Extracellular Vesicles in Metabolic and Vascular Insulin Resistance.

BACKGROUND: Insulin resistance is a major etiological factor in obesity, type 2 diabetes, and cardiovascular disease (CVD). Endothelial dysfunction may precede impairments in insulin-stimulated glucose uptake, thereby making it a key feature in development of CVD. However, the mechanism by which vascular tissue becomes dysfunctional is not clear. SUMMARY: Extracellular vesicles (EVs) have emerged as potential mediators of insulin resistance and vascular dysfunction. EVs are membrane-bound particles released by tissues following cellular stress or activation. They carry "cargo" (e.g., insulin signaling proteins, eNOS-nitric oxide, and miRNA) that are believed to promote inter-cellular and interorgan communications. Herein, we review the underlying physiology of EVs in relation to type 2 diabetes and CVD risk. Specifically, we discuss how EVs may modulate metabolic (e.g., skeletal muscle, liver, and adipose) insulin sensitivity, and propose that EVs may modulate vascular insulin action to influence both endothelial function and arterial stiffness. We lastly identify how EVs may play a unique role following exercise to promote metabolic and vascular insulin sensitivity changes. KEY MESSAGE: Gaining insight toward insulin-mediated EV mechanism has potential to identify novel pathways regulating cardiometabolic health and provide foundation for examining EVs as unique biomarkers and targets to prevent and/or treat chronic diseases.

Intermediate versus morning chronotype has lower vascular insulin sensitivity in adults with obesity.

AIM: Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN). MATERIALS AND METHODS: Adults with obesity were classified per Morningness-Eveningness Questionnaire (MEQ) as either MORN (n = 27, 22 female, MEQ = 63.7 ± 4.7, 53.8 ± 6.7 years, 35.3 ± 4.9 kg/m2) or INT (n = 29, 23 female, MEQ = 48.8 ± 6.7, 56.6 ± 9.0 years, 35.7 ± 6.1 kg/m2). A 120 min euglycaemic-hyperinsulinaemic clamp (40 mU/m2/min, 90 mg/dl) was conducted to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation (%FMD; conduit artery), post-ischaemic flow velocity (resistance arteriole), as well as microvascular insulin sensitivity via contrast-enhanced ultrasound [e.g. microvascular blood volume (perfusion)]. Fasting plasma arginine and citrulline, as well as fasting and clamp-derived plasma endothelin-1 and nitrate/nitrite, were assessed as surrogates of vasoconstriction and nitric oxide-mediated vasodilation. Aerobic fitness (VO2max) and body composition (dual-energy X-ray absorptiometry) were also collected. RESULTS: MORN had a higher VO2max compared with INT (p < .01), although there was no difference in fat mass. While fasting FMD was similar between groups, insulin lowered FMD corrected to shear stress and microvascular blood volume in INT compared with MORN after co-varying for VO2max (both p ≤ .02). INT also had a lower fasting nitrate (p = .03) and arginine (p = .07). Higher MEQ correlated with elevated FMD (r = 0.33, p = .03) and lower post-ischaemic flow velocity (r = -0.33, p = .03) as well as shear rate (r = -0.36, p = .02) at 120 min. CONCLUSION: When measured during the morning, INT had a lower vascular insulin sensitivity than MORN. Additional work is needed to understand endothelial function differences among chronotypes to optimize cardiovascular disease risk reduction.

Cardiorespiratory fitness and submaximal exercise dynamics in normal-weight obesity and metabolically healthy obesity.

