PURPOSE: Obese women have increased rates of metabolic diseases compared to those of healthy weight status. Additionally, African-American (AA) women have higher rates of metabolic disease compared to Caucasian (CA) women. Metabolic inflexibility is the inability to adjust substrate oxidation in response to dietary intake; potentially leading to weight gain and the development of metabolic disease. Few studies have investigated the impact of weight status and/or ethnicity on the metabolic response of women to a single high fat meal. An acute unfavorable metabolic response may contribute to the higher incidence of metabolic disease among not only obese, but also AA women. Therefore, the purpose of this study was to determine the impact that weight status (lean vs. overweight/obese) and/or ethnicity (CA vs. AA) has on metabolic health in women in response to a single high fat meal. METHODS: CA (n= 15; age=26.27±5.65 yrs; BMI=30.72±11.92kg/m2) and AA (n= 12; age=26.75±6.65yrs; BMI=28.32±6.91kg/m2) women consumed a high fat shake (1062 calories, 56% fat). Blood was drawn and resting energy expenditure (REE) and substrate oxidation (estimated using indirect calorimetry) were assessed at baseline/fasted (T1), 120 minutes post-shake, (T2) 240 minutes post-shake (T3). RESULTS: Lipid and carbohydrate oxidation significantly increased among all women in response to the high fat meal (p<0.01). Significant increases in fat oxidation were seen from T1-T2 for all women (CA lean: +57.9±24.5%; CA overweight/obese: +30.2±11.8%; AA lean: +10.2±18.1%; AA overweight/obese: +40.6±52.6%; p<0.01). Among the CA women only, CA lean women displayed a significantly higher increase in fat oxidation in response to the meal compared to CA overweight/obese women, but there were no differences among lean and overweight/obese AA women. Similarly, weight status influenced changes in apolipoproteins after consuming the high fat meal among CA women, but not AA women. CONCLUSIONS: CA lean women displayed the most metabolic flexibility in response to the high fat meal. A metabolic system that is less able to respond to metabolic stimuli such as a high fat diet (as noted in all groups compared to lean CA women) may play a role in the increased metabolic disease prevalence among obese and AA women.

Inflammation is a central feature of various metabolic diseases including obesity and type-II diabetes. For this study, we hypothesized postprandial metabolism following an acute, high fat (HF) meal to be impaired in mice pre-injected with an inflammatory agonist. To this end, C57BL/6J mice were injected with saline or lipopolysaccharide (LPS, 1μg/kgbw) following an overnight fast and gavaged 2hr post-injection with water or a HF meal in liquid form (5kcal; 21.4%SF, 40.8%UF, 27.1%CHO, 10.7%PRO). Blood and muscle samples taken 3hr post-gavage underwent ex vivo analysis. Overall, results demonstrated a metabolic response to a HF meal that was blocked in the presence of LPS. Metabolic flexibility, though unchanged following the HF meal alone, was reduced following the HF meal in the presence of LPS. Additionally, state-4 uncoupled mitochondrial respiration, which was increased following the HF meal, was also reduced following the HF meal in the presence of LPS. Similar near-significant trends were also observed with total palmitate oxidation. Although no independent response to a HF meal or LPS exposure was observed, a unique interaction between treatments significantly diminished ADP dependent, state-3 and maximal respiration. These effects do not appear to be dependent on the production of reactive oxygen species (ROS) since neither the HF meal nor LPS exposure resulted in increased production of ROS. In conclusion, these results demonstrate that acute activation of inflammatory pathways results in alterations in metabolic response to a HF meal in skeletal muscle from mice, although the mechanism underlying these effects is not yet understood. / Master of Science

