Nathan C. Winn

Postdinner resistance exercise improves postprandial risk factors more effectively than predinner resistance exercise in patients with type 2 diabetes

Abnormally elevated postprandial glucose and triacylglycerol (TAG) concentrations are risk factors for cardiovascular disease in type 2 diabetes. The most effective time to exercise to lower postprandial glucose and TAG concentrations is unknown. Thus the aim of this study was to determine what time is more effective, either pre- or postdinner resistance exercise (RE), at improving postprandial risk factors in patients with type 2 diabetes. Thirteen obese patients with type 2 diabetes completed three trials in a random order in which they consumed a dinner meal with 1) no RE (NoRE), 2) predinner RE (RE → M), and 3) postdinner RE beginning 45 min after dinner (M → RE). Clinical outcome measures included postprandial glucose and TAG concentrations. In addition, postprandial acetaminophen (gastric emptying), endocrine responses, free fatty acids, and β-cell function (mathematical modeling) were measured to determine whether these factors were related to changes in glucose and TAG. The TAG incremental area under the curve (iAUC) was ∼92% lower (P ≤ 0.02) during M → RE compared with NoRE and RE → M, an effect due in part to lower very-low-density lipoprotein-1 TAG concentrations. The glucose iAUC was reduced (P = 0.02) by ∼18 and 30% during the RE → M and M → RE trials, respectively, compared with NoRE, with no difference between RE trials. RE → M and M → RE reduced the insulin iAUC by 35 and 48%, respectively, compared with NoRE (P < 0.01). The glucagon-like peptide-1 iAUC was ∼50% lower (P ≤ 0.02) during M → RE compared with NoRE and RE → M. Given that predinner RE only improves postprandial glucose concentrations, whereas postdinner RE improves both postprandial glucose and TAG concentrations, postdinner RE may lower the risk of cardiovascular disease more effectively.

Moderate amounts of fructose- or glucose-sweetened beverages do not differentially alter metabolic health in male and female adolescents

BACKGROUND Adolescents consume more sugar-sweetened beverages than do individuals in any other age group, but it is unknown how the type of sugar-sweetened beverage affects metabolic health in this population. OBJECTIVE The objective was to compare the metabolic health effects of short-term (2-wk) consumption of high-fructose (HF) and high-glucose (HG)-sweetened beverages in adolescents (15-20 y of age). DESIGN In a counterbalanced, single-blind fashion, 40 male and female adolescents completed two 2-wk trials that included 1) an HF trial in which they consumed 710 mL of a sugar-sweetened beverage/d (equivalent to 50 g fructose/d and 15 g glucose/d) for 2 wk and 2) an HG trial in which they consumed 710 mL of a sugar-sweetened beverage/d (equivalent to 50 g glucose/d and 15 g fructose/d) for 2 wk in addition to their normal ad libitum diet. In addition, the participants maintained similar physical activity levels during each trial. The day after each trial, insulin sensitivity and resistance [assessed via Quantitative Insulin Sensitivity Check Index (QUICKI) and homeostatic model assessment of insulin resistance (HOMA-IR) index] and fasting and postprandial glucose, lactate, lipid, cholesterol, insulin, C-peptide, insulin secretion, and clearance responses to HF or HG mixed meals were assessed. RESULTS Body weight, QUICKI (whole-body insulin sensitivity), HOMA-IR (hepatic insulin resistance), and fasting lipids, cholesterol, glucose, lactate, and insulin secretion or clearance were not different between trials. Fasting HDL- and HDL₃-cholesterol concentrations were ∼10-31% greater (P < 0.05) in female adolescents than in male adolescents. Postprandial triacylglycerol, HDL-cholesterol, HDL₃-cholesterol, and glucose concentrations were not different between HF and HG trials. The lactate incremental area under the curve was ∼3.7-fold greater during the HF trial (P < 0.05), whereas insulin secretion was 19% greater during the HG trial (P < 0.05). CONCLUSIONS Moderate amounts of HF- or HG-sweetened beverages for 2 wk did not have differential effects on fasting or postprandial cholesterol, triacylglycerol, glucose, or hepatic insulin clearance in weight-stable, physically active adolescents.

Plasma Irisin Modestly Increases during Moderate and High-Intensity Afternoon Exercise in Obese Females.

