Gastric bypass surgery with exercise alters plasma microRNAs that predict improvements in cardiometabolic risk.

BACKGROUND/OBJECTIVES: Roux-en-Y gastric bypass (RYGB) surgery improves insulin sensitivity (SI) and ß-cell function in obese non-diabetic subjects. Exercise also improves SI and may be an effective adjunct therapy to RYGB surgery. However, the mechanisms by which exercise or weight loss improve peripheral SI after RYGB surgery are unclear. We hypothesized that microRNAs (miRNAs) mediate at least some of the regulatory processes driving such mechanisms. Consequently, this work aimed at profiling plasma miRNAs in participants of the Physical Activity Following Surgery Induced Weight Loss study (clinicaltrials.gov identifier: NCT00692367), to assess whether miRNA levels track with improvements in SI and cardiometabolic risk factors. SUBJECTS/METHODS: Ninety-four miRNAs implicated in metabolism were profiled in plasma samples from 22 severely obese subjects who were recruited 1-3 months after RYGB surgery and followed for 6 months of RYGB surgery-induced weight loss, with (exercise program (EX), N=11) or without (CON, N=11) an exercise training intervention. The subjects were selected, considering a priori sample size calculations, among the participants in the parent study. Mixed-effect modeling for repeated measures and partial correlation analysis was implemented in the R environment for statistical analysis. RESULTS: Mirroring results in the parent trial, both groups experienced significant weight loss and improvements in cardiometabolic risk. In the CON group, weight loss significantly altered the pattern of circulating miR-7, miR-15a, miR-34a, miR-106a, miR-122 and miR-221. In the EX group, a distinct miRNA signature was altered: miR-15a, miR-34a, miR-122, miR-135b, miR-144, miR-149 and miR-206. Several miRNAs were significantly associated with improvements in acute insulin response, SI, and other cardiometabolic risk factors. CONCLUSIONS: These findings present novel insights into the RYGB surgery-induced molecular changes and the effects of mild exercise to facilitate and/or maintain the benefits of a 'comprehensive' weight-loss intervention with concomitant improvements in cardiometabolic functions. Notably, we show a predictive value for miR-7, miR-15a, miR-106b and miR-135b.

African American women exhibit similar adherence to intervention but lose less weight due to lower energy requirements.

BACKGROUND: African American (AA) women have been shown to lose less weight than Caucasian women in response to behavioral interventions. Our objective was to examine adherence to intervention and metabolic factors that may explain this difference. DESIGN AND SUBJECTS: We examined longitudinal changes in body weight and energy expenditure (EE), and objective assessment of physical activity (PA) and energy intake (EI) during 6 months of a weight-loss intervention program, including prescribed calorie restriction and increased PA in 66 Caucasian and 39 AA severely obese women. Comparisons were also made in 25 Caucasian and 25 AA women matched for initial body weight. RESULTS: The AA women lost 3.6 kg less weight than Caucasian women. Total daily EE (TDEE) and resting metabolic rate (RMR) adjusted for fat free mass (FFM) were significantly lower in the AA women, whereas the decrease in RMR in response to weight loss was greater in Caucasian women. Adherence to the prescribed PA and change in PA in response to intervention were similar in AA and Caucasian women. Prescribed EI (1794±153 and 1806±153 kcal per day) and measured EI during intervention (2591±371 vs 2630±442 kcal per day) were nearly identical in matched AA and Caucasian women. However, the AA women lost significantly less body weight due to lower energy requirements (2924±279 vs 3116±340 kcal per day; P<0.04), resulting in a lower energy deficit (333±210 vs 485±264 kcal per day). CONCLUSION: Adherence to the behavioral intervention was similar in AA and Caucasian women. However, neglecting to account for the lower energy requirements in AA women when calculating the energy prescription resulted in a lower level of calorie restriction and, hence, less body weight loss. Therefore, to achieve similar weight loss in AA women, the prescribed caloric restriction cannot be based on weight alone, but must be lower than in Caucasians, to account for lower energy requirements.

PPARα gene polymorphisms modulate the association between physical activity and cardiometabolic risk.