Metabolic flexibility plays a significant role in energy homeostasis by regulating fuel selection in correspondence to energy demand. Obese and type II diabetic populations have displayed a hindered ability to properly transition from fat oxidation while in a fasted state to carbohydrate oxidation once fed, leading to a buildup of mitochondrial metabolites such as acylcarnitines. Carnitine, essential for fatty acyl-CoA transport through the inner and outer mitochondrial membranes, can be an indicator of mitochondrial distress as elevated levels tend to spill over into plasma suggesting a disruption in oxidation. The current study was designed to examine the effect of short term, high fat feeding on plasma acylcarnitine species diversity and levels and if acylcarnitines are associated with metabolic flexibility. 13 healthy, non-obese, sedentary males, aged 18-40 years participated in this study. Following a 12-hour overnight fast a biopsy was taken from the quadricep before and 4 hours after a high fat meal. Blood draws were obtained pre-biopsy while fasted and every hour for 4 hours post high fat meal consumption. Acylcarnitines from plasma were converted to their butyl esters and analyzed by electrospray ionization tandem mass spectrometry (MS/MS). Changes were observed in acetylcarntine (P=0.0125), glucose oxidation (P=0.0295), C16:1/C16:0 desaturation index (P= 0.0397), and C18:1/C18:0 desaturation index (P=0.0012). We did not find that individual changes in flexibility correlated with circulating acylcarnitine measurements in a fasted state / Master of Science

The ability to adapt fuel usage to nutrient availability is termed metabolic flexibility, and is influenced by activity of the pyruvate dehydrogenase complex (PDC). The Virginia lines of chickens are a unique model of anorexia and obesity that have resulted from 56 generations of artificial selection for high (HWS) or low (LWS) juvenile body weight. We hypothesized that hyperphagia and obesity in juvenile HWS chickens are associated with altered fatty acid oxidation efficiency and metabolic flexibility in tissues associated with energy sensing and storage, and relative cellular hypertrophy in white adipose tissue. Hypothalamus, liver, Pectoralis major, gastrocnemius, abdominal fat, clavicular fat and subcutaneous fat were collected from juvenile (56-65 day-old) HWS and LWS chickens for metabolic, gene expression and histological assays. The HWS chickens had reduced fatty acid oxidation efficiency in abdominal fat (P < 0.0001) and reduced rates of oxidation in abdominal fat and gastrocnemius (P < 0.0001) as compared to LWS. There was reduced citrate synthase activity in white adipose tissue (P < 0.0001) and greater metabolic inflexibility in skeletal muscle (P = 0.006) of HWS compared to LWS. Greater pyruvate dehydrogenase kinase 4 (PDK4) and forkhead box O1 (FoxO1) mRNA were found in skeletal muscle and white adipose tissue of 56-day-old HWS than LWS. Expression of peroxisome proliferator-activated receptor γ (PPARγ) in all adipose tissue depots was greater (P < 0.05) in LWS than in HWS chickens. The HWS chickens had larger (P < 0.0001) and fewer (P < 0.0001) adipocytes per unit area than LWS. These results suggest that the HWS chickens have impaired metabolic flexibility and fatty acid oxidation efficiency due to an up-regulation of pyruvate dehydrogenase activity to accommodate the influx of acetyl CoA from fatty acid oxidation in skeletal muscle and white adipose tissue. These metabolic adaptations can be linked to differences in gene expression regulation and body composition between the lines. Adipocyte cellularity data are consistent with greater oxidative efficiency in the adipose tissue of LWS, because of the greater number of unfilled cells in all depots that were sampled. Results can be extrapolated to agricultural production in the understanding of factors regulating the amount of lipid deposition in chicken carcass fat. Results may also provide insight into eating disorders and the development of obesity. / Master of Science

Energy metabolism involves processes of energy intake and energy expenditure, including storage of excessive energy in a form of lipids. White adipose tissue stores energy and plays an important role in maintenance of energy homeostasis. Animals obtain energy by oxidation of substrates from diet. Indirect calorimetry is a method for assessment of energy expenditure based on a measurement of oxygen consumption and carbon dioxide production. The VCO2/VO2 ratio (Respiratory Quotient) indicates oxidation of specific metabolic substrates. Metabolic flexibility is the ability of an organism to match substrate oxidation to its availability. The decrease of a metabolic flexibility is linked to inability to adapt to available substrate and with excessive lipid storage in the body. In this thesis we evaluated correlation between the metabolic flexibility defined by indirect calorimetry and the adipose tissue metabolism in two strains of mice, C57Bl/6J and AJ, that differ in their propensity to diet-induced obesity. Increased whole-body metabolic flexibility in A/J mice was connected to higher ability of adipose tissue to release and uptake lipids. The study of reaction to high-fat diet enables us to distinguish "metabolically healthy" and "metabolically unhealthy" adipose tissue. The knowlegde of these...