PURPOSE: Cardiorespiratory fitness (CRF) is critical for cardiovascular health. Normal-weight obesity (NWO) and metabolically healthy obesity (MHO) may be at increased risk for cardiovascular disease, but a comparison of CRF and submaximal exercise dynamics against rigorously defined low- and high-risk groups is lacking. METHODS: Four groups (N = 40; 10/group) based on body mass index (BMI), body fat %, and metabolic syndrome (MetS) risk factors were recruited: healthy controls (CON; BMI 18.5-24.9 kg/m2, body fat < 25% [M] or < 35% [F], 0-1 risk factors), NWO (BMI 18.5-24.9 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F]), MHO (BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 0-1 risk factors), or metabolically unhealthy obesity (MUO; BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 2 + risk factors). All participants completed a V ˙ O2peak test on a cycle ergometer. RESULTS: V ˙ O2peak was similarly low in NWO (27.0 ± 4.8 mL/kg/min), MHO (25.4 ± 6.7 mL/kg/min) and MUO (24.6 ± 10.0 mL/kg/min) relative to CON (44.2 ± 11.0 mL/kg/min) when normalized to total body mass (p's < 0.01), and adjusting for fat mass or lean mass did not alter these results. This same differential V ˙ O2 pattern was apparent beginning at 25% of the exercise test (PGroup*Time < 0.01). CONCLUSIONS: NWO and MHO had similar peak and submaximal CRF to MUO, despite some favorable health traits. Our work adds clarity to the notion that excess adiposity hinders CRF across BMI categories. CLINICALTRIALS: gov registration: NCT05008952.

Acute exercise decreases insulin-stimulated extracellular vesicles in conjunction with augmentation index in adults with obesity.

Extracellular vesicles (EVs) are often elevated in obesity and may modulate disease risk. Although acute exercise reduces fasting EVs in adults with obesity, no data exist on insulin-mediated EV responses. This study evaluated the effects of exercise on EV responses to insulin in relation to vascular function. Ten (5M/5F) sedentary adults with obesity (34.3 ± 3.7 kg/m2 ) completed an evening control and acute exercise condition (70% V ̇ O 2 max ${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ to expend 400 kcal). Following an overnight fast, participants underwent a 2 h euglycaemic-hyperinsulinaemic clamp (90 mg/dl; 40 mU/m2 /min) to determine metabolic insulin sensitivity (M-value), phenotypes of medium- to large-sized EVs, and aortic waveform measures. Endothelial (CD105+ , CD41- /CD31+ )-, leukocyte (CD45+ )-, platelet (CD41+ , CD41+ /31+ )- and tetraspanin (TX+ )-derived EVs, as well as platelet endothelial cell adhesion molecule (CD31+ ), were determined before and after the clamp using high resolution spectral flow cytometry. Although exercise did not alter fasting haemodynamics, it lowered the augmentation index (AIx75, P = 0.024) and increased the M-value (P = 0.042). Further, exercise decreased all fasting EVs (P < 0.01) and decreased insulin-stimulated TX+ (P = 0.060), CD31+ (P = 0.060) and CD41- /31+ (P = 0.045) compared to rest. Interestingly, greater insulin-stimulated decreases in CD41- /31+ were associated with reduced AIx75 during the clamp (r = 0.62, P = 0.059), while insulin-stimulated decreases in CD41+ (r = -0.68, P = 0.031), CD41+ /31+ (r = -0.69, P = 0.262), TX+ (r = -0.66, P = 0.037) and CD31+ (r = -0.69, P = 0.028) correlated with M-value following exercise. Thus, acute exercise may decrease fasting and insulin-stimulated medium- to large-size EVs in conjunction with improved M-value and AIx75. More research is needed to understand effects of exercise on EVs in the regulation of glucose homeostasis and vascular function. KEY POINTS: Extracellular vesicles (EVs) are increased in states of obesity and may play a role in altered insulin sensitivity and blood pressure; aerobic exercise decreases fasting EV concentrations the following day in adults with obesity. This study directly tested the effects of insulin on EVs and how a single bout of exercise impacts these responses. Together, these data highlight the positive effects of a single bout of exercise on fasting and insulin-stimulated EVs, with the latter relating to increased insulin sensitivity and decreased augmentation index. These results support future research identifying EVs as mechanistic factors in glucose regulation and vascular function as well as clinical use of exercise to reduce cardiovascular disease risk.