BACKGROUND AND AIMS: Habitual physical activity is understood to help prevent type 2 diabetes and atherosclerotic cardiovascular disease via beneficial effects on both metabolism and the vascular system. However, individuals do not have uniform cardiometabolic responses to physical activity. Here we explore the extent to which variation in the proliferator-activated receptor-alpha (PPARα) gene, which modulates carbohydrate and lipid metabolism, vascular function, and inflammation, predicts the overall cardiometabolic risk (CMR) profile of individuals engaging in various levels of physical activity. METHODS AND RESULTS: 917 unrelated, community volunteers (52% female, of Non-Hispanic European ancestry) aged 30-54 years, participated in the cross-sectional study. Subjects were genotyped for 5 single nucleotide polymorphisms in the PPARα gene, from which common haplotypes were defined. A continuous measure of CMR was calculated as an aggregate of 5 traditional risk factors: waist circumference, resting blood pressure, fasting serum triglycerides, HDL-cholesterol and glucose. Regression models were used to examine the main and interactive effects of physical activity and genetic variation on CMR. One common PPARα haplotype (H-23) was associated with a higher CMR. This association was moderated by daily physical activity (B = -0.11, SE = 0.053, t = -2.05, P = 0.04). Increased physical activity was associated with a steeper reduction of CMR in persons carrying the otherwise detrimental H-23 haplotype. CONCLUSIONS: Variations in the PPARα gene appear to magnify the cardiometabolic benefits of habitual physical activity.

High energy expenditure masks low physical activity in obesity.

OBJECTIVE: To investigate energy expenditure in lean and obese individuals, focusing particularly on physical activity and severely obese individuals. DESIGN: Total daily energy expenditure (TDEE) was assessed using doubly labeled water, resting metabolic rate (RMR) by indirect calorimetry, activity energy expenditure (AEE) by difference and time spent in physical activity by multisensor activity monitors. SUBJECTS: In all, 177 lean, Class I and severely obese individuals (age 31-56 years, body mass index 20-64 kg m(-2)) were analyzed. RESULTS: All components of energy expenditure were elevated in obese individuals. For example, TDEE was 2404±95 kcal per day in lean and 3244±48 kcal per day in Class III obese individuals. After appropriate adjustment, RMR was similar in all groups. Analysis of AEE by body weight and obesity class indicated a lower AEE in obese individuals. Confirming lower physical activity, obese individuals spent less time engaged in moderate-to-vigorous physical activity (2.7±1.3, 1.8±0.6, 2.0±1.4 and 1.2±1.0 h per day in lean, Class I, Class II and Class III individuals) and more time in sedentary behaviors. CONCLUSIONS: There was no indication of metabolic efficiency in even the severely obese, as adjusted RMR was similar across all groups. The higher AEE observed in the obese is consistent with a higher cost of activities due to higher body weight. However, the magnitude of the higher AEE (20-25% higher in obese individuals) is lower than expected (weight approximately 100% higher in Class III individuals). Confirming a lower volume of physical activity in the obese, the total time spent in moderate-to-vigorous physical activity and average daily metabolic equivalent of task level were lower with increasing obesity. These findings demonstrate that high body weight in obese individuals leads to a high TDEE and AEE, which masks the fact that they are less physically active, which can be influenced by duration or intensity of activity, than in lean individuals.

Femoral-gluteal adiposity is not associated with insulin sensitivity in type 1 diabetes.

AIMS: To quantify and compare associations between femoral-gluteal adiposity and insulin sensitivity in adults with Type 1 diabetes mellitus with adults with normal glucose tolerance. METHODS: Individuals with Type 1 diabetes (n = 28) were recruited from the Pittsburgh Epidemiology of Diabetes Complication study, a 24-year prospective study of childhood-onset diabetes, and compared cross-sectionally with individuals with normal glucose tolerance (n = 56) of similar age, sex and BMI. Insulin sensitivity was defined as whole-body glucose disposal measured by hyperinsulinaemic-euglycaemic clamps. Adiposity was quantified by dual energy X-ray absorptiometry. RESULTS: Individuals with Type 1 diabetes exhibited lower insulin sensitivity (5.8 vs. 8.2 mg min(-1) kg fat-free mass(-1), P < 0.01), lower total fat mass (20.1 vs. 29.0 kg, P < 0.001) and lower proportional leg fat mass (36.0 vs.37.7%, P = 0.03), but similar proportional trunk fat (% trunk fat mass) compared with individuals with normal glucose tolerance. Overall, results from linear regression demonstrated that higher % leg fat mass (P < 0.01) and lower % trunk fat mass (P < 0.01) were independently associated with lower insulin sensitivity after adjustments for age, sex, height, total fat mass (kg) and diabetes status. Higher % leg fat mass was independently associated with higher insulin sensitivity in individuals with normal glucose tolerance (P < 0.01) after similar adjustment; significant associations were not observed in Type 1 diabetes. CONCLUSIONS: Reduced insulin sensitivity is a prominent feature of Type 1 diabetes and is associated with total and abdominal adiposity. Compared with adults with normal glucose tolerance, leg fat mass does not show any positive association with insulin sensitivity in Type 1 diabetes.

Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide.

AIMS/HYPOTHESIS: Intramyocellular lipids, including diacylglycerol (DAG) and ceramides, have been linked to insulin resistance. This randomised repeated-measures study examined the effects of diet-induced weight loss (DIWL) and aerobic exercise (EX) on insulin sensitivity and intramyocellular triacylglycerol (IMTG), DAG and ceramide. METHODS: Sixteen overweight to obese adults (BMI 30.6 ± 0.8; 67.2 ± 4.0 years of age) with either impaired fasting glucose, or impaired glucose tolerance completed one of two lifestyle interventions: DIWL (n = 8) or EX (n = 8). Insulin sensitivity was determined using hyperinsulinaemic-euglycaemic clamps. Intramyocellular lipids were measured in muscle biopsies using histochemistry and tandem mass spectrometry. RESULTS: Insulin sensitivity was improved with DIWL (20.6 ± 4.7%) and EX (19.2 ± 12.9%). Body weight and body fat were decreased by both interventions, with greater decreases in DIWL compared with EX. Muscle glycogen, IMTG content and oxidative capacity were all significantly (p < 0.05) decreased with DIWL and increased with EX. There were decreases in DAG with DIWL (-12.4 ± 14.6%) and EX (-40.9 ± 12.0%). Ceramide decreased with EX (-33.7 ± 11.2%), but not with DIWL. Dihydroceramide was decreased with both interventions. Sphingosine was decreased only with EX. Changes in total DAG, total ceramides and other sphingolipids did not correlate with changes in glucose disposal. Stearoyl-coenzyme A desaturase 1 (SCD1) content was decreased with DIWL (-19.5 ± 8.5%, p < 0.05), but increased with EX (19.6 ± 7.4%, p < 0.05). Diacylglycerol acyltransferase 1 (DGAT1) was unchanged with the interventions. CONCLUSIONS/INTERPRETATION: Diet-induced weight loss and exercise training both improved insulin resistance and decreased DAG, while only exercise decreased ceramides, despite the interventions having different effects on IMTG. These alterations may be mediated through differential changes in skeletal muscle capacity for oxidation and triacylglycerol synthesis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00766298.

Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat.

Whether visceral adipose tissue has a uniquely powerful association with insulin resistance or whether subcutaneous abdominal fat shares this link has generated controversy in the area of body composition and insulin sensitivity. An additional issue is the potential role of fat deposition within skeletal muscle and the relationship with insulin resistance. To address these matters, the current study was undertaken to measure body composition, aerobic fitness, and insulin sensitivity within a cohort of sedentary healthy men (n = 26) and women (n = 28). The subjects, who ranged from lean to obese (BMI 19.6-41.0 kg/m2), underwent dual energy X-ray absorptiometry (DEXA) to measure fat-free mass (FFM) and fat mass (FM), computed tomography to measure cross-sectional abdominal subcutaneous and visceral adipose tissue, and computed tomography (CT) of mid-thigh to measure muscle cross-sectional area, muscle attenuation, and subcutaneous fat. Insulin sensitivity was measured using the glucose clamp technique (40 mU.m-2.min-1), in conjunction with [3-3H]glucose isotope dilution. Maximal aerobic power (VO2max) was determined using an incremental cycling test. Insulin-stimulated glucose disposal (Rd) ranged from 3.03 to 16.83 mg.min-1.kg-1 FFM. Rd was negatively correlated with FM (r = -0.58), visceral fat (r = -0.52), subcutaneous abdominal fat (r = -0.61), and thigh fat (r = -0.38) and positively correlated with muscle attenuation (r = 0.48) and VO2max (r = 0.26, P < 0.05). In addition to manifesting the strongest simple correlation with insulin sensitivity, in stepwise multiple regression, subcutaneous abdominal fat retained significance after adjusting for visceral fat, while the converse was not found. Muscle attenuation contributed independent significance to multiple regression models of body composition and insulin sensitivity, and in analysis of obese subjects, muscle attenuation was the strongest single correlate of insulin resistance. In summary, as a component of central adiposity, subcutaneous abdominal fat has as strong an association with insulin resistance as visceral fat, and altered muscle composition, suggestive of increased fat content, is an important independent marker of insulin resistance in obesity.

