Bret H. Goodpaster

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.

Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss

The current study was undertaken to investigate fatty acid metabolism by skeletal muscle to examine potential mechanisms that could lead to increased muscle triglyceride in obesity. Sixteen lean and 40 obese research volunteers had leg balance measurement of glucose and free fatty acid (FFA) uptake (fractional extraction of [9,103H]oleate) and indirect calorimetry across the leg to determine substrate oxidation during fasting and insulin-stimulated conditions. Muscle obtained by percutaneous biopsy had lower carnitine palmitoyl transferase (CPT) activity and oxidative enzyme activity in obesity ( P < 0.05). During fasting conditions, obese subjects had an elevated leg respiratory quotient (RQ, 0.83 ± 0.02 vs. 0.90 ± 0.01; P < 0.01) and reduced fat oxidation but similar FFA uptake across the leg. During insulin infusions, fat oxidation by leg tissues was suppressed in lean but not obese subjects; rates of FFA uptake were similar. Fasting values for leg RQ correlated with insulin sensitivity ( r = -0.57, P < 0.001). Thirty-two of the obese subjects were restudied after weight loss (WL, -14.0 ± 0.9 kg); insulin sensitivity and insulin suppression of fat oxidation improved ( P < 0.01), but fasting leg RQ (0.90 ± 0.02 vs. 0.90 ± 0.02, pre-WL vs. post-WL) and muscle CPT activity did not change. The findings suggest that triglyceride accumulation in skeletal muscle in obesity derives from reduced capacity for fat oxidation and that inflexibility in regulating fat oxidation, more than fatty acid uptake, is related to insulin resistance.The current study was undertaken to investigate fatty acid metabolism by skeletal muscle to examine potential mechanisms that could lead to increased muscle triglyceride in obesity. Sixteen lean and 40 obese research volunteers had leg balance measurement of glucose and free fatty acid (FFA) uptake (fractional extraction of [9,10 (3)H]oleate) and indirect calorimetry across the leg to determine substrate oxidation during fasting and insulin-stimulated conditions. Muscle obtained by percutaneous biopsy had lower carnitine palmitoyl transferase (CPT) activity and oxidative enzyme activity in obesity (P < 0.05). During fasting conditions, obese subjects had an elevated leg respiratory quotient (RQ, 0.83 +/- 0.02 vs. 0.90 +/- 0.01; P < 0.01) and reduced fat oxidation but similar FFA uptake across the leg. During insulin infusions, fat oxidation by leg tissues was suppressed in lean but not obese subjects; rates of FFA uptake were similar. Fasting values for leg RQ correlated with insulin sensitivity (r = -0.57, P < 0.001). Thirty-two of the obese subjects were restudied after weight loss (WL, -14.0 +/- 0.9 kg); insulin sensitivity and insulin suppression of fat oxidation improved (P < 0.01), but fasting leg RQ (0.90 +/- 0.02 vs. 0.90 +/- 0.02, pre-WL vs. post-WL) and muscle CPT activity did not change. The findings suggest that triglyceride accumulation in skeletal muscle in obesity derives from reduced capacity for fat oxidation and that inflexibility in regulating fat oxidation, more than fatty acid uptake, is related to insulin resistance.

