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.

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.

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.

The impact of sarcopenia on a physical activity intervention: the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).

OBJECTIVE: To determine if sarcopenia modulates the response to a physical activity intervention in functionally limited older adults. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Three academic centers. PARTICIPANTS: Elders aged 70 to 89 years at risk for mobility disability who underwent dual-energy x-ray absorptiometry (DXA) for body composition at enrollment and follow-up at twelve months (N = 177). INTERVENTION: Subjects participated in a physical activity program (PA) featuring aerobic, strength, balance, and flexibility training, or a successful aging (SA) educational program about healthy aging. MEASUREMENTS: Sarcopenia as determined by measuring appendicular lean mass and adjusting for height and total body fat mass (residuals method), Short Physical Performance Battery score (SPPB), and gait speed determined on 400 meter course. RESULTS: At twelve months, sarcopenic and non-sarcopenic subjects in PA tended to have higher mean SPPB scores (8.7±0.5 and 8.7±0.2 points) compared to sarcopenic and non-sarcopenic subjects in SA (8.3±0.5 and 8.4±0.2 points, p = 0.24 and 0.10), although the differences were not statistically significant. At twelve months, faster mean gait speeds were observed in PA: 0.93±0.4 and 0.95±0.03 meters/second in sarcopenic and non-sarcopenic PA subjects, and 0.89±0.4 and 0.91±0.03 meters/second in sarcopenic and non-sarcopenic SA subjects (p = 0.98 and 0.26), although not statistically significant. There was no difference between the sarcopenic and non-sarcopenic groups in intervention adherence or number of adverse events. CONCLUSION: These data suggest that older adults with sarcopenia, who represent a vulnerable segment of the elder population, are capable of improvements in physical performance after a physical activity intervention.

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.

Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity.

OBJECTIVE: The link between a reduced capacity for skeletal muscle mitochondrial fatty acid oxidation (FAO) and lipotoxicity in human insulin resistance has been the subject of intense debate. The objective of this study was to investigate whether reduced FAO is associated with elevated acyl CoA, ceramide, and diacylglycerol (DAG) in severely obese insulin resistant subjects. METHODS: Muscle biopsies were conducted in lean (L, 22.6 ± 0.5 kg/m(2) , n = 8), Class I (CI, 32.1 ± 0.4 kg/m(2) , n = 7) and Class II&III obese (CII&III, 45.6 ± 1.1 kg/m(2) , n = 15) women for acyl CoA, sphingolipid and DAG profiling. Intramyocellular triglyceride (IMTG) content was determined by histology. FAO was assessed by incubating muscle homogenates with [1-C]palmitate and measuring CO2 production. Cardiolipin content was quantified as an index of mitochondrial content. Lipid metabolism proteins, DGAT1, PLIN5, and PNPLA2 were quantified in biopsy samples by western blot. RESULTS: CII&III were more insulin resistant (HOMA-IR: 4.5 ± 0.5 vs. 1.1 ± 0.1, P < 0.001), and had lower FAO (∼58%, P = 0.007) and cardiolipin content (∼31%, P = 0.013) compared to L. IMTG was elevated in CI (P = 0.04) and CII&III (P = 0.04) compared to L. Sphingolipid content was higher in CII&III compared to L (13.6 ± 1.1 vs. 10.3 ± 0.5 pmol/mg, P = 0.031) whereas DAG content was not different among groups. DGAT1 was elevated in CII&III, and PLIN5 was elevated in CI compared to L. CONCLUSIONS: Severe obesity is associated with reduced muscle oxidative capacity and occurs concomitantly with elevated IMTG, ceramide and insulin resistance.

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.

Low subcutaneous thigh fat is a risk factor for unfavourable glucose and lipid levels, independently of high abdominal fat. The Health ABC Study.