Effects of weight loss on regional fat distribution and insulin sensitivity in obesity.

Weight loss (WL) decreases regional depots of adipose tissue and improves insulin sensitivity, two parameters that correlate before WL. To examine the potential relation of WL-induced change in regional adiposity to improvement in insulin sensitivity, 32 obese sedentary women and men completed a 4-month WL program and had repeat determinations of body composition (dual-energy X-ray absorptiometry and computed tomography) and insulin sensitivity (euglycemic insulin infusion). There were 15 lean men and women who served as control subjects. VO2max was unaltered with WL (39.2 +/- 0.8 vs. 39.8 +/- 1.1 ml x fat-free mass [FFM](-1) x min(-1)). The WL intervention achieved significant decreases in weight (100.2 +/- 2.6 to 85.5 +/- 2.1 kg), BMI (34.3 +/- 0.6 to 29.3 +/- 0.6 kg/m2), total fat mass (FM) (36.9 +/- 1.5 to 26.1 +/- 1.3 kg), percent body fat (37.7 +/- 1.3 to 31.0 +/- 1.5%), and FFM (59.2 +/- 2.3 to 55.8 +/- 2.0 kg). Abdominal subcutaneous and visceral adipose tissue (SAT and VAT) were reduced (494 +/- 19 to 357 +/- 18 cm2 and 157 +/- 12 to 96 +/- 7 cm2, respectively). Cross-sectional area of low-density muscle (LDM) at the mid-thigh decreased from 67 +/- 5 to 55 +/- 4 cm2 after WL. Insulin sensitivity improved from 5.9 +/- 0.4 to 7.3 +/- 0.5 mg x FFM(-1) x min(-1) with WL. Rates of insulin-stimulated nonoxidative glucose disposal accounted for the majority of this improvement (3.00 +/- 0.3 to 4.3 +/- 0.4 mg x FFM(-1) x min(-1)). Serum leptin, triglycerides, cholesterol, and insulin all decreased after WL (P < 0.01). After WL, insulin sensitivity continued to correlate with generalized and regional adiposity but, with the exception of the percent decrease in VAT, the magnitude of improvement in insulin sensitivity was not predicted by the various changes in body composition. These interventional weight loss data underscore the potential importance of visceral adiposity in relation to insulin resistance and otherwise suggest that above a certain threshold of weight loss, improvement in insulin sensitivity does not bear a linear relationship to the magnitude of weight loss.

Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance.

Recent evidence derived from four independent methods indicates that an excess triglyceride storage within skeletal muscle is linked to insulin resistance. Potential mechanisms for this association include apparent defects in fatty acid metabolism that are centered at the mitochondria in obesity and in type 2 diabetes. Specifically, defects in the pathways for fatty acid oxidation during postabsorptive conditions are prominent, leading to diminished use of fatty acids and increased esterification and storage of lipid within skeletal muscle. These impairments in fatty acid metabolism during fasting conditions may be related to a metabolic inflexibility in insulin resistance that is not limited to defects in glucose metabolism during insulin-stimulated conditions. Thus, there is substantial evidence implicating perturbations in fatty acid metabolism during accumulation of skeletal muscle triglyceride and in the pathogenesis of insulin resistance. Weight loss by caloric restriction improves insulin sensitivity, but the effects on fatty acid metabolism are less conspicuous. Nevertheless, weight loss decreases the content of triglyceride within skeletal muscle, perhaps contributing to the improvement in Insulin action with weight loss. Alterations in skeletal muscle substrate metabolism provide insight into the link between skeletal muscle triglyceride accumulation and insulin resistance, and they may lead to more appropriate therapies to improve glucose and fatty acid metabolism in obesity and in type 2 diabetes.

Effects of Changes in Regional Body Composition on Physical Function in Older Adults: A Pilot Randomized Controlled Trial.