Longitudinal study of muscle strength, quality, and adipose tissue infiltration

BACKGROUND Sarcopenia is thought to be accompanied by increased muscle fat infiltration. However, no longitudinal studies have examined concomitant changes in muscle mass, strength, or fat infiltration in older adults. OBJECTIVE We present longitudinal data on age-related changes in leg composition, strength, and muscle quality (MQ) in ambulatory, well-functioning men and women. We hypothesized that muscle cross-sectional area (CSA) and strength would decrease and muscular fat infiltration would increase over 5 y. DESIGN Midthigh muscle, subcutaneous fat (SF), and intermuscular fat (IMF) CSAs and isokinetic leg muscle torque (MT) and MQ (MT/quadriceps CSA) were examined over 5 y in the Health, Aging, and Body Composition study cohort (n = 1678). RESULTS Men experienced a 16.1% loss of MT, whereas women experienced a 13.4% loss. Adjusted annualized decreases in MT were 2-5 times greater than the loss of muscle CSA in those who lost weight and in those who remained weight-stable. Weight gain did not prevent the loss of MT, despite a small increase in muscle CSA. Only those who gained weight had an increase in SF (P < 0.001), whereas those who lost weight also lost SF (P < 0.001). There was an age-related increase in IMF in men and women (P < 0.001), and IMF increased in those who lost weight, gained weight, or remained weight-stable (all P < 0.001). CONCLUSIONS Loss of leg MT in older adults is greater than muscle CSA loss, which suggests a decrease in MQ. Additionally, aging is associated with an increase in IMF regardless of changes in weight or SF.

Sarcopenia: Alternative Definitions and Associations with Lower Extremity Function

Objectives: To compare two sarcopenia definitions and examine the relationship between them and lower extrem‐ity function and other health related factors using data from the baseline examination of the Health Aging and Body Composition (Health ABC) Study.

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.

Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial.

CONTEXT The prevalence of severe obesity is increasing markedly, as is prevalence of comorbid conditions such as hypertension and type 2 diabetes mellitus; however, apart from bariatric surgery and pharmacotherapy, few clinical trials have evaluated the treatment of severe obesity. OBJECTIVE To determine the efficacy of a weight loss and physical activity intervention on the adverse health risks of severe obesity. DESIGN, SETTING, AND PARTICIPANTS Single-blind randomized trial conducted from February 2007 through April 2010 at the University of Pittsburgh. Participants were 130 (37% African American) severely obese (class II or III) adult participants without diabetes recruited from the community. INTERVENTIONS One-year intensive lifestyle intervention consisting of diet and physical activity. One group (initial physical activity) was randomized to diet and physical activity for the entire 12 months; the other group (delayed physical activity) had the identical dietary intervention but with physical activity delayed for 6 months. MAIN OUTCOME MEASURES Changes in weight. Secondary outcomes were additional components comprising cardiometabolic risk, including waist circumference, abdominal adipose tissue, and hepatic fat content. RESULTS Of 130 participants randomized, 101 (78%) completed the 12-month follow-up assessments. Although both intervention groups lost a significant amount of weight at 6 months, the initial-activity group lost significantly more weight in the first 6 months compared with the delayed-activity group (10.9 kg [95% confidence interval {CI}, 9.1-12.7] vs 8.2 kg [95% CI, 6.4-9.9], P = .02 for group × time interaction). Weight loss at 12 months, however, was similar in the 2 groups (12.1 kg [95% CI, 10.0-14.2] vs 9.9 kg [95% CI, 8.0-11.7], P = .25 for group × time interaction). Waist circumference, visceral abdominal fat, hepatic fat content, blood pressure, and insulin resistance were all reduced in both groups. The addition of physical activity promoted greater reductions in waist circumference and hepatic fat content. CONCLUSION Among patients with severe obesity, a lifestyle intervention involving diet combined with initial or delayed initiation of physical activity resulted in clinically significant weight loss and favorable changes in cardiometabolic risk factors. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00712127.

Decreased Muscle Strength and Quality in Older Adults With Type 2 Diabetes: The Health, Aging, and Body Composition Study

Adequate skeletal muscle strength is essential for physical functioning and low muscle strength is a predictor of physical limitations. Older adults with diabetes have a two- to threefold increased risk of physical disability. However, muscle strength has never been investigated with regard to diabetes in a population-based study. We evaluated grip and knee extensor strength and muscle mass in 485 older adults with diabetes and 2,133 without diabetes in the Health, Aging, and Body Composition study. Older adults with diabetes had greater arm and leg muscle mass than those without diabetes because they were bigger in body size. Despite this, muscle strength was lower in men with diabetes and not higher in women with diabetes than corresponding counterparts. Muscle quality, defined as muscle strength per unit regional muscle mass, was significantly lower in men and women with diabetes than those without diabetes in both upper and lower extremities. Furthermore, longer duration of diabetes (≥6 years) and poor glycemic control (HbA1c >8.0%) were associated with even poorer muscle quality. In conclusion, diabetes is associated with lower skeletal muscle strength and quality. These characteristics may contribute to the development of physical disability in older adults with diabetes.

