Jacob B. Blumenthal

Aerobic Exercise and Weight Loss Reduce Vascular Markers of Inflammation and Improve Insulin Sensitivity in Obese Women

To examine the relationships between plasma and tissue markers of systemic and vascular inflammation and obesity and insulin resistance and determine the effects of aerobic exercise training plus weight loss (AEX+WL) and weight loss (WL) alone on these biomarkers.

Weight Loss and Low-Intensity Exercise for the Treatment of Metabolic Syndrome in Obese Postmenopausal Women

BACKGROUND The prevalence of the metabolic syndrome (MetSyn) approaches 50% in postmenopausal women. This study examines the efficacy of lifestyle modification for the treatment of MetSyn and its associated risk for cardiovascular disease and diabetes in this population. METHODS This prospective controlled study examines the effects of a 6-month weight loss and low-intensity exercise program (WL+LEX) on body composition (dual-energy X-ray absorptiometry and abdominal computed tomography scans), fasting glucose and lipid levels, cytokines, and blood pressure in postmenopausal women with and without MetSyn. RESULTS WL+LEX reduced body weight (MetSyn: -5% vs non-MetSyn: -7%) and fat mass (-11% vs -15%) and increased VO(2max) (+2% vs +3%) in both MetSyn (N = 35) and non-MetSyn (N = 41) groups. Constituents of MetSyn decreased comparably in both groups. Fifteen (45%) MetSyn participants responded (R) by converting to non-MetSyn, 18 remained MetSyn (NR), and 2 had missing data. Reduction in fat mass (-15% vs -8%, p = .02) was greater in R than NR, but there were no between-group differences in changes in VO(2max), cytokines, or other variables. The decrease in the number of MetSyn criteria was greater in R than in NR (-27 vs -13, p < .0001) due to decreases in blood pressure (p < .01), glucose (p = .02), and with a trend for triglyceride (p = .07). Reductions in fat mass best predicted resolution of MetSyn (p = .04). CONCLUSIONS Women who lose more fat are more likely to lower blood pressure, glucose, and triglyceride levels to resolve MetSyn. Thus, a WL+LEX program effectively treats postmenopausal women with MetSyn.

Increased Skeletal Muscle Capillarization Independently Enhances Insulin Sensitivity in Older Adults After Exercise Training and Detraining

Intramuscular signaling and glucose transport mechanisms contribute to improvements in insulin sensitivity after aerobic exercise training. This study tested the hypothesis that increases in skeletal muscle capillary density (CD) also contribute to exercise-induced improvements in whole-body insulin sensitivity (insulin-stimulated glucose uptake per unit plasma insulin [M/I]) independent of other mechanisms. The study design included a 6-month aerobic exercise training period followed by a 2-week detraining period to eliminate short-term effects of exercise on intramuscular signaling and glucose transport. Before and after exercise training and detraining, 12 previously sedentary older (65 ± 3 years) men and women underwent research tests, including hyperinsulinemic-euglycemic clamps and vastus lateralis biopsies. Exercise training increased Vo2max (2.2 ± 0.2 vs. 2.5 ± 0.2 L/min), CD (313 ± 13 vs. 349 ± 18 capillaries/mm2), and M/I (0.041 ± 0.005 vs. 0.051 ± 0.007 μmol/kg fat-free mass/min) (P < 0.05 for all). Exercise training also increased the insulin activation of glycogen synthase by 60%, GLUT4 expression by 16%, and 5′ AMPK-α1 expression by 21%, but these reverted to baseline levels after detraining. Conversely, CD and M/I remained 15% and 18% higher after detraining, respectively (P < 0.05), and the changes in M/I (detraining minus baseline) correlated directly with changes in CD in regression analysis (partial r = 0.70; P = 0.02). These results suggest that an increase in CD is one mechanism contributing to sustained improvements in glucose metabolism after aerobic exercise training.