BACKGROUND/OBJECTIVE: Obesity exacerbates age-related physical disability; however, observational studies show that any weight loss in old age is associated with greater risk of mortality. Conversely, randomized controlled trials in older adults show that weight loss is beneficial. The discrepancy may be due to weight loss intention and differential changes to regional body composition. The purpose of this research was to evaluate the independent role of regional body composition remodeling in improving physical function. DESIGN: Pilot Randomized Controlled Trial. SETTING: Community based research center. PARTICIPANTS: Thirty-six community dwelling, overweight to moderately obese (BMI 28.0-39.9 kg/m2) older adults (age 70.6±6.1 yrs). INTERVENTION: Physical activity plus weight loss (PA+WL, n=21) or PA plus successful aging (SA) education. PA consisted primary of treadmill walking supplemented with lower extremity resistance and balance training. The WL program was based on the Diabetes Prevention Project and aimed at achieving a 7% weight loss by cutting calories, specifically those from fat. MEASUREMENTS: At baseline, 6- and 12-months, body composition was measured using computerized tomography and dual x-ray absorptiometry. Abdominal visceral (VAT) and thigh intermuscular (IMAT) adipose tissue were quantified. Physical function was assessed using the short physical performance battery (SPPB). RESULTS: Separate multivariable linear regression models with both groups combined demonstrated that decreases in IMAT and VAT were significantly associated with improvements in SPPB (P<0.05) independent of change in total fat mass. PA+WL improved SPPB scores from baseline (0.8±1.4, P<0.05), whereas PA+SA did not; however no intergroup difference was detected. Of note, these effects were mainly achieved during the intensive intervention phase. CONCLUSION: Decreases in IMAT and VAT are important mechanisms underlying improved function following intentional weight loss plus physical activity.

A review of the relationship between leg power and selected chronic disease in older adults.

OBJECTIVE: This review investigates the relationship between leg muscle power and the chronic conditions of osteoarthritis, diabetes mellitus, and cardiovascular disease among older adults. Current literature assessing the impact of chronic disease on leg power has not yet been comprehensively characterized. Importantly, individuals with these conditions have shown improved leg power with training. METHODS: A search was performed using PubMed to identify original studies published in English from January 1998 to August 2013. Leg power studies, among older adults ≥ 50 years of age, which assessed associations with osteoarthritis, diabetes mellitus, and/or cardiovascular disease were selected. Studies concerning post-surgery rehabilitation, case studies, and articles that did not measure primary results were excluded. RESULTS: Sixteen studies met inclusion criteria, addressing osteoarthritis (n=5), diabetes mellitus (n=5), and cardiovascular disease (n=6). Studies generally supported associations of lower leg power among older adults with chronic disease, although small sample sizes, cross-sectional data, homogenous populations, varied disease definitions, and inconsistent leg power methods limited conclusions. CONCLUSIONS: Studies suggest that osteoarthritis, diabetes mellitus, and cardiovascular disease are associated with lower leg power compared to older adults without these conditions. These studies are limited, however, by the heterogeneity in study populations and a lack of standardized measurements of leg power. Future larger studies of more diverse older adults with well-defined chronic disease using standard measures of leg power and interventions to improve leg power in these older adults with chronic disease are needed.

Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes.

We examined the hypothesis that an excess accumulation of intramuscular lipid (IMCL) is associated with insulin resistance and that this may be mediated by the oxidative capacity of muscle. Nine sedentary lean (L) and 11 obese (O) subjects, 8 obese subjects with type 2 diabetes mellitus (D), and 9 lean, exercise-trained (T) subjects volunteered for this study. Insulin sensitivity (M) determined during a hyperinsulinemic (40 mU x m(-2)min(-1)) euglycemic clamp was greater (P < 0.01) in L and T, compared with O and D (9.45 +/- 0.59 and 10.26 +/- 0.78 vs. 5.51 +/- 0.61 and 1.15 +/- 0.83 mg x min(-1)kg fat free mass(-1), respectively). IMCL in percutaneous vastus lateralis biopsy specimens by quantitative image analysis of Oil Red O staining was approximately 2-fold higher in D than in L (3.04 +/- 0.39 vs. 1.40 +/- 0.28% area as lipid; P < 0.01). IMCL was also higher in T (2.36 +/- 0.37), compared with L (P < 0.01). The oxidative capacity of muscle determined with succinate dehydrogenase staining of muscle fibers was higher in T, compared with L, O, and D (50.0 +/- 4.4, 36.1 +/- 4.4, 29.7 +/- 3.8, and 33.4 +/- 4.7 optical density units, respectively; P < 0.01). IMCL was negatively associated with M (r = -0.57, P < 0.05) when endurance-trained subjects were excluded from the analysis, and this association was independent of body mass index. However, the relationship between IMCL and M was not significant when trained individuals were included. There was a positive association between the oxidative capacity and M among nondiabetics (r = 0.37, P < 0.05). In summary, skeletal muscle of trained endurance athletes is markedly insulin sensitive and has a high oxidative capacity, despite having an elevated lipid content. In conclusion, the capacity for lipid oxidation may be an important mediator of the association between excess muscle lipid accumulation and insulin resistance.

