation during exercise are unclear but probably relate to impairments in skeletal muscle blood flow. This study was conducted to compare skeletal muscle deoxygenation (deoxygenated hemoglobin/myoglobin [HHb]) responses and estimated microvascular blood flow (Qm) kinetics in type 2 diabetic and healthy subjects after the onset of moderate exercise. RESEARCH DESIGN AND METHODS: Pulmonary VO2 kinetics and [HHb] (using near-infrared spectroscopy) were measured in 11 type 2 diabetic and 11 healthy subjects during exercise transitions from unloaded to moderate cycling exercise. Qm responses were calculated using VO2 kinetics and [HHb] responses via rearrangement of the Fick principle. RESULTS: VO2 kinetics were slowed in type 2 diabetic compared with control subjects (43.8 +/- 9.6 vs. 34.2 +/- 8.2 s, P < 0.05), and the initial [HHb] response after the onset of exercise exceeded the steady-state level of oxygen extraction in type 2 diabetic compared with control subjects. The mean response time of the estimated Qm increase was prolonged in type 2 diabetic compared with healthy subjects (47.7 +/- 14.3 vs. 35.8 +/- 10.7 s, P < 0.05). CONCLUSIONS: Type 2 diabetic skeletal muscle demonstrates a transient imbalance of muscle O2 delivery relative to O2 uptake after onset of exercise, suggesting a slowed Qm increase in type 2 diabetic muscle. Impaired vasodilatation due to vascular dysfunction in type 2 diabetes during exercise may contribute to this observation. Further study of the mechanisms leading to impaired muscle oxygen delivery may help explain the abnormal exercise responses in type 2 diabetes.

Skeletal muscle StO2 kinetics are slowed during low work rate calf exercise in peripheral arterial disease.

The time course of muscle oxygen desaturation (StO2 kinetics) following exercise onset reflects the dynamic interaction between muscle blood flow and muscle oxygen consumption. In patients with peripheral arterial disease (PAD), muscle StO2 kinetics are slowed during walking exercise; potentially reflecting altered muscle oxygen consumption relative to blood flow. This study evaluated whether StO2 kinetics measured using near infrared spectroscopy (NIRS) would be slowed in PAD during low work rate calf exercise compared with healthy subjects under conditions in which blood flow did not differ. Eight subjects with PAD and eight controls performed 3 min of calf exercise at 5, 10, 30, and 50% of maximal voluntary contraction (MVC). Calf blood flow responses were measured by plethysmography. Power outputs were similar between groups for all work rates. In PAD, the time constants of StO2 kinetics were significantly slower than controls during 5% MVC (13.5 +/- 1.7 vs. 6.9 +/- 1.2 s, P < 0.05) and 10% MVC work rates (14.5 +/- 2.7 vs. 6.8 +/- 1.1 s, P < 0.05). Blood flow assessed when exercise was interrupted after 30 s did not differ between PAD and control subjects at these work rates. In contrast, the StO2 time constants were not different between groups during 30 and 50% MVC work rates, where blood flow responses in PAD subjects were lower as compared with controls. Thus in PAD, the slowed StO2 kinetic responses under conditions of unimpaired calf blood flow reflect slowed muscle oxygen consumption in PAD skeletal muscle during low work rate plantar flexion exercise as compared with healthy skeletal muscle.

Contributions of working muscle to whole body lipid metabolism are altered by exercise intensity and training.

To evaluate the contribution of working muscle to whole body lipid oxidation, we examined the effects of exercise intensity and endurance training (9 wk, 5 days/wk, 1 h, 75% Vo(2 peak)) on whole body and leg free fatty acid (FFA) kinetics in eight male subjects (26 +/- 1 yr, means +/- SE). Two pretraining trials [45 and 65% Vo(2 max) (45UT, 65UT)] and two posttraining trials [65% of pretraining Vo(2 peak) (ABT), and 65% of posttraining Vo(2 peak) (RLT)] were performed using [1-(13)C]palmitate infusion and femoral arteriovenous sampling. Training increased Vo(2 peak) by 15% (45.2 +/- 1.2 to 52.0 +/- 1.8 ml.kg(-1).min(-1), P < 0.05). Muscle FFA fractional extraction was lower during exercise (EX) compared with rest regardless of workload or training status ( approximately 20 vs. 48%, P < 0.05). Two-leg net FFA balance increased from net release at rest ( approximately -36 micromol/min) to net uptake during EX for 45UT (179 +/- 75), ABT (236 +/- 63), and RLT (136 +/- 110) (P < 0.05), but not 65UT (51 +/- 127). Leg FFA tracer measured uptake was higher during EX than rest for all trials and greater during posttraining in RLT (716 +/- 173 micromol/min) compared with pretraining (45UT 450 +/- 80, 65UT 461 +/- 72, P < 0.05). Leg muscle lipid oxidation increased with training in ABT (730 +/- 163 micromol/min) vs. 65UT (187 +/- 94, P < 0.05). Leg muscle lipid oxidation represented approximately 62 and 30% of whole body lipid oxidation at lower and higher relative intensities, respectively. In summary, training can increase working muscle tracer measured FFA uptake and lipid oxidation for a given power output, but both before and after training the association between whole body and leg lipid metabolism is reduced as exercise intensity increases.

