Summary Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA) or standard chow (SC) diets. Despite having reduced food intake and weight gain equivalent to the SC group, HF/BCAA rats were equally insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1(ser307), accumulation of multiple acylcarnitines in muscle, and was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a poor dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

The highest amount of weekly exercise, with minimal weight change, had widespread beneficial effects on the lipoprotein profile. The improvements were related to the amount of activity and not to the intensity of exercise or improvement in fitness.

In preparation of the paper, there were several errors in the figure labeling, which were regretfully missed in the preparation and proofreading of the manuscript and which the authors would like to correct. None of these changes affects the data or the conclusions of the paper.(1) The heading of Figure 2H should read ''Glucose Infusion Rate,'' not ''Insulin Infusion Rate.'' (2) In the corresponding text on page 431 (right column, paragraph 2, line 13), the units for glucose infusion rate should be ''mg/kg/min,'' not ''mg/dl.'' (3) Likewise, on the y axis in Figure 2I, the units for glucose should read ''mg/kg/min'' rather than ''mg/dl.'' (4) On the y axis in Figures 3C, 4F, 4G, 4H, and 5D, the parenthetical reference to ''ARNT/Actin'' carried over from previous figures should simply be deleted. The correct specific genes or proteins measured in each panel are already indicated. (5) In Figure 5A, the correct units are ''mM,'' not ''mM/l.

Physical activity enhances insulin action in obese/overweight individuals. However, the exercise prescription required for the optimal enhancement is not known. The purpose of this study was to test the hypothesis that exercise training consisting of vigorous-intensity activity would enhance insulin sensitivity more substantially than moderate-intensity activity. Sedentary, overweight/obese subjects (n = 154) were randomly assigned to either control or an exercise group for 6 mo: 1) low-volume/moderate-intensity group [ approximately 12 miles walking/wk at 40-55% peak O2 consumption (Vo2 peak)], 2) low-volume/high-intensity group ( approximately 12 miles jogging/wk at 65-80% Vo2 peak), and 3) high-volume/high-intensity group ( approximately 20 miles jogging/wk at 65-80% Vo2 peak). Training volume (miles/wk) was achieved by exercising approximately 115 min/wk (low-volume/high-intensity group) or approximately 170 min/wk (low-volume/moderate-intensity and high-volume/high-intensity groups). Insulin action was measured with an insulin sensitivity index (SI) from an intravenous glucose tolerance test. In the control group, there was a decrement (P < 0.05) in SI. In contrast, all the exercise groups significantly (P < 0.05) increased SI; the relative increment in the low-volume/moderate-intensity and high-volume/high-intensity groups ( approximately 85%) were greater than in the low-volume/high-intensity group ( approximately 40%). In conclusion, physical activity encompassing a wide range of intensity and volume minimizes the insulin resistance that develops with a sedentary lifestyle. However, an exercise prescription that incorporated approximately 170 min of exercise/wk improved insulin sensitivity more substantially than a program utilizing approximately 115 min of exercise/wk, regardless of exercise intensity and volume. Total exercise duration should thus be considered when designing training programs with the intent of improving insulin action.

BackgroundIndividuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed.Methodology/Principal FindingsAn adverse response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors.Conclusions/SignificanceAdverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.

OBJECTIVETo determine whether circulating metabolic intermediates are related to insulin resistance and β-cell dysfunction in individuals at risk for type 2 diabetes.RESEARCH DESIGN AND METHODSIn 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry–based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates.RESULTSThe 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (SI) (R2 = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R2 = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) (R2 = 0.39). Sex differences were found for metabolic predictors of SI and DI.CONCLUSIONSIn addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.

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 (SI) 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 O2 consumption) with no loss of body mass (PRE, 91.9 ± 3.8 kg vs. POST, 91.6 ± 3.9 kg) or fat mass (PRE, 26.5 ± 1.8 kg vs. POST, 26.7 ± 2.2 kg). Insulin action significantly ( P < 0.05) improved with exercise training (SI +98%); however, plasma adiponectin concentration did not change (PRE, 6.3 ± 1.5 μg/ml vs. POST, 6.6 ± 1.8 μg/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 (SI, +432%). These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity.

Although exercise improves individual risk factors for metabolic syndrome (MS), there is little research on the effect of exercise on MS as a whole. The objective of this study was to determine how much exercise is recommended to decrease the prevalence of MS. Of 334 subjects randomly assigned, 227 finished and 171 (80 women, 91 men) had complete data for all 5 Adult Treatment Panel III-defined MS risk factors and were included in this analysis. Subjects were randomly assigned to a 6-month control or 1 of 3 eight-month exercise training groups of (1) low amount/moderate intensity (equivalent to walking approximately 19 km/week), (2) low amount/vigorous intensity (equivalent to jogging approximately 19 km/week), or (3) high amount/vigorous intensity (equivalent to jogging approximately 32 km/week). The low-amount/moderate-intensity exercise prescription improved MS relative to inactive controls (p <0.05). However, the same amount of exercise at vigorous intensity was not significantly better than inactive controls, suggesting that lower-intensity exercise may be more effective in improving MS. The high-amount/vigorous-intensity group improved MS relative to controls (p <0.0001), the low-amount/vigorous-intensity group (p = 0.001), and the moderate-intensity group (p = 0.07), suggesting an exercise-dose effect. In conclusion, a modest amount of moderate-intensity exercise in the absence of dietary changes significantly improved MS and thus supported the recommendation that adults get 30 minutes of moderate-intensity exercise every day. A higher amount of vigorous exercise had greater and more widespread benefits. Finally, there was an indication that moderate-intensity may be better than vigorous-intensity exercise for improving MS.