Background and Purpose Irisin is an exercise-responsive myokine that has been proposed to exert anti-obesity benefits; yet its response during exercise in obese women is not described. This study characterized plasma irisin levels during a single bout of afternoon isocaloric-exercise of different intensities (moderate- vs high-intensity) in obese females. Methods Eleven obese females participated in 3 randomized study days beginning at 1600h: 1) no exercise (NoEx), 2) moderate exercise (ModEx; 55%VO2max) and 3) high intensity interval exercise (IntEx; 4 min (80%VO2max)/3 min (50% VO2max). Frequent blood samples were analyzed for glucose and lactate (whole-blood), and insulin, c-peptide, glucagon, and irisin (plasma) throughout 190 min of testing. Results Plasma irisin increased above baseline during ModEx and IntEx (P<0.05), but not NoEx (P>0.05). Peak irisin levels during ModEx and IntEx exercise were 11.9± 3.4% and 12.3 ± 4.1% relative to baseline (P<0.05), respectively, with no differences between exercise intensities (P>0.05). Irisin levels remained elevated above resting for 125 minutes post-exercise during ModEx, whereas levels returned to baseline within 15 minutes post-exercise during IntEx. Similarly, no associations were found between plasma irisin levels and circulating lactate, glucose, insulin, c-peptide, or glucagon among study days (P>0.05). However, there was an inverse association between basal irisin and lean mass (r = -0.70, P = 0.01). Conclusion A single bout of moderate and high intensity afternoon exercise induces modest increases in circulating irisin concentrations during exercise; however the regulation post-exercise appears to be dimorphic between exercise intensity in obese females. Future studies are needed to compare morning and afternoon exercise on irisin secretion.

Prior exercise does not alter the incretin response to a subsequent meal in obese women

Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0kg/m(2); Age 24.3±4.6year) participated in 3 counter- balanced study days, where a standardized meal was preceded by: (1) No exercise (NoEx), (2) ModEx (55% VO2max), and (3) IntEx (4min (80% VO2max)/3min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (p<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (p<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (p<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response.

Energy-matched moderate and high intensity exercise training improves nonalcoholic fatty liver disease risk independent of changes in body mass or abdominal adiposity — A randomized trial☆

BACKGROUND AND PURPOSE Exercise training is commonly prescribed for individuals diagnosed with nonalcoholic fatty liver disease (NAFLD); however, consensus regarding the volume and intensity of exercise for optimal benefits is lacking. Thus, we determined whether high intensity interval exercise training (HIIT) produced greater reductions in intrahepatic lipid (IHL) content and NAFLD risk factors compared with energy-matched moderate intensity continuous exercise training (MICT) in obese adults with liver steatosis. METHODS Eighteen obese adults were randomized to either 4weeks of HIIT (4min 80% VO2peak/3min, 50% VO2peak) or MICT (55% VO2peak, ~60min), matched for energy expenditure (~400kcal/session) and compared to five non-exercising age-matched control subjects. IHL was measured by 1H-MRS and frequent blood samples were analyzed for glucose, insulin, c-peptide, and NEFA levels during a liquid meal test (180min) to characterize metabolic phenotype. RESULTS Baseline body weight, visceral abdominal adiposity, and fasting insulin concentrations were greater in the MICT vs HIIT group (P<0.05), while IHL was tightly matched between MICT and HIIT subjects (P>0.05), albeit higher than control subjects (P<0.01). Visceral abdominal adiposity, body mass, liver aminotransferases (ALT, AST), and hepatic apoptotic/inflammatory markers (cytokeratin 18 and fetuin a) were not reduced with either exercise training intervention (P>0.05). Both HIIT and MICT lowered IHL (HIIT, -37.0±12.4%; MICT, -20.1±6.6%, P<0.05); however, the reduction in IHL was not statistically different between exercise intensities (P=0.25). Furthermore, exercise training decreased postprandial insulin, c-peptide, and lipid peroxidation levels (iAUC, P<0.05). CONCLUSIONS Collectively, these findings indicate that energy-matched high intensity and moderate intensity exercise are effective at decreasing IHL and NAFLD risk that is not contingent upon reductions in abdominal adiposity or body mass.

Walking Reduces Postprandial Insulin Secretion in Obese Adolescents Consuming a High-Fructose or High-Glucose Diet

BACKGROUND This study assessed if walking at a self-selected pace could improve postprandial glucose and insulin concentrations in obese adolescents consuming high-fructose (HF) or high-glucose (HG) diets. METHODS Seven obese male and female adolescents (18 ± 1 yr) performed 4, 15-day trials in a random order, including 1) HF-diet (50 g fructose/d added to normal diet) while being sedentary, 2) HG-diet (50 g glucose/d) while sedentary, 3) HF-diet with additional walking, and 4) HG-diet with additional walking. On the 15th day of each trial, the participants performed mixed meal testing in the laboratory in which they consumed three liquid shakes (either HF or HG) and during the HF and HG sedentary trials, the participants took < 4000 steps while in the laboratory but during the walking trials took ≥ 13,000 steps during testing. RESULTS Walking did not alter postprandial glucose concentrations. Although walking reduced insulin secretion by 34% and 25% during the HF- and HG-diet, respectively (P < .05), total insulin concentrations were only significantly reduced (P > .05) with walking during the HF trial, possibly because walking enhanced insulin clearance to a greater extent during the HF-diet. CONCLUSIONS Walking reduces postprandial insulin secretion in obese adolescents consuming a high-fructose or high-glucose diet.