Endurance training has little effect on active muscle free fatty acid, lipoprotein cholesterol, or triglyceride net balances.

We evaluated the hypothesis that net leg total FFA, LDL-C, and TG uptake and HDL-C release during moderate-intensity cycling exercise would be increased following endurance training. Eight sedentary men (26 +/- 1 yr, 77.4 +/- 3.7 kg) were studied in the postprandial state during 90 min of rest and 60 min of exercise twice before (45% and 65% V(O2 peak)) and twice after 9 wk of endurance training (55% and 65% posttraining V(O2 peak)). Measurements across an exercising leg were taken to be a surrogate for active skeletal muscle. To determine limb lipid exchange, femoral arterial and venous blood samples drawn simultaneously at rest and during exercise were analyzed for total and individual FFA (e.g., palmitate, oleate), LDL-C, HDL-C, and TG concentrations, and limb blood flow was determined by thermodilution. The transition from rest to exercise resulted in a shift from net leg total FFA release (-44 +/- 16 micromol/min) to uptake (193 +/- 49 micromol/min) that was unaffected by either exercise intensity or endurance training. The relative net leg release and uptake of individual FFA closely resembled their relative abundances in the plasma with approximately 21 and 41% of net leg total FFA uptake during exercise accounted for by palmitate and oleate, respectively. Endurance training resulted in significant changes in arterial concentrations of HDL-C (49 +/- 5 vs. 52 +/- 5 mg/dl, pre vs. post) and LDL-C (82 +/- 9 vs. 76 +/- 9 mg/dl, pre vs. post), but there was no net TG or LDL-C uptake or HDL-C release across the resting or active leg before or after endurance training. In conclusion, endurance training favorably affects blood lipoprotein profiles, even in young, healthy normolipidemic men, but muscle contractions per se have little effect on net leg LDL-C, or TG uptake or HDL-C release during moderate-intensity cycling exercise. Therefore, the favorable effects of physical activity on the lipid profiles of young, healthy normolipidemic men in the postprandial state are not attributable to changes in HDL-C or LDL-C exchange across active skeletal muscle.

Rosiglitazone improves exercise capacity in individuals with type 2 diabetes.

OBJECTIVE: Although exercise is recommended as a cornerstone of treatment for type 2 diabetes, it is often poorly adopted by patients. We have noted that even in the absence of apparent cardiovascular disease, persons with type 2 diabetes have an impaired ability to carry out maximal exercise, and the impairment is correlated with insulin resistance and endothelial dysfunction. We hypothesized that administration of a thiazolidinedione (TZD) agent would improve exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty participants with uncomplicated type 2 diabetes were randomly assigned in a double-blind study to receive either 4 mg/day of rosiglitazone or matching placebo after baseline measurements to assess endothelial function (brachial artery diameter by brachial ultrasound), maximal oxygen consumption (VO(2max)), oxygen uptake (VO(2)) kinetics, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Measurements were reassessed after 4 months of treatment. RESULTS: Participant groups did not differ at baseline in any measure. Rosiglitazone-treated participants (n = 10) had significantly improved VO(2max) (19.8 +/- 5.3 ml . kg(-1) . min(-1) before rosiglitazone vs. 21.2 +/- 5.1 ml . kg(-1) . min(-1) after rosiglitazone, P < 0.01), insulin sensitivity, and endothelial function. A change in VO(2max) correlated with improved insulin sensitivity measured by clamp (r = 0.68, P < 0.05) and with improved brachial artery diameter (r = 0.70, P < 0.05). Placebo-treated participants (n = 10) showed no changes in VO(2max) (19.4 +/- 5.2 ml . kg(-1) . min(-1) before rosiglitazone vs. 18.1 +/- 5.3 ml . kg(-1) . min(-1) after rosiglitazone, NS) or brachial artery diameter. CONCLUSIONS: This is the first known report showing that a TZD improved exercise function in type 2 diabetes. Whether this is due to the observed improvements in insulin sensitivity and/or endothelial function or to another action of the TZD class requires further exploration.