Increased Skeletal Muscle Capillarization After Aerobic Exercise Training and Weight Loss Improves Insulin Sensitivity in Adults With IGT

OBJECTIVE Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus, a reduction in capillary density (CD) may worsen insulin sensitivity. Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and may be modifiable through aerobic exercise training and weight loss (AEX+WL). We tested the hypothesis that 6-month AEX+WL would increase CD to improve insulin sensitivity and glucose tolerance in older adults with IGT. RESEARCH DESIGN AND METHODS Sixteen sedentary, overweight-obese (BMI 27–35 kg/m2), older (63 ± 2 years) men and women with IGT underwent hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, oral glucose tolerance tests, exercise and body composition testing, and vastus lateralis muscle biopsies to determine CD before and after 6-month AEX+WL. RESULTS Insulin sensitivity (M) and 120-min postprandial glucose (G120) correlated with CD at baseline (r = 0.58 and r = −0.60, respectively, P < 0.05). AEX+WL increased maximal oxygen consumption (VO2max) 18% (P = 0.02) and reduced weight and fat mass 8% (P < 0.02). CD increased 15% (264 ± 11 vs. 304 ± 14 capillaries/mm2, P = 0.01), M increased 21% (42.4 ± 4.0 vs. 51.4 ± 4.3 µmol/kg FFM/min, P < 0.05), and G120 decreased 16% (9.35 ± 0.5 vs. 7.85 ± 0.5 mmol/L, P = 0.008) after AEX+WL. Regression analyses showed that the AEX+WL-induced increase in CD independently predicted the increase in M (r = 0.74, P < 0.01) as well as the decrease in G120 (r = −0.55, P < 0.05). CONCLUSIONS Six-month AEX+WL increases skeletal muscle CD in older adults with IGT. This represents one mechanism by which AEX+WL improves insulin sensitivity in older adults with IGT.

Aerobic exercise + weight loss decreases skeletal muscle myostatin expression and improves insulin sensitivity in older adults

To determine whether aerobic exercise training + weight loss (AEX + WL) would affect the expression of myostatin and its relationship with insulin sensitivity in a longitudinal, clinical intervention study.

Resistance to the antilipolytic effect of insulin in adipocytes of African-American compared to Caucasian postmenopausal women

High fatty acid (FA) flux is associated with systemic insulin resistance, and African-American (AA) women tend to be more insulin resistant. We assessed possible depot and race difference in the antilipolytic effect of insulin in adipocytes isolated from abdominal (Abd) and gluteal (Glt) subcutaneous (sc) adipose tissue of overweight, postmenopausal AA and Caucasian (C) women. Percent body fat, fasting insulin, visceral adiposity, and adipocyte size was higher in AA women. Disinhibited lipolysis (presence of adenosine deaminase) per unit adipocyte surface area was similar in Abd and Glt and in AA and C. However, rates of ‘basal’ [submaximal phenylisopropyl adenosine (PIA)-suppressed] and insulin-suppressed lipolysis were higher in Abd of AA compared with C women even after adjustment for percent fat and visceral fat area. The race difference in rates of PIA- and insulin-suppressed lipolysis in AA were correlated with their hyperinsulinemia, but AA race, independent of fasting insulin, was associated with lower responsiveness (percent suppression) to submaximal insulin concentrations, although sensitivity (ED50) was not affected. Overall, these data are consistent with the hypothesis that decreased responsiveness of Abd adipocytes to antilipolytic effectors may contribute to higher FA availability and thereby to racial differences in insulin resistance.

Sarcopenia Is Associated With Lower Skeletal Muscle Capillarization and Exercise Capacity in Older Adults

BACKGROUND Skeletal muscle capillary rarefaction limits the transcapillary transport of nutrients and oxygen to muscle and may contribute to sarcopenia and functional impairment in older adults. We tested the hypothesis that skeletal muscle capillarization and exercise capacity (VO2max) are lower in sarcopenic than in nonsarcopenic older adults and that the degree of sarcopenia is related to lower skeletal muscle capillarization. METHODS Body composition, VO2max, and vastus lateralis capillarization were determined in 76 middle-aged and older men and women (age = 61±1 years, body mass index [BMI] = 30.7±0.5kg/m(2) [mean ± SEM]). Participants were classified as sarcopenic if appendicular lean mass divided by BMI (ALMBMI) was less than 0.789 for men or less than 0.512 for women. RESULTS Sarcopenic subjects (ALMBMI = 0.65±0.04, n = 16) had 20% lower capillary-to-fiber ratio, as well as 13% and 15% lower VO2max expressed as mL/kg/min or L/min, respectively, compared with sex-, race-, and age-matched participants without sarcopenia (ALMBMI = 0.81±0.05, n = 16; p < .05). In all 76 subjects, ALMBMI, thigh muscle cross-sectional area, and VO2max correlated directly with capillarization (r = .30-.37, p ≤ .05), after accounting for age, sex, and race. CONCLUSIONS These findings suggest that low skeletal muscle capillarization is one factor that may contribute to sarcopenia and reduced exercise capacity in older adults by limiting diffusion of substrates, oxygen, hormones, and nutrients. Strategies to prevent the aging-related decline in skeletal muscle capillarization may help to prevent or slow the progression of sarcopenia and its associated functional declines in generally healthy older adults.

