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The objectives of this study were to 1) examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2) determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [n = 8; body mass index (BMI) 23.8 [+ or -] 0.58 kg/[m.sup.2]], overweight/obese (n = 8; BMI 30.2 [+ or -] 0.81 kg/[m.sup.2]), and extremely obese (n = 8; BMI 53.8 [+ or -] 3.5 kg/[m.sup.2]) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 [+ or -] 5.2 nmol*[g.sup.-1]*[h.sup.-1]) patients compared with normal-weight (71.0 [+ or -] 5.0 nmol*[g.sup.-1]*[h.sup.-1]) and overweight/obese (82.2 [+ or -] 8.7 nmol*[g.sup.-1]*[h.sup.-1]) patients, respectively. Palmitate oxidation was negatively (R = -0.44, P = 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation. long-chain fatty acyl-coenzyme A; intramyocellular triacylglycerol; fatty acids

The purpose of this study was to test the hypothesis that weight loss results in a reduction in intramuscular lipid (IMCL) content that is concomitant with enhanced insulin action. Muscle biopsies were obtained from morbidly obese individuals [body mass index (BMI) 52.2 [+ or -]2.5 kg/[m.sup.2]; n = 6] before and after gastric bypass surgery, an intervention that improves insulin action. With intervention, there was a 47% reduction (P < 0.01) in BMI and a 93% decrease in homeostasis model assessment, or HOMA (7.0 [+ or -] 1.9 vs. 0.5 +_ 0.1). Histochemically determined IMCL content decreased (P < 0.05) by ~30%. In relation to fiber type, IMCL was significantly higher in type I vs. type II fibers. In both fiber types, there were reductions in IMCL and trends for muscle atrophy. Despite these two negating factors, the IMCL-to-fiber area ratio still decreased by ~44% with weight loss. In conclusion, despite differing initial levels and possible atrophy, weight loss appears to decrease IMCL deposition to a similar relative extent in type I and II muscle fibers. This reduction in intramuscular triglyceride may contribute to enhanced insulin action seen with weight loss. insulin resistance; obesity; skeletal muscle; triglyceride

Adiponectin is an adipocytokine that is hypothesized to be involved in the regulation of insulin action. The purpose of the present investigation was to determine whether plasma adiponectin is altered in conjunction with enhanced insulin action with exercise training. An insulin sensitivity index ([S.sub.I]) and fasting levels of glucose, insulin, and adiponectin were assessed before and after 6 mo of exercise training (4 days/wk for ~45 min at 65-80% peak [0.sub.2] consumption) with no loss of body mass (PRE, 91.9 [+ or -] 3.8 kg vs. POST, 91.6 [+ or -] 3.9 kg) or fat mass (PRE, 26.5 [+ or -] 1.8 kg vs. POST, 26.7 [+ or -] 2.2 kg). Insulin action significantly (P < 0.05) improved with exercise training ([S.sub.I] +98%); however, plasma adiponectin concentration did not change (PRE, 6.3 [+ or -] 1.5 [micro]g/ml vs. POST, 6.6 [+ or -] 1.8 [micro]g/ml). In contrast, in a separate group of subjects examined before and after weight loss, there was a substantial increase in adiponectin (+281%), which was accompanied by enhanced insulin action ([S.sub.I], +432%). These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity. weight loss

The purpose of this study was to test the hypothesis that muscle fiber type is related to obesity. Fiber type was compared 1) in lean and obese women, 2) in Caucasian (C) and African-American (AA) women, and 3) in obese individuals who lost weight after gastric bypass surgery. When lean (body mass index 24.0 [+ or -] 0.9 kg/[m.sup.2], n = 28) and, obese (34.8 [+ or -] 0.9 kg/[m.sup.2], n = 25) women were compared, there were significant (P < 0.05) differences in muscle fiber type. The obese women possessed fewer type I (41.5 [+ or -] 1.8 vs. 54.6 [+ or -] 1.8%) and more type IIb (25.1 [+ or -] 1.5 vs. 14.4 [+ or -] 1.5%) fibers than the lean women. When ethnicity was accounted for, the percentage of type IIb fibers in obese AA was significantly higher than in obese C (31.0 [+ or -] 2.4% vs. 19.2 [+ or -] 1.9%); fewer type I fibers were also found in obese AA (34.5 [+ or -] 2.8% vs. 48.6 [+ or -] 2.2%). These data are consistent with the higher incidence of obesity and greater weight gain reported in AA women. With weight loss intervention, there was a positive relationship (r = 0.72, P < 0.005) between the percentage of excess weight loss and the percentage of type I fibers in morbidly obese patients. These findings indicate that there is a relationship between muscle fiber type and obesity. adiposity; African-American; insulin resistance; morbid obesity; skeletal muscle

Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in middle-aged men. Am J Physiol Endocrinol Metab 282: E147-E153, 2002.--The purpose of this study was to determine whether the improved insulin action with short-term exercise training in middle-aged individuals is associated with enhanced phosphatidylinositol (PI) 3-kinase activity in skeletal muscle. Nine men of ages 50-70 yr were studied before and after 7 consecutive days of supervised exercise (60 min/day, 70% peak [O.sub.2] consumption). Insulin sensitivity was measured with a euglycemic hyperinsulinemic glucose clamp in the sedentary condition and 15-17 h after the final exercise session. Anti-phosphotyrosine-associated PI 3-kinase activity was determined from muscle samples obtained in the fasted condition and after 60 min of insulin infusion during the clamp. With exercise, the glucose infusion rate increased (P < 0.001) by 33%, indicating enhanced insulin action (mean [+ or -] SE, 6.6 [+ or -] 0.6 vs. 8.7 [+ or -] 0.8 mg*[kg.sup.- 1]*[min.sup.-1]). Short-term exercise training did not, however, increase insulin-stimulated (insulin stimulated/fasting) PI 3-kinase activity (1.8 [+ or -] 0.8 vs. 1.8 [+ or -] 0.7-fold stimulation with insulin pre- vs. posttraining, respectively). There was also no change in insulin-stimulated protein kinase B activity (1.3 [+ or -] 0.1 vs. 1.4 [+ or -] 0.2-fold stimulation with insulin) with training. These data suggest that insulin action is enhanced with short-term exercise training via an adaptation distal to PI 3-kinase in middle-aged, insulin-resistant individuals. aging; glucose transport; insulin resistance; physical activity; skeletal muscle

The relationship among skeletal muscle fiber composition, in vitro glucose transport rate and adiposity is investigated in human beings. The study reveals that there is no independent relationship between these factors. The study also further indicates that a multifactorial process is involved in the maintenance of the relationship between these three factors.

The purpose of this study was to determine whether intramyocellular glucose partitioning was altered in primary human myotubes derived from severely obese women with type 2 diabetes. Human skeletal muscle cells were obtained from lean nondiabetic and severely obese Caucasian females with type 2 diabetes [body mass index (BMI): 23.6 ± 2.6 vs. 48.8 ± 1.9 kg/m2, fasting glucose: 86.9 ± 1.6 vs. 135.6 ± 12.0 mg/dL, n = 9/group]. 1-[14C]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1- and 2-[14C]- pyruvate oxidation were examined in fully differentiated myotubes under basal and insulin-stimulated conditions. Tricarboxylic acid cycle intermediates were determined via targeted metabolomics. Myotubes derived from severely obese individuals with type 2 diabetes exhibited impaired insulin-mediated glucose partitioning with reduced rates of glycogen synthesis and glucose oxidation and increased rates of nonoxidized glycolytic products, when compared with myotubes derived from the nondiabetic individuals (P < 0.05). Both 1- and 2-[14C]-pyruvate oxidation rates were significantly blunted in myotubes from severely obese women with type 2 diabetes compared with myotubes from the nondiabetic controls. Lastly, concentrations of tricarboxylic acid cycle intermediates, namely, citrate (P < 0.05), cis-aconitic acid (P = 0.07), and α-ketoglutarate (P < 0.05), were lower in myotubes from severely obese women with type 2 diabetes. These data suggest that intramyocellular insulin-mediated glucose partitioning is intrinsically altered in the skeletal muscle of severely obese women with type 2 diabetes in a manner that favors the production of glycolytic end products. Defects in pyruvate dehydrogenase and tricarboxylic acid cycle may be responsible for this metabolic derangement associated with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Cortright, Ronald N., John L. Azevedo, Jr., Qian Zhou, Madhur Sinha, Walter J. Pories, Samar I. Itani, and G. Lynis Dohm. Protein kinase C modulates insulin action in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 278: E553-E562, 2000.--There is good evidence from cell lines and rodents that elevated protein kinase C (PKC) overexpression/activity causes insulin resistance. Therefore, the present study determined the effects of PKC activation/ inhibition on insulin-mediated glucose transport in incubated human skeletal muscle and primary adipocytes to discern a potential role for PKC in insulin action. Rectus abdominus muscle strips or adipocytes from obese, insulin-resistant, and insulin-sensitive patients were incubated in vitro under basal and insulin (100 nM)-stimulated conditions in the presence of GF 109203X (GF), a PKC inhibitor, or 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a PKC activator. PKC inhibition had no effect on basal glucose transport. GF increased (P [is less than] 0.05) insulin-stimulated 2-deoxyglucose (2-DOG) transport approximately twofold above basal. GF plus insulin also increased (P [is less than] 0.05) insulin receptor tyrosine phosphorylation 48% and phosphatidylinositol 3-kinase (PI 3-kinase) activity ~50% (P [is less than] 0.05) vs. insulin treatment alone. Similar results for GF on glucose uptake were observed in human primary adipocytes. Further support for the hypothesis that elevated PKC activity is related to insulin resistance comes from the finding that PKC activation by dPPA was associated with a 40% decrease (P [is less than] 0.05) in insulin-stimulated 2-DOG transport. Incubation of insulin-sensitive muscles with GF also resulted in enhanced insulin action (~3-fold above basal). These data demonstrate that certain PKC inhibitors augment insulin-mediated glucose uptake and suggest that PKC may modulate insulin action in human skeletal muscle. insulin resistance; diabetes; non-insulin-dependent diabetes mellitus; glucose transport; muscle