AIMS: We investigated whether low subcutaneous thigh fat is an independent risk factor for unfavourable glucose and lipid levels, and whether these associations differ between sexes, and between white and black adults. Our secondary aim was to investigate which body composition characteristics (lean tissue, fat tissue) are reflected by anthropometric measures (waist and thigh circumference). METHODS: Anthropometric measurements and computed tomography of the abdomen and of the thigh were performed for all participants of the Health, Aging and Body Composition Study, who were aged 70-79 years. Fasting glucose, triglycerides and HDL-cholesterol, and 2-h postload glucose were determined. RESULTS: After excluding those already diagnosed with diabetes or dyslipidaemia, we analysed data from 2,106 participants. After adjustment for abdominal subcutaneous and visceral fat, and intermuscular thigh fat, larger thigh subcutaneous fat area was statistically significantly associated with lower ln-transformed triglycerides [standardised beta (95% CI) -0.12 (-0.20 to -0.04) in men and -0.13 (-0.21 to -0.05) in women] and higher ln-HDL-cholesterol [0.10 (0.02 to 0.19) and 0.09 (0.01 to 0.18), respectively]. The associations with lower glucose levels were strong in men [-0.11 (-0.20 to -0.02) for fasting and -0.14 (-0.23 to -0.05) for postload glucose], but not statistically significant in women [-0.02 (-0.10 to 0.07) and -0.04 (-0.13 to 0.05), respectively]. There were no differences in the associations between white and black persons. Waist circumference was more strongly associated with abdominal subcutaneous fat, and this association became stronger with increasing BMI, whereas the association with visceral fat became weaker. Thigh circumference was equally dependent on thigh fat and thigh muscle in men, whereas in women the fat component was the main contributor. CONCLUSION: Larger subcutaneous thigh fat is independently associated with more favourable glucose (in men) and lipid levels (in both sexes) after accounting for abdominal fat depots, which are associated with unfavourable glucose and lipid levels. Anthropometric measures reflect different fat depots at different levels of BMI at the abdomen, and reflect both fat and lean tissue at the thigh. These results emphasise the importance of accurate measures of regional body composition when investigating potential health risks.

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.

Fat content in individual muscle fibers of lean and obese subjects.

OBJECTIVE: To examine skeletal muscle intracellular triglyceride concentration in different fiber types in relation to obesity. DESIGN: Skeletal muscle fiber type distribution and intracellular lipid content were measured in vastus lateralis samples obtained by needle biopsy from lean and obese individuals. SUBJECTS: Seven lean controls (body mass index (BMI) 23.0+/-3.3 kg/m(2); mean+/-s.d.) and 14 obese (BMI 33.7+/-2.7 kg/m(2)) individuals; both groups included comparable proportions of men and women. MEASUREMENTS: Samples were histochemically stained for the identification of muscle fiber types (myosin ATPase) and intracellular lipid aggregates (oil red O dye). The number and size of fat aggregates as well as their concentration within type I, IIA and IIB muscle fiber types were measured. The cellular distribution of the lipid aggregates was also examined. RESULTS: The size of fat aggregates was not affected by obesity but the number of lipid droplets within muscle fibers was twice as abundant in obese compared to lean individuals. This was seen in type I (298+/-135 vs 129+/-75; obese vs lean, P<0.05), IIA (132+/-67 vs 79+/-29; P<0.05), and IIB (103+/-63 vs 51+/-13; P<0.05) muscle fibers. A more central distribution of lipid droplets was observed in muscle fibers of obese compared to lean subjects (27.2+/-5.7 vs 19.7+/-6.4%; P<0.05). CONCLUSION: The higher number of lipid aggregates and the disposition to a greater central distribution in all fiber types in obesity indicate important changes in lipid metabolism and/or storage that are fiber type-independent.

Effects of exercise on glucose homeostasis in Type 2 diabetes mellitus.

PURPOSE: This review has evaluated the effectiveness of physical activity in the treatment and prevention of Type 2 diabetes mellitus (DM). METHODS: The available literature was reviewed through a computerized search (MEDLINE, 1966--2000) to classify studies examining the influence of physical activity on the treatment and prevention of Type 2 DM. Additional studies were reviewed through ancestral searches from their bibliographies. RESULTS: It is not possible at the present time to discern from the available literature whether a dose-response relationship exists between exercise volume or intensity and improvements in glucose control in Type 2 DM. Large-scale, prospective studies indicate that higher levels of physical activity are clearly associated with a lower incidence of Type 2 DM. However, no randomized controlled trials have been conducted to address the dose-response effect of exercise or physical activity on diabetes treatment or prevention. CONCLUSION: It is uncertain whether there is a dose-response effect of exercise on improved glucose control in Type 2 DM. There does appear to be, however, a limited amount of evidence suggesting that increasing levels of physical activity contribute to better diabetes prevention. Clearly, additional studies are needed to determine the influence of physical activity on the treatment and prevention of Type 2 DM.

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.

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.

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.

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.