Exercise blood pressure and heart rate responses to graded exercise testing in intermediate versus morning chronotypes with obesity.

Exaggerated exercise blood pressure (BP) is linked to cardiovascular disease (CVD). Although evening chronotypes have greater CVD risk than morning (Morn) types, it is unknown if exercise BP differs in intermediate (Int) types. Adults with obesity were classified as either Morn [n = 23 (18 females), Morning-Eveningness Questionnaire (MEQ) = 63.96 ± 1.0, 54.74 ± 1.4 yr, 33.7 ± 0.6 kg/m2] or Int [n = 23 (19 females), MEQ = 51.36 ± 1.1, 55.96 ± 1.8 yr, 37.2 ± 1.2 kg/m2] chronotype per MEQ. A graded, incremental treadmill test to maximal aerobic capacity (V̇o2max) was conducted. Systolic (SBP) and diastolic (DBP) blood pressure and mean arterial pressure (MAP), rate pressure product (RPP), heart rate (HR), and rate of perceived intensity (RPE) were determined at baseline, 4 min, 6 min, and maximal stages. HR recovery (HRR; maximum postexercise) was determined at 1 and 2 min postexercise. Preexercise fasted aortic waveforms (applanation tonometry), plasma leptin, nitrate/nitrite (nitric oxide bioavailability), and body composition (dual X-ray, DXA) were also collected. Int had lower V̇o2max and plasma nitrate (both P ≤ 0.02) than Morn. No difference in preexercise BP, aortic waveforms, or body composition were noted between groups, although higher plasma leptin was seen in Int compared with Morn (P = 0.04). Although Int had higher brachial DBP and MAP across exercise stages (both P ≤ 0.05) and higher HR, RPE, and RPP at 6 min of exercise (all P ≤ 0.05), covarying for V̇o2max nullified the BP, but not HR or RPE, difference. HRR was greater in Morn independent of V̇o2max (P = 0.046). Fasted leptin correlated with HR at exercise stage 4 (r = 0.421, P = 0.041) and 6 min (r = 0.593, P = 0.002). This observational study suggests that Int has exaggerated BP and HR responses to exercise compared with Morn, although fitness abolished BP differences.NEW & NOTEWORTHY This study compares blood pressure and heart rate responses with graded, incremental exercise between morning and intermediate chronotype adults with obesity. Herein, blood pressure responses to exercise were elevated in intermediate compared with morning chronotype, although V̇o2max abolished this observation. However, heart rate responses to exercise were higher in intermediate vs. morning chronotypes independent of fitness. Collectively, this exercise hemodynamic response among intermediate chronotype may be related to reduced aerobic fitness, altered nitric oxide metabolism, and/or elevated aortic waveforms.

ß-Cell function during a high-fat meal in young versus old adults: role of exercise.