We examined the hypothesis that metabolic surgery-induced massive weight loss causes mass-driven and behavioral adaptations in the kinematics and kinetics of obese gait. Gait analyses were performed at three time points over ~1 yr in initially morbidly obese (mass: 125.7 kg; body mass index: 43.2 kg/m²) but otherwise healthy adults. Ten obese adults lost 27.1% ± 5.1 (34.0 ± 9.4 kg) weight by the first follow-up at 7.0 mo (±0.7) and 6.5 ± 4.2% (8.2 ± 6.0 kg) more by the second follow-up at 12.8 mo (±0.9), with a total weight loss of 33.6 ± 8.1% (42.2 ± 14.1 kg; P = 0.001). Subjects walked at a self-selected and a standard 1.5 m/s speed at the three time points and were also compared with an age- and gender-matched comparison group at the second follow-up. Weight loss increased swing time, stride length, gait speed, hip range of motion, maximal knee flexion, and ankle plantarflexion. Weight loss of 27% led to 3.9% increase in gait speed. An additional 6.5% weight loss led to an additional 7.3% increase in gait speed. Sagittal plane normalized knee torque increased and absolute ankle and frontal plane knee torques decreased after weight loss. We conclude that large weight loss produced mechanical plasticity by modifying ankle and knee torques and gait behavior. There may be a weight loss threshold of 30 kg limiting changes in gait kinematics. Implications for exercise prescription are also discussed. [ABSTRACT FROM AUTHOR]

Individuals with insulin resistance and obesity display higher skeletal muscle production of nonoxidized glycolytic products (i.e., lactate), and lower complete mitochondrial substrate oxidation to CO2. These findings have also been observed in individuals without obesity and are associated with an increased risk for metabolic disease. The purpose of this study was to determine if substrate preference is evident at the earliest stage of life (birth) and to provide a clinical blood marker (lactate) that could be indicative of a predisposition for metabolic disease later. We used radiolabeled tracers to assess substrate oxidation and insulin sensitivity of myogenically differentiated mesenchymal stem cells (MSCs), a proxy of infant skeletal muscle tissue, derived from umbilical cords of full-term infants. We found that greater production of nonoxidized glycolytic products (lactate, pyruvate, alanine) is directly proportional to lower substrate oxidation and insulin sensitivity in MSCs. In addition, we found an inverse relationship between the ratio of complete glucose oxidation to CO2 and infant blood lactate at 1 mo of age. Collectively, considering that higher lactate was associated with lower MSC glucose oxidation and has been shown to be implicated with metabolic disease, it may be an early indicator of infant skeletal muscle phenotype. NEW & NOTEWORTHY In infant myogenically differentiated mesenchymal stem cells, greater production of nonoxidized glycolytic products was directly proportional to lower substrate oxidation and insulin resistance. Glucose oxidation was inversely correlated with infant blood lactate. This suggests that innate differences in infant substrate oxidation exist at birth and could be associated with the development of metabolic disease later in life. Clinical assessment of infant blood lactate could be used as an early indicator of skeletal muscle phenotype.