AMPK is a master regulator of cellular energy homeostasis. The gain-of-function AMPKg3 R225W mutation in human skeletal muscle increases resistance to fatigue during exercise, mitochondrial content, and glycogen storage. We demonstrate that primary myotubes exhibit increased OCR, decreased ECAR, increased FAO, and increased activities of several mitochondrial complexes. To examine whether functional effects are attributable to mitochondrial content, we inhibited AMPK; differences between R225W and control were diminished. Glycogen phosphorylase inhibition demonstrated normal respiration independent of glycogen. We examined markers of quality/quantity control of mitochondria. In R225W muscle, fusion markers increased, biogenesis markers remained unchanged, mTOR pathway was inhibited, and there was greater capacity for autophagic flux and mitophagy. We thus determine that bioenergetic effects of R225W are in part due to active AMPK, but also due to capacity for more robust mitochondria. Overall, R225W provides a model for evaluating effects of AMPK, and new avenues toward treatment of metabolic disease.

Insulin resistance (IR), T2DM, and obesity together form a cluster of interrelated metabolic challenges that may be linked by metabolic inflexibility. Metabolic inflexibility is characterized by the resistance to switching substrate oxidation preference based on substrate availability and can be measured in either fasted or insulin-stimulated conditions. As the largest site for glucose disposal and a primary tissue influencing regulation of blood glucose concentrations, skeletal muscle likely plays a central role in regulating substrate oxidation preference based on substrate availability. Skeletal muscle lipotoxicity caused by an impaired regulation of fat uptake and oxidation is postulated to disrupt insulin signaling and lead to skeletal muscle IR. High dietary saturated fat intake results in reduced basal fat oxidation and a resistance to switching to carbohydrate oxidation during insulin-stimulated conditions in susceptible individuals. This metabolic inflexibility may lead to an accumulation of intramyocellular species that impair insulin signaling. Endurance exercise training improves the capacity for fat oxidation in metabolically inflexible individuals. However, relatively little is known about how endurance exercise training influences substrate oxidation preference when paired with a high fat diet (HFD). Therefore, the purpose of this study was to determine the effects of a HFD on substrate metabolism in skeletal muscle of sedentary and endurance trained (ET) males. Healthy, sedentary (n=17) and ET (n=7) males first consumed a 10-day moderate carbohydrate diet (55% carbohydrate, 30% total fat, <10% saturated fat) isocaloric to their individual energy requirements and then underwent a 4- hour high fat challenge testing session. During the session, they consumed a high fat meal (820 kcals; 25% carbohydrate, 63% total fat [26% saturated fat]), and skeletal muscle biopsies were taken in the fasted and 4-hour postprandial conditions. Participants then consumed a 5-day HFD (30% carbohydrate, 55% total fat, 25% saturated fat) and repeated the high fat challenge testing session. Substrate oxidation measures were performed on the collected skeletal muscle tissue, and the meal effect, defined as the percent change from the fasting to 4- hour postprandial condition, for each measure was calculated. There was a HFD by physical activity group interaction on meal effect for metabolic flexibility (P<0.05) and a HFD effect on meal effect for glucose oxidation (P<0.05). Meal effects for metabolic flexibility and glucose oxidation were maintained in the ET (20 ± 4% to 41 ± 21% and 128 ± 92% and 41 ± 15%, respectively; both P>0.05) but decreased in the sedentary (34 ± 7% to 4 ± 5% and 78 ± 26% to -21 ± 6%, respectively; both P<0.01) group. There were trends toward HFD effects on reductions in meal effects for total (P=0.062) and incomplete (P=0.075) fat oxidation, which were driven primarily by an increase in fasting total (12.1 ± 2.6 nmol/mg protein/h to 18.5 ± 2.3 nmol/mg protein/h; P<0.01) and incomplete (11.5 ± 2.5 nmol/mg protein/h to 17.6 ± 2.3 nmol/mg protein/h; P<0.01) fat oxidation in the ET group as a result of the HFD. Fasting total and incomplete fat oxidation did not change in the sedentary group (7.3 ± 0.8 nmol/mg protein/h to 7.8 ± 0.8 nmol/mg protein/h and 6.8 ± 0.7 nmol/mg protein/h to 7.2 ± 0.8 nmol/mg protein/h, respectively; both P>0.05). Overall, these findings suggest the ET state attenuates deleterious effects of a short-term HFD on reduced metabolic flexibility and insulin-stimulated glucose oxidation. In addition, a HFD-induced reduction in fat oxidation during the fasted-to-fed transition may be caused by differing mechanisms in sedentary and ET individuals. These findings provide a basis for future work targeting the elucidation of potential mechanistic differences in substrate oxidation preference between sedentary and ET individuals. / Ph. D. / Type 2 diabetes (T2DM) is a commonly occurring disease worldwide, and treatment of the disease is considerably burdensome for individuals and societies. T2DM is closely related to insulin resistance (IR) and obesity, and in each of these conditions, the characteristic of metabolic inflexibility has been observed. Metabolic inflexibility is a reduced ability to adjust fat or carbohydrate utilization for energy based on the availability of each of these macronutrients. Skeletal muscle may be an important tissue in the regulation of macronutrient utilization since it plays a key role in blood glucose regulation. High dietary saturated fat intake may lead to metabolic inflexibility in skeletal muscle in susceptible individuals. This metabolic inflexibility may result in increased storage of fat within skeletal muscle, which is hypothesized to disrupt insulin signaling. This disruption can lead to IR. Endurance exercise training improves metabolic flexibility. However, little is known about how endurance exercise training influences macronutrient utilization when paired with a high fat diet (HFD). Therefore, the purpose of this study was to determine the effects of a HFD on macronutrient utilization in skeletal muscle of sedentary and endurance trained (ET) males. Seventeen healthy, sedentary males and seven ET males first consumed a 10-day moderate-carbohydrate diet that was provided by the study investigators and designed to keep each participant weight stable. Participants then underwent a high fat challenge testing session in which they consumed a high fat meal and had skeletal muscle biopsies taken both before and after the meal. Participants then consumed a 5-day HFD, also designed to keep them weight stable, and repeated the high fat challenge testing session. Macronutrient utilization measures were performed on the collected skeletal muscle samples. Overall, metabolic flexibility was reduced in the sedentary group but was maintained in the ET group, which suggests that ET individuals may be protected against developing a HFD-induced metabolic inflexibility in skeletal muscle and its associated downstream negative effects on insulin signaling. In addition, fat utilization during the high fat challenge meal decreased in both sedentary and ET individuals as a result of the HFD. However, fat utilization in the fasted state was higher in ET individuals after the HFD compared with baseline, but fat utilization was the same in sedentary individuals before and after the HFD. This suggests there may be differences between sedentary and ET individuals in the mechanisms involved in the adjustment of fat utilization to dietary fat intake. Further research is needed to understand these differences, as they may play important roles in understanding how IR and T2DM develop.

Background: There has been very little research regarding the metabolic health of women during the postpartum period. Metabolic flexibility is the physiological ability to alter substrate oxidation in response to substrate availability and is a good indicator of overall metabolic health. Metabolic flexibility can be assessed by placing metabolic demands on the body and observing metabolic responsiveness- two examples of such metabolic stressors are lipid oxidation rates in response to a high-fat meal and as well as exercise. However, it is unknown whether postpartum women will respond similarly to these two different types of metabolic stressors. This information will allow researchers and clinicians to understand whether postpartum women can be considered more or less metabolically flexible based on one of these tests alone, or if both types of metabolic stress should be incorporated into research designs and/or clinical practice to fully understand one’s metabolic health during this critical time period. Objective: To determine the association between the metabolic responsiveness to a high-fat meal and a 30- minute continuous, moderate-intensity exercise among women during the sixth- month postpartum period. Methods: Seventeen healthy, postpartum women (age: 32 ± 4.5 year; body mass index: 24.74 ± 3.97 kg/m²) participated approximately six months after delivery. Metabolic measurements VO2 and VCO2 (L. min ̄ ¹) were measured and used to calculate the rates of lipid oxidation (g. min ̄ ¹) at baseline, two-hour post consumption of a high-fat meal and during a moderate-intensity exercise for 30-minutes. Results: A correlation was found between the lipid oxidation fold change in response to a high-fat meal and exercise (r= 0.45, p= 0.08; however, it was not statistically significant. There was a significant effect of time on lipid and carbohydrate oxidation rates (p<0.001) during baseline, after consumption of a high-fat meal and during a 30-minute exercise bout. Conclusion: A trending relationship was observed between the metabolic responsiveness to a high-fat meal and a 30-minute moderate-intensity exercise bout among women during the six-month postpartum

