Nicole L. Helbling

Exercise and Weight Loss Improve Muscle Mitochondrial Respiration, Lipid Partitioning, and Insulin Sensitivity After Gastric Bypass Surgery

Both Roux-en-Y gastric bypass (RYGB) surgery and exercise can improve insulin sensitivity in individuals with severe obesity. However, the impact of RYGB with or without exercise on skeletal muscle mitochondria, intramyocellular lipids, and insulin sensitivity index (SI) is unknown. We conducted a randomized exercise trial in patients (n = 101) who underwent RYGB surgery and completed either a 6-month moderate exercise (EX) or a health education control (CON) intervention. SI was determined by intravenous glucose tolerance test. Mitochondrial respiration and intramyocellular triglyceride, sphingolipid, and diacylglycerol content were measured in vastus lateralis biopsy specimens. We found that EX provided additional improvements in SI and that only EX improved cardiorespiratory fitness, mitochondrial respiration and enzyme activities, and cardiolipin profile with no change in mitochondrial content. Muscle triglycerides were reduced in type I fibers in CON, and sphingolipids decreased in both groups, with EX showing a further reduction in a number of ceramide species. In conclusion, exercise superimposed on bariatric surgery–induced weight loss enhances mitochondrial respiration, induces cardiolipin remodeling, reduces specific sphingolipids, and provides additional improvements in insulin sensitivity.

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

BACKGROUND Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S(I)) in obese patients. Regular exercise can also improve S(I) in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S(I) and other cardiometabolic factors. METHODS We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S(I) and glucose effectiveness (S(G)), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week). RESULTS 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S(I) improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min⁻¹/μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S(I) improvement (PP: CON vs. EX; +1.57 vs. +2.69 min⁻¹/μU/ml, P = 0.019) above that of surgery. Exercise also improved S(G) (ITT: CON vs. EX; +0.0023 vs. +0.0063 min⁻¹, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group. CONCLUSION Moderate exercise following RYGB surgery provides additional improvements in S(I), S(G), and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00692367. FUNDING This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153).

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload.

Dynamic PET imaging reveals heterogeneity of skeletal muscle insulin resistance.

PURPOSE Skeletal muscle insulin resistance (IR) often precedes hyperglycemia and type 2 diabetes. However, variability exists within different skeletal muscle types and can be influenced by 3 primary steps of control: glucose delivery, transport, and phosphorylation. We performed dynamic positron emission tomography imaging studies to determine the extent to which heterogeneity in muscle type and control of insulin action contribute to IR. METHODS Thirteen volunteers from normal weight to obese underwent dynamic positron emission tomography imaging of [15O]H2O, [11C]3-O-methylglucose, and [18F]fluorodeoxyglucose, measuring delivery, transport, and phosphorylation rates, respectively, in soleus and tibialis anterior muscle during a hyperinsulinemic-euglycemic clamp. Subjects were classified as insulin-sensitive (IS) or insulin-resistant (IR) based on the median systemic glucose infusion rate needed to maintain euglycemia. RESULTS In soleus, transport kinetic rates were significantly higher (P<.05) in IS (0.126±0.028 min(-1)) vs IR (0.051±0.008 min(-1)) subjects. These differences were not as evident in tibialis anterior. These differences were paralleled in overall insulin-stimulated tissue activity, higher in IS (0.017±0.001 mL·cm3·min(-1)) vs IR (0.011±0.002 mL·cm3·min(-1)) in soleus (P<.05), without significant differences in tibialis anterior. No significant differences were observed for either muscle in delivery or phosphorylation. Both muscle types displayed a control shift from an even distribution among the steps in IS to transport exerting greater control of systemic insulin sensitivity in IR. CONCLUSION Lower glucose transport rates are the major feature underlying IR preceding type 2 diabetes, although substantial heterogeneity in insulin action across muscle types highlight the complexity of skeletal muscle IR.

Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and NitrateNovelty and Significance

Dietary NO3− (nitrate) and NO2− (nitrite) support ˙NO (nitric oxide) generation and downstream vascular signaling responses. These nitrogen oxides also generate secondary nitrosating and nitrating species that react with low molecular weight thiols, heme centers, proteins, and unsaturated fatty acids. To explore the kinetics of NO3−and NO2−metabolism and the impact of dietary lipid on nitrogen oxide metabolism and cardiovascular responses, the stable isotopes Na15NO3 and Na15NO2 were orally administered in the presence or absence of conjugated linoleic acid (cLA). The reduction of 15NO2− to 15NO was indicated by electron paramagnetic resonance spectroscopy detection of hyperfine splitting patterns reflecting 15NO-deoxyhemoglobin complexes. This formation of 15NO also translated to decreased systolic and mean arterial blood pressures and inhibition of platelet function. Upon concurrent administration of cLA, there was a significant increase in plasma cLA nitration products 9- and 12-15NO2-cLA. Coadministration of cLA with 15NO2− also impacted the pharmacokinetics and physiological effects of 15NO2−, with cLA administration suppressing plasma NO3−and NO2−levels, decreasing 15NO-deoxyhemoglobin formation, NO2−inhibition of platelet activation, and the vasodilatory actions of NO2−, while enhancing the formation of 9- and 12-15NO2-cLA. These results indicate that the biochemical reactions and physiological responses to oral 15NO3−and 15NO2−are significantly impacted by dietary constituents, such as unsaturated lipids. This can explain the variable responses to NO3−and NO2−supplementation in clinical trials and reveals dietary strategies for promoting the generation of pleiotropic nitrogen oxide-derived lipid signaling mediators. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01681836.