Plasma fatty acids, adiposity, and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus.

Skeletal muscle insulin resistance (IR) is typically severe in type 2 diabetes mellitus (DM). However, the factors that account for interindividual differences in the severity of IR are not well understood. The current study was undertaken to examine the respective roles of plasma FFA, regional adiposity, and other metabolic factors as determinants of the severity of skeletal muscle IR in type 2 DM. Twenty-three subjects (12 women and 11 men) with type 2 DM underwent positron emission tomography imaging using [18F]2-fluoro-2-deoxyglucose during euglycemic insulin infusions (120 mU/min x m2) to measure skeletal muscle IR, using Patlak analysis of the tissue activity curves. Body composition analysis included body mass index, fat mass, and fat-free mass by dual energy x-ray tomography, and computed tomography determinations of visceral adiposity, thigh adipose tissue distribution, and muscle composition. Body mass index, fat mass, subfascial adiposity in the thigh, and visceral adipose tissue (VAT) were all significantly related to skeletal muscle IR (r = -0.48 to -0.63; P < 0.01). However, the strongest simple correlate of IR in skeletal muscle was insulin-suppressed plasma FFA (r = -0.81; P < 0.001). VAT was the sole component of adiposity that significantly correlated with insulin-suppressed plasma FFA concentration (r = 0.64; P < 0.001). These findings indicate that the severity of skeletal muscle IR in type 2 DM is closely related to the IR of suppressing lipolysis and that plasma fatty acids and VAT are key elements mediating the link between obesity and skeletal muscle IR in type 2 DM.

Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus.

BACKGROUND: Adipose tissue (AT) content of the thigh is generally not considered to be associated with insulin resistance (IR), but it is unclear whether the distribution of AT in the thigh is a determinant of IR. OBJECTIVE: We investigated whether subcompartments of AT within the thigh are determinants of IR. DESIGN: Midthigh AT, muscle composition, and insulin sensitivity were compared in 11 obese patients with type 2 diabetes mellitus (DM); 40 obese, glucose-tolerant (GT) and 15 lean, GT volunteers; and 38 obese subjects who completed a weight-loss program. Midthigh AT area measured with computed tomography was partitioned into 3 components: subcutaneous AT (SCAT), AT beneath the fascia (SFAT), and AT infiltrating muscle groups (IMAT). Muscle attenuation characteristics were determined. RESULTS: Obese DM and obese GT subjects had lower insulin sensitivity than lean GT subjects. SCAT was greater in obesity, yet did not correlate with insulin sensitivity. SFAT was approximately 8% of total thigh AT and correlated with insulin sensitivity. IMAT was highest in obese DM, and although it accounted for only approximately 3% of thigh AT, it was a strong correlate of insulin sensitivity. Mean attenuation was highest in lean subjects and was associated with higher insulin sensitivity. Weight loss reduced the amount of thigh AT, the proportion of thigh IMAT, and the amount of low-density thigh muscle. CONCLUSIONS: SFAT and IMAT are markers of IR in obesity and DM although they are much smaller than SCAT, which does not predict IR. Muscle composition reflecting increased fat content is also associated with IR.

Composition of skeletal muscle evaluated with computed tomography.