Les missions spatiales et les études de simulation par alitement prolongé ont montré que l’inactivité physique induite par la microgravité affecte l’ensemble des systèmes physiologiques chez l’humain. En condition d’alitement prolongé notre laboratoire (UMR7178, IPHC, DEPE, Strasbourg) a montré que l’adaptation métabolique était proche de celle retrouvée dans le syndrome métabolique associé, dans la population générale, à de nombreuses pathologies. Une hypothèse a été émise pour décrire la cascade des événements entraînant les dérèglements métaboliques en microgravité simulée. Cette cascade d’adaptations aurait pour conséquence le développement d’un état d’inflexibilité métabolique, définie comme une incapacité à ajuster l’utilisation des nutriments comme substrats aux changements de disponibilité des nutriments et dont la compréhension reste toutefois incomplète. Lors de ce projet de thèse, nous nous sommes attachés à caractériser le syndrome d’inflexibilité métabolique chez l’Humain à travers l’investigation clinique de l’état musculaire, de l’inflammation et du stress oxydant, de la sensibilité à l’insuline et de l’oxydation des substrats énergétiques au cours d’une étude de preuve de concept et d’une étude de simulation de microgravité de 60 jours. Sur la base d’études récentes démontrant l’impact de compléments nutritionnels sur les adaptations métaboliques associées à de nombreuses maladies métaboliques chroniques, une étude de preuve de concept a permis de tester l’efficacité d’un cocktail nutritionnel composé de polyphénols, d’oméga-3, de vitamine E et de sélénium. La supplémentation a permis de réduire l’atrophie musculaire, le stress oxydant et le développement d’une inflexibilité métabolique par l’intermédiaire d’une meilleure oxydation lipidique et d’une réduction de la lipogenèse de novo suite à une période d’inactivité physique de 20 jours. Sur la base de ces premiers résultats, une étude d’alitement de 60 jours a été menée chez l’Humain pour tester les effets du cocktail nutritionnel en condition de microgravité simulée. Dans cette seconde étude, la supplémentation nutritionnelle a permis de prévenir au moins partiellement des adaptations aigües et chroniques engendrées par l’inactivité physique au cours de l’alitement. En particulier la supplémentation a augmenté les défenses sanguines anti-oxydantes, a prévenu l’augmentation de la lipidémie et la réduction de l’oxydation lipidique et a contenu le développement d’une inflexibilité métabolique aiguë et chronique en absence de challenge métabolique. Toutefois la contremesure n’a pas eu d’effet protecteur suite à un challenge métabolique sous forme de surnutrition glucidique. L’ensemble des résultats indique que le développement d’une inflexibilité métabolique apparaît comme un événement précoce, qui, décelé à temps pourrait se révéler comme un biomarqueur d’intolérance au glucose dans des stratégies de prévention des maladies chroniques du XXIème siècle. Plus encore, cette étude a permis de démontrer l’atout d’un cocktail antioxydant et anti-inflammatoire en limitant les altérations métaboliques sans avoir d'effets néfastes sur les autres systèmes, tout en étant une contremesure facile à mettre en œuvre et peu coûteuse. Quand bien même la contremesure nutritionnelle utilisée lors de cette étude ne serait pas suffisante pour maintenir l’ensemble des systèmes physiologiques intacts, d’autres études devront être menées afin de trouver la combinaison de contremesures idéale permettant de limiter les dégradations induites par la microgravité et ainsi permettre des nouvelles avancées dans l’exploration spatiale (Lune, Mars) au cours des prochaines décennies. En ce sens, un protocole adapté d’activité physique combiné à une contremesure nutritionnelle sous forme de cocktail semble être une piste prometteuse. / Space missions and bedrest simulation studies have shown that physical inactivity affects all physiological systems in humans. In prolonged bed rest conditions, our laboratory (UMR7178, IPHC, DEPE, Strasbourg) showed that metabolic adaptations were close to that found in the metabolic syndrome associated with metabolic chronic diseases in the general population. Based on these results, we proposed a hypothesis to describe the cascade of events leading to metabolic alterations in simulated microgravity, leading to the development of metabolic inflexibility. Metabolic inflexibility is defined as the inability of the body to adjust fuel use to changes in fuel availability. The first objective of this Thesis was to test this hypothesis and understand the mechanisms underlying the simulated microgravity induced metabolic alterations. Specifically, we focused on characterizing the metabolic inflexibility syndrome in humans through clinical investigation of muscle condition, inflammation and oxidative stress, insulin sensitivity and oxidation of energy substrates in a proof of concept study and a 60-day microgravity simulation study in healthy male adults. Based on recent studies demonstrating the impact of nutritional supplements on metabolic adaptations associated with many chronic metabolic diseases, a