Accelerated Loss of Skeletal Muscle Strength in Older Adults With Type 2 Diabetes The Health, Aging, and Body Composition Study

OBJECTIVE—It has been shown that adults with either long-standing type 1 or type 2 diabetes had lower skeletal muscle strength than nondiabetic adults in cross-sectional studies. The aim of the study was to investigate longitudinal changes of muscle mass and strength in community-dwelling older adults with and without type 2 diabetes. RESEARCH DESIGN AND METHODS—We examined leg and arm muscle mass and strength at baseline and 3 years later in 1,840 older adults aged 70–79 years in the Health, Aging, and Body Composition Study. Regional muscle mass was measured by dual energy X-ray absorptiometry, and muscle strength was measured using isokinetic and isometric dynamometers. RESULTS—Older adults with type 2 diabetes (n = 305) showed greater declines in the leg muscle mass (−0.29 ± 0.03 vs. −0.23 ± 0.01 kg, P < 0.05) and strength (−16.5 ± 1.2 vs. −12.4 ± 0.5 Nm, P = 0.001) compared with older adults without diabetes. Leg muscle quality, expressed as maximal strength per unit of muscle mass (Newton meters per kilogram), also declined more rapidly in older adults with diabetes (−1.6 ± 0.2 vs. −1.2 ± 0.1 Nm/kg, P < 0.05). Changes in arm muscle strength and quality were not different between those with and without diabetes. Rapid declines in leg muscle strength and quality were attenuated but remained significant after controlling for demographics, body composition, physical activity, combined chronic diseases, interleukin-6, and tumor necrosis factor-α. CONCLUSIONS—In older adults, type 2 diabetes is associated with accelerated loss of leg muscle strength and quality.

Strength and muscle quality in a well-functioning cohort of older adults: the Health, Aging and Body Composition Study.

OBJECTIVES:  To determine whether lower lean mass and higher fat mass have independent effects on the loss of strength and muscle quality in older adults and might explain part of the effect of age.

Excessive Loss of Skeletal Muscle Mass in Older Adults with Type 2 Diabetes

OBJECTIVE A loss of skeletal muscle mass is frequently observed in older adults. The aim of the study was to investigate the impact of type 2 diabetes on the changes in body composition, with particular interest in the skeletal muscle mass. RESEARCH DESIGN AND METHODS We examined total body composition with dual-energy X-ray absorptiometry annually for 6 years in 2,675 older adults. We also measured mid-thigh muscle cross-sectional area (CSA) with computed tomography in year 1 and year 6. At baseline, 75-g oral glucose challenge tests were performed. Diagnosed diabetes (n = 402, 15.0%) was identified by self-report or use of hypoglycemic agents. Undiagnosed diabetes (n = 226, 8.4%) was defined by fasting plasma glucose (≥7 mmol/l) or 2-h postchallenge plasma glucose (≥11.1 mmol/l). Longitudinal regression models were fit to examine the effect of diabetes on the changes in body composition variables. RESULTS Older adults with either diagnosed or undiagnosed type 2 diabetes showed excessive loss of appendicular lean mass and trunk fat mass compared with nondiabetic subjects. Thigh muscle CSA declined two times faster in older women with diabetes than their nondiabetic counterparts. These findings remained significant after adjusting for age, sex, race, clinic site, baseline BMI, weight change intention, and actual weight changes over time. CONCLUSIONS Type 2 diabetes is associated with excessive loss of skeletal muscle and trunk fat mass in community-dwelling older adults. Older women with type 2 diabetes are at especially high risk for loss of skeletal muscle mass.