Computed tomography (CT) can yield quantitative imaging data from detailed maps of linear attenuation coefficients within tissue. The attenuation characteristics of skeletal muscle and adipose tissue can be quantified in vivo to provide information about the composition of skeletal muscle and the distribution of adipose tissue within muscle. Several studies have taken advantage of this utility to quantify skeletal muscle composition and fatty infiltration of muscle, in particular to quantify the attenuation characteristics of muscle as a marker of its lipid content. In this manner we found that the mean muscle attenuation of skeletal muscle reflects an increase in its fat content in obesity, and that this regional body composition parameter is strongly related to insulin-resistant glucose metabolism. In addition, muscle composition and adipose tissue distribution within muscle may be altered with clinical weight-loss interventions. CT may also provide important information about the changes in muscle mass and composition with aging and disease, which may, in turn, affect the muscle's function. In summary, CT can provide important quantitative data on the composition of muscle, and the distribution of adipose tissue within it, and this may be important in examining the relationships among skeletal muscle metabolism, lipid accumulation within muscle, and muscle function.

Reexamining the sarcopenia hypothesis. Muscle mass versus muscle strength. Health, Aging, and Body Composition Study Research Group.

The association of muscle mass and muscle strength with lower-extremity performance, as measured by timed repeated chair stands, was investigated using preliminary data from 3,075 Black and White participants (70-79 years old) in the Health, Aging, and Body Composition Study. Leg muscle mass (LM) was measured by dual-energy X-ray absorptiometry (Hologic QDR 4500). The maximal isokinetic torque of the leg extensors (LS) was measured at 60 degrees/s using a Kin-Com isokinetic dynamometer. Men were stronger, had greater LM, and better performance than women. As expected, low LS was associated with poorer performance after adjusting for race, study site, and body fat. Low LM was associated with poorer performance in men and women, with a potential threshold effect in women only. When LS and LM were modeled simultaneously, only LS remained independently associated with performance. In conclusion, muscle strength, but not muscle mass, is independently associated with lower-extremity performance.

Intramuscular lipid content is increased in obesity and decreased by weight loss.

The triglyceride content of skeletal muscle samples determined by lipid extraction correlates with the severity of insulin-resistant glucose metabolism in muscle. To determine whether this reflects increased triglyceride within muscle fibers and to test the hypothesis that the lipid content in muscle fibers is increased in obesity, the present study was undertaken using quantitative histochemistry of Oil Red O staining of vastus lateralis muscle. A percutaneous muscle biopsy was performed in 9 lean subjects, 15 obese subjects without type 2 diabetes mellitus (DM), and 10 obese subjects with type 2 DM (body mass index [BMI], 23.4+/-1.0, 33.6+/-0.6, and 36.0+/-1.1 kg x m(-2) for lean, obese, and DM, respectively). Eight obese and 7 DM subjects had a weight loss and reassessment of muscle lipid content. Transverse muscle cryosections were examined by light microscopy with quantitative image analysis (grayscale images obtained by analog to digital conversion) to determine a lipid accumulation index (LAI) based on the percentage of cross-sectional fiber area occupied by lipid droplets. Muscle fiber lipid content was greater in obese individuals with DM than in lean individuals (3.62%+/-0.65% v 1.42%+/-0.28%, P < .05) but was not different in obese individuals without DM (2.53%+/-0.41%). Weight loss reduced the LAI from 3.43%+/-0.53% to 2.35%+/-0.31%. In summary, lipid accumulation within muscle fibers is significantly increased in obesity and is reduced by weight loss. This provides important information regarding the accumulation and distribution of skeletal muscle triglyceride in type 2 DM and obesity.

Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content.

The purpose of this investigation was to validate that in vivo measurement of skeletal muscle attenuation (MA) with computed tomography (CT) is associated with muscle lipid content. Single-slice CT scans performed on phantoms of varying lipid concentrations revealed good concordance between attenuation and lipid concentration (r(2) = 0.995); increasing the phantom's lipid concentration by 1 g/100 ml decreased its attenuation by approximately 1 Hounsfield unit (HU). The test-retest coefficient of variation for two CT scans performed in six volunteers was 0.51% for the midthigh and 0.85% for the midcalf, indicating that the methodological variability is low. Lean subjects had significantly higher (P < 0.01) MA values (49.2 +/- 2.8 HU) than did obese nondiabetic (39.3 +/- 7.5 HU) and obese Type 2 diabetic (33.9 +/- 4. 1 HU) subjects, whereas obese Type 2 diabetic subjects had lower MA values that were not different from obese nondiabetic subjects. There was also good concordance between MA in midthigh and midcalf (r = 0.60, P < 0.01), psoas (r = 0.65, P < 0.01), and erector spinae (r = 0.77, P < 0.01) in subsets of volunteers. In 45 men and women who ranged from lean to obese (body mass index = 18.5 to 35.9 kg/m(2)), including 10 patients with Type 2 diabetes mellitus, reduced MA was associated with increased muscle fiber lipid content determined with histological oil red O staining (P = -0.43, P < 0. 01). In a subset of these volunteers (n = 19), triglyceride content in percutaneous biopsy specimens from vastus lateralis was also associated with MA (r = -0.58, P = 0.019). We conclude that the attenuation of skeletal muscle in vivo determined by CT is related to its lipid content and that this noninvasive method may provide additional information regarding the association between muscle composition and muscle function.