Relationship among physical activity, sedentary behaviors, and cardiometabolic risk factors during gastric bypass surgery–induced weight loss

BACKGROUND The impact of daily physical activity (PA) on the cardiometabolic risk of bariatric surgery patients is not known. OBJECTIVE We examined the influence of physical activity and sedentary behavior on modifying cardiometabolic risk after Roux-en-Y gastric bypass (RYGB) surgery. SETTING University of Pittsburgh Medical Center and East Carolina University bariatric surgery centers. METHODS Data from 43 women and 7 men who completed testing at 1-3 months after RYGB surgery and again at 9 months postsurgery were analyzed. Outcomes measured included PA level (min/d), steps/d, sedentary time, and body composition. Insulin sensitivity was determined with an intravenous glucose tolerance test. Weight and blood lipid profiles also were obtained. RESULTS Patients reduced body mass index by a mean of -8.0±3.4 kg/m2 (P<.001), increased moderate-to-vigorous PA by 17.0±47.0 min/d (P = .014), and decreased sedentary time (-47.9±101.0 min/d, P = .002). However, 24% of patients decreased overall PA (P<.001), and 39% increased sedentary behavior (P<.001). Changes in overall PA (rho = -.33, P = .006) and steps/d (rho = -.31, P = .0106) were related to weight loss. Insulin sensitivity was associated with light PA before (rho = .37, P<.001) and after (rho = .37, P = .015) intervention. Increasing overall PA also was related to higher levels of high-density lipoprotein cholesterol (rho = .33, P<.01). Decreasing sedentary time was related to decreased fat mass (rho = .35, P = .012) but not to other cardiometabolic risk factors. CONCLUSIONS The majority of patients increased PA (76%) and decreased sedentary time (61%) after RYGB surgery, but the amount of PA and sedentary time varied substantially. Higher PA, even at low intensity levels, was related to beneficial outcomes in body composition, insulin sensitivity, and high-density lipoprotein cholesterol.

Resting and exercise energy metabolism in weight-reduced adults with severe obesity

To determine effects of physical activity (PA) with diet‐induced weight loss on energy metabolism in adults with severe obesity.

Insulin sensitivity predicts brain network connectivity following a meal

&NA; There is converging evidence that insulin plays a role in food‐reward signaling in the brain and has effects on enhancing cognition. Little is known about how these effects are altered in individuals with insulin resistance. The present study was designed to identify the relationships between insulin resistance and functional brain connectivity following a meal. Eighteen healthy adults (7 male, 11 female, age: 41‐57 years‐old) completed a frequently‐sampled intravenous glucose tolerance test to quantify insulin resistance. On separate days at least one week apart, a resting state functional magnetic resonance imaging scan was performed: once after a mixed‐meal and once after a 12‐h fast. Seed‐based resting state connectivity of the caudate nucleus and eigenvector centrality were used to identify relationships between insulin resistance and functional brain connectivity. Individuals with greater insulin resistance displayed stronger connectivity within reward networks following a meal suggesting insulin was less able to suppress reward. Insulin resistance was negatively associated with eigenvector centrality in the dorsal anterior cingulate cortex following a meal. These data suggest that individuals with less sensitivity to insulin may fail to shift brain networks away from reward and toward cognitive control following a meal. This altered feedback loop could promote overeating and obesity. HighlightsInsulin plays a role in food‐reward signaling in the brain.It is not understood how insulin resistance affects insulins ability to modulate brain networks.We examined associations between insulin resistance and brain connectivity.Individuals with lower insulin sensitivity maintain reward connectivity after a meal.Higher insulin sensivity is associated with stronger connectivity in cognitive control regions.

Oral Sodium Nitrite Improves Insulin Sensitivity, Blood Pressure, and Arterial Thickening in Adults with Uncontrolled Hypertension and Metabolic Syndrome

Introduction: Although nitrate and nitrite have traditionally been considered to be inert and potentially toxic metabolites of nitric oxide (NO) oxidation, it is now appreciated that both can be recycled to bioactive NO. Recent evidence suggests that the human nitrate-nitrite-NO pathway mediates signaling through NO to reduce blood pressure and endothelial function. The effects of oral nitrite on insulin sensitivity, however, are not known. Therefore, we developed the investigational drug, oral inorganic sodium nitrite, to assess its therapeutic effects. Methods: Our goal was to examine the effect of 12 weeks of open-label oral sodium nitrite 40 mg three times daily in this pilot study. We employed hyperinsulinemic-euglycemic clamps to assess insulin sensitivity, flow mediated dilation (FMD) to measure endothelial function, and pulse wave velocity (PWV) and carotid intima media thickness (IMT) to measure arterial stiffening and thickening, respectively, in obese adults with metabolic syndrome and uncontrolled hypertension. Results: Eighteen subjects were recruited with mean age 53 years, BMI 41 kg/m2 and BP 147/88 mmHg and 72% were female. Following 12 weeks of nitrite treatment, systolic (-10 mmHg), diastolic (-13 mmHg) and mean arterial pressures were reduced (-12 mmHg; all p Conclusion: Oral sodium nitrite treatment is a promising therapeutic to improve insulin sensitivity, blood pressure and arterial thickening in at-risk obese adults with metabolic syndrome and uncontrolled hypertension. Disclosure K.S. Hughan: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. N.L. Helbling: None. S.J. Anthony: None. J. DeLany: None. B.H. Goodpaster: None. M. Gladwin: Other Relationship; Self; National Institutes of Health, Globin Solutions, Bayer AG.