Immunogenetics of allergy and asthma

Asthma and allergies are conditions that involve the interaction of genetic and environmental factors such as allergen exposure (both time and amount). In addition, variables such as age, concurrent infections, and psychological factors promote variations in susceptibility. An understanding of all these factors enriches our understanding of allergies and asthma as well as allows the development of rational methods for their prevention and management.

Exercise-induced endothelial progenitor cell mobilization is attenuated in impaired glucose tolerance and type 2 diabetes

Circulating endothelial progenitor cells (EPCs) contribute to vascular homeostasis and are fewer in those with type 2 diabetes mellitus (T2DM) compared with normal glucose tolerance (NGT), suggesting a link between EPCs and T2DM-associated vasculopathies. The purpose of this study was to assess EPC number and mobilization by acute submaximal exercise in older adults with NGT, impaired glucose tolerance (IGT) or T2DM. We tested the hypothesis that EPC mobilization is lower in IGT compared with NGT and further reduced in older adults with T2DM. Forty-five older (50-75 yr of age) men and women with NGT (n = 18), IGT (n = 10), or T2DM (n = 17) were characterized and underwent submaximal aerobic exercise tests with blood sampling for enumeration of vascular endothelial growth factor receptor 2+ (VEGFR2+) cells, CD34+ hematopoetic progenitor cells, and CD34+/VEGFR2+ EPCs by flow cytometry before and after exercise. Basal EPC number was 65 and 61% lower in the IGT and T2DM groups, respectively, compared with the NGT group (P < 0.05). EPC number increased 23% after acute exercise in the NGT group (P < 0.01), but did not change in the IGT or T2DM groups. Before and after exercise, VEGFR2+ cell number was lower in a stepwise manner across the NGT, IGT, and T2DM groups (P < 0.05). Basal CD34+ cell number was lower in the IGT group compared with NGT (P < 0.05), but did not change after exercise in any group. These findings suggest a CD34+/VEGFR2+ EPC mobilization defect in IGT and T2DM that could play a role in the cardiovascular diseases and capillary rarefaction associated with insulin resistance.

Patient-Reported Safety Events in Chronic Kidney Disease Recorded With an Interactive Voice-Inquiry Dial-Response System: Monthly Report Analysis

Background Monitoring patient-reported outcomes (PROs) may improve safety of chronic kidney disease (CKD) patients. Objective Evaluate the performance of an interactive voice-inquiry dial-response system (IVRDS) in detecting CKD-pertinent adverse safety events outside of the clinical environment and compare the incidence of events using the IVDRS to that detected by paper diary. Methods This was a 6-month study of Stage III-V CKD patients in the Safe Kidney Care (SKC) study. Participants crossed over from a paper diary to the IVDRS for recording patient-reported safety events defined as symptoms or events attributable to medications or care. The IVDRS was adapted from the SKC paper diary to record event frequency and remediation. Participants were auto-called weekly and permitted to self-initiate calls. Monthly reports were reviewed by two physician adjudicators for their clinical significance. Results 52 participants were followed over a total of 1384 weeks. 28 out of 52 participants (54%) reported events using the IVDRS versus 8 out of 52 (15%) with the paper diary; hypoglycemia was the most common event for both methods. All IVDRS menu options were selected at least once except for confusion and rash. Events were reported on 121 calls, with 8 calls reporting event remediation by ambulance or emergency room (ER) visit. The event rate with the IVDRS and paper diary, with and without hypoglycemia, was 26.7 versus 4.7 and 18.3 versus 0.8 per 100 person weeks, respectively (P=.002 and P<.001). The frequent users (ie, >10 events) largely differed by method, and event rates excluding the most frequent user of each were 16.9 versus 2.5 per 100 person weeks, respectively (P<.001). Adjudicators found approximately half the 80 reports clinically significant, with about a quarter judged as actionable. Hypoglycemia was often associated with additional reports of fatigue and falling. Participants expressed favorable satisfaction with the IVDRS. Conclusions Use of the IVDRS among CKD patients reveals a high frequency of clinically significant safety events and has the potential to be used as an important supplement to clinical care for improving patient safety.