Exogenous carbohydrate oxidation from different carbohydrate sources during exercise.

The exogenous carbohydrate (CHO) oxidation of naturally enriched [13C]CHO sources with different solubilities was studied during cycling exercise (150 min, 60% maximum work output). Moreover, the effect of adding a 13C tracer with different physical properties than the tracee on exogenous CHO oxidation was investigated. Test solutions (28.5 ml/kg body wt) were water for control of 13C background, 15% soluble partially hydrolyzed corn starch (SOL), 15% insoluble corn starch (In-SOL), and 15% InSOL with [13C6]glucose as tracer. Both the mean and peak exogenous oxidation rates were significantly greater (P < 0.05) in the SOL trial than in the InSOL trial (mean oxidation rate, 0.84 +/- 0.21 and 0.50 +/- 0.15 g/min, respectively; peak oxidation rate, 1.10 +/- 0.18 and 0.81 +/- 0.25 g/min, respectively). The amount of the ingested CHO that was oxidized was significantly higher (P < 0.05) in the SOL trial (126 +/- 31 g) than in the InSOL trial (75 +/- 25 g). When we added an extrinsic tracer ([13C]glucose), the apparent mean and peak oxidation rates of the trial with InSOL and [13C6]glucose were significantly (P < 0.05) higher (0.91 +/- 0.30 and 1.23 +/- 0.41, respectively) than the InSOL values. These results 1) indicate that the addition of the soluble [13C]glucose tracer to an insoluble starch tracee leads to overestimation of the exogenous CHO oxidation rates and 2) suggest that soluble CHO is oxidized at a higher rate during exercise than isocaloric insoluble CHO.

Attenuation of skeletal muscle and strength in the elderly: The Health ABC Study.

Although loss of muscle mass is considered a cause of diminished muscle strength with aging, little is known regarding whether composition of aging muscle affects strength. The skeletal muscle attenuation coefficient, as determined by computed tomography, is a noninvasive measure of muscle density, and lower values reflect increased muscle lipid content. This investigation examined the hypothesis that lower values for muscle attenuation are associated with lower voluntary isokinetic knee extensor strength at 60 degrees/s in 2,627 men and women aged 70-79 yr participating in baseline studies of the Health ABC Study, a longitudinal study of health, aging, and body composition. Strength was higher in men than in women (132.3 +/- 34.5 vs. 81.4 +/- 22.0 N x m, P < 0.01). Men had greater muscle attenuation values (37.3 +/- 6.5 vs. 34.7 +/- 7.0 Hounsfield units) and muscle cross-sectional area (CSA) at the midthigh than women (132.7 +/- 22.4 vs. 93.3 +/- 17.5 cm(2), P < 0.01 for both). The strength per muscle CSA (specific force) was also higher in men (1.00 +/- 0.21 vs. 0.88 +/- 0.21 N x m x cm(-2)). The attenuation coefficient was significantly lower for hamstrings than for quadriceps (28.7 +/- 8.7 vs. 41.1 +/- 6.9 Hounsfield units, P < 0.01). Midthigh muscle attenuation values were lowest (P < 0.01) in the eldest men and women and were negatively associated with total body fat (r = -0.53, P < 0.01). Higher muscle attenuation values were also associated with greater specific force production (r = 0.26, P < 0.01). Multivariate regression analysis revealed that the attenuation coefficient of muscle was independently associated with muscle strength after adjustment for muscle CSA and midthigh adipose tissue in men and women. These results demonstrate that the attenuation values of muscle on computed tomography in older persons can account for differences in muscle strength not attributed to muscle quantity.