proof-of-concept study tested the efficacy of a nutritional cocktail composed of polyphenols, omega-3, vitamin E and selenium. In the feasibility study, we showed that supplementation reduced muscle atrophy, oxidative stress and the development of metabolic inflexibility via an improvement in lipid oxidation and a reduction in de novo lipogenesis following a 20-day period of physical inactivity induced by daily step reduction. Based on these first results, a 60-day bed rest study was conducted in health men to test the effects of the dietary cocktail in simulated microgravity conditions. In this second human clinical research study, nutritional supplementation prevented at least partially acute and chronic adaptations caused by physical inactivity induced by bed rest. In particular, supplementation increased antioxidant blood defenses, prevented increased lipid levels, reduced lipid oxidation and mitigated the development of acute and chronic metabolic inflexibility in absence of metabolic challenge. However, the countermeasure did not have a protective effect following a metabolic challenge in the form of carbohydrate overnutrition. All the results indicate that the development of metabolic inflexibility appears to be an early event, which, if detected in time, could prove to be a useful biomarker to use to prevent chronic diseases in the 21st century. Moreover, this study demonstrated the advantage of an antioxidant and anti-inflammatory cocktail by limiting metabolic alterations without having harmful effects on other systems, while being easy to implement and cost-effective. Even if the nutritional countermeasure used in this study is not sufficient to keep all physiological systems intact, further studies will have to be carried out to find the ideal combination of countermeasures to limit microgravity-induced degradation and thus allow new advances in space exploration (Moon, Mars) over the next decades. In this line, an adapted protocol of physical activity combined with a nutritional countermeasure in the form of a cocktail could be a promising approach.

Introduction . Non-Hispanic blacks (blacks) are more insulin resistant compared to non-Hispanic whites (whites), increasing their risk for Type 2 diabetes. The role played by ethnic/racial disparities in the response to physical activity in mediating those higher rates of insulin resistance in blacks is unknown. Because the beneficial effects of exercise are transient and require subsequent doses of exercise to maintain the effect; the metabolic and psychosocial responses to single exercise bouts have strong implications for both opposing insulin resistance and raising the probability that an individual will continue to exercise. Purpose . To compare the metabolic and psychosocial responses to individual bouts of exercise, at the intensity and duration corresponding to the current Institute of Medicine guidelines, in blacks and age/gender/BMI-matched whites. Methods . Insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic flexibility (suppression of resting fat oxidation) along with exercise task self-efficacy, mood, and state-anxiety were assessed before and after a bout of exercise in black and white men and women (metabolic n = 21; psychosocial n = 31). Participants walked on a treadmill at 75% of maximum heart rate for 75 minutes. Exercise sessions were repeated on three separate occasions to assess the cumulative change in psychosocial responses to exercise. Results . There were no ethnic/racial differences in baseline measures of whole-body insulin sensitivity (p = 0.95). Black participants demonstrated larger improvements in the insulin sensitivity response to individual bouts of exercise compared to their white counterparts (+18% vs. -1.8%), which was primarily the result of enhanced non-oxidative glucose disposal during the clamp. Additionally, blacks demonstrated a greater capacity to switch from primarily fat oxidation at rest to primarily carbohydrate oxidation during the clamp (p <0.003). There were no ethnic/racial differences in the psychosocial response to individual bouts of exercise; individual bouts of exercise improved exercise task self-efficacy and reduced psychological distress in both black and white participants (p = 0.006). Black participants reported higher positive in-task mood during all three bouts of exercise (p = 0.003) and lower RPE scores (p = 0.04) during the third exercise bout compared to white participants, despite similar heart rates in both groups. Conclusions . These data demonstrate that metabolic and psychosocial responses to individual bouts of exercise do not help to explain the increased insulin resistance and lower adherence rates to exercise programs reported in blacks compared to whites. If these results are confirmed in a larger, more diverse, free-living population, future research should focus on social determinants of insulin resistance and physical inactivity to obtain a better understanding of the root causes of increased risk of Type 2 diabetes in black populations.