Deletion of UCP1 enhances ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction

Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin resistance (IR) despite no significant differences in BAT UCP1 content. UCP1 ablation increased HOMA-IR, AT-IR, and whitening of BAT in both sexes. Expression of UCP1 in thoracic aorta was greater in wild-type females compared with males. Importantly, deletion of UCP1 enhanced aortic vasomotor function in females only. UCP1 ablation did not promote oxidative stress in interscapular BAT. Furthermore, daily administration of the free radical scavenger tempol for 8 wk did not abrogate UCP1 deficiency-induced increases in adiposity, hyperinsulinemia, or liver steatosis. Collectively, we report that 1) in normal chow-fed mice housed at 25°C, aortic UCP1 content was greater in females than males and its deletion improved ex vivo aortic vasomotor function in females only; 2) constitutive UCP1 content in BAT was similar between females and males and loss of UCP1 did not abolish sex differences in insulin sensitivity; and 3) the metabolic disruptions caused by UCP1 ablation did not appear to be contingent upon increased oxidative stress in mice under normal dietary conditions.

When gain is greater than loss: effects of physical activity on insulin sensitivity after short‐term inactivity in older subjects

Lack of physical activity is an instigator of numerous chronic diseases and a leading cause of mortality in the Western world (Booth et al. 2012). Among the chronic diseases most influenced by physical inactivity are metabolic and cardiovascular diseases, a notion strongly supported by epidemiological data as well as by studies using experimental models in animals and humans (Booth et al. 2012). Indeed, data are pouring out of studies demonstrating that reduced activity disrupts metabolic function. In humans, an attractive and highly translational experimental model to study the ramifications of free-living physical inactivity, due to its simulation of real-life scenarios, is reduced ambulatory activity via step reduction. In this model, individuals are subjected to an 50–80% reduction in daily steps for several days to weeks. Studies using this model have revealed that decreased ambulatory activity reduces insulin sensitivity in non-obese healthy young men (Knudsen et al. 2012). Whether reduced ambulatory activity produces similar metabolic effects in older adults, and the mechanisms by which this occurs, has remained unknown. In addition, an important but previously unaddressed question is whether, in older individuals, insulin resistance caused by short-term modest inactivity can be fully rescued by the return to previous activity levels. Studying the metabolic effects of short-term inactivity in older individuals, and their capacity to re-establish normal function, is particularly relevant because ageing is associated with both greater occurrence and severity of debilitating life events (illness, orthopaedic injuries, etc.) that substantially impinge physical activity levels. In this issue of The Journal of Physiology, Reidy et al. (2018) eloquently fill this important information gap by studying a cohort of older adults (5 women and 7 men) before, after 2 weeks of reduced physical activity, and following 2 weeks of recovery (i.e. return to activity). The authors found that a short-term 60% decline in daily steps reduced whole-body insulin sensitivity by 15% (assessed via hyperinsulinaemic–euglycaemic clamp), an effect that was interestingly driven by data from men. Remarkably, after the 2 weeks of return to activity insulin sensitivity rebounded above baseline levels (i.e. above pre-inactivity) by 14% (Fig. 1). Insulin resistance caused by inactivity was accompanied by some mild indices of skeletal muscle inflammation; however, in contrast to the hypothesis proposed by the authors, changes in inactivity-induced insulin sensitivity were not related to changes in serum or intramuscular ceramides. As noted, a main observation of this study is the capacity of older subjects to not only recover their levels of insulin sensitivity with return to activity but to actually surpass them. This regain of function after 2 weeks of inactivity followed by return to ambulatory activity is fundamentally

Endothelial dysfunction occurs independently of adipose tissue inflammation and insulin resistance in ovariectomized Yucatan miniature-swine

ABSTRACT In rodents, experimentally-induced ovarian hormone deficiency increases adiposity and adipose tissue (AT) inflammation, which is thought to contribute to insulin resistance and increased cardiovascular disease risk. However, whether this occurs in a translationally-relevant large animal model remains unknown. Herein, we tested the hypothesis that ovariectomy would promote visceral and perivascular AT (PVAT) inflammation, as well as subsequent insulin resistance and peripheral vascular dysfunction in female swine. At sexual maturity (7 months of age), female Yucatan mini-swine either remained intact (control, n = 9) or were ovariectomized (OVX, n = 7). All pigs were fed standard chow (15–20 g/kg), and were euthanized 6 months post-surgery. Uterine mass and plasma estradiol levels were decreased by ∼10-fold and 2-fold, respectively, in OVX compared to control pigs. Body mass, glucose homeostasis, and markers of insulin resistance were not different between control and OVX pigs; however, OVX animals exhibited greater plasma triglycerides and triglyceride:HDL ratio. Ovariectomy enhanced visceral adipocyte expansion, although this was not accompanied by brachial artery PVAT adipocyte expansion, AT inflammation in either depot, or increased systemic inflammation assessed by plasma C-reactive protein concentrations. Despite the lack of AT inflammation and insulin resistance, OVX pigs exhibited depressed brachial artery endothelial-dependent vasorelaxation, which was rescued with blockade of endothelin receptor A. Together, these findings indicate that in female Yucatan mini-swine, increased AT inflammation and insulin resistance are not required for loss of ovarian hormones to induce endothelial dysfunction.