The acute effect of exercise on ß-cell function during a high-fat meal (HFM) in young adults (YA) versus old adults (OA) is unclear. In this randomized crossover trial, YA (n = 5 M/7 F, 23.3 ± 3.9 yr) and OA (n = 8 M/4 F, 67.7 ± 6.0 yr) underwent a 180-min HFM (12 kcal/kg body wt; 57% fat, 37% CHO) after a rest or exercise [∼65% heart rate peak (HRpeak)] condition ∼12 h earlier. After an overnight fast, plasma lipids, glucose, insulin, and free fatty acid (FFA) were determined to estimate peripheral, or skeletal muscle, insulin sensitivity (Matsuda index) as well as hepatic [homeostatic model assessment of insulin resistance (HOMA-IR)] and adipose insulin resistance (adipose-IR). ß-Cell function was derived from C-peptide and defined as early-phase (0-30 min) and total-phase (0-180 min) disposition index [DI, glucose-stimulated insulin secretion (GSIS) adjusted for insulin sensitivity/resistance]. Hepatic insulin extraction (HIE), body composition [dual-energy X-ray absorptiometry (DXA)], and peak oxygen consumption (V̇o2peak) were also assessed. OA had higher total cholesterol (TC), LDL, HIE, and DI across organs as well as lower adipose-IR (all, P < 0.05) and V̇o2peak (P = 0.056) despite similar body composition and glucose tolerance. Exercise lowered early-phase TC and LDL in OA versus YA (P < 0.05). However, C-peptide area under the curve (AUC), total phase GSIS, and adipose-IR were reduced postexercise in YA versus OA (P < 0.05). Skeletal muscle DI increased in YA and OA after exercise (P < 0.05), whereas adipose DI tended to decline in OA (P = 0.06 and P = 0.08). Exercise-induced skeletal muscle insulin sensitivity (r = -0.44, P = 0.02) and total-phase DI (r = -0.65, P = 0.005) correlated with reduced glucose AUC180min. Together, exercise improved skeletal muscle insulin sensitivity/DI in relation to glucose tolerance in YA and OA, but only raised adipose-IR and reduced adipose-DI in OA.NEW & NOTEWORTHY High-fat diets may induce ß-cell dysfunction. This study compared how young and older adults responded to a high-fat meal with regard to ß-cell function and whether exercise comparably impacted glucose regulation. Older adults secreted more insulin during the high-fat meal than younger adults. Although exercise increased ß-cell function adjusted for skeletal muscle insulin sensitivity in relation to glucose tolerance, it raised adipose insulin resistance and reduced pancreatic ß-cell function relative to adipose tissue in older adults. Additional work is needed to discern nutrient-exercise interactions across age to mitigate chronic disease risk.

Getting Into Light Exercise (GENTLE-HF) for Patients With Heart Failure: the Design and Methodology of a Live-Video Group Exercise Study.

OBJECTIVE: Newer therapies have increased heart failure (HF) survival rates, but these therapies are rarely curative. The consequence of increased longevity is the likelihood that patients with HF will experience higher symptom burdens over time. Exercise such as cardiac rehabilitation programs can palliate symptom burdens, but numerous barriers prevent exercise participation and adherence. Small pilot studies indicate short-term beneficial effects of gentle forms of exercise such as yoga to address symptom burdens and accommodate comorbidities. Long-term symptom benefit and adherence to yoga are currently unknown. Therefore, a novel a home-based, gentle-stretching intervention that addresses issues of exercise access and adherence is described in this article. PURPOSE: The purpose of this article is to describe the background, design and study methodology of the Getting Into Light Exercise for HF (GENTLE-HF) randomized controlled trial. Gentle-HF will test a gentle stretching and education intervention compared to an education control group concerning symptom burden (dyspnea, exercise, activity adherence, depression, and anxiety) and quality of life. As an exploratory aim, we also will determine whether rurality moderates the relationships between exercise participation and symptom burden as a measure of health equity. METHODS: We designed a randomized controlled trial study (n = 234) with 2 arms: a gentle stretching intervention arm with HF education and an HF education-only control. Participants will be recruited from U.S. cardiology clinics in the mid-Atlantic and the San Francisco Bay areas. This recruitment strategy will include individuals from urban, suburban and rural areas and individuals that have diverse racial and ethnic backgrounds. All participants will be provided with an iPad set up to access HF educational topics, and the intervention arm will have both educational and gentle-stretching class links. Both arms will access the HF health education icons on their iPads weekly; they correspond to the 6 months (26 weeks) of study participation. Symptom burden (dyspnea, fatigue, exercise intolerance, depression, anxiety) and quality of life will be measured at the study's start and completion. Study adherence will be measured by using attendance rates and number of class minutes attended. RESULTS: The GENTLE-HF study is a randomized study that will test the effect of a home-based, video-conference-delivered gentle stretching and HF education intervention designed for patients with HF. The findings will inform whether gentle stretching can decrease symptom burden and potentially provide access to symptom palliation for a diverse population of patients with HF.

Nutrition Interactions With Exercise Training on Endothelial Function.

Exercise is advised to improve overall cardiovascular health and endothelial function. However, the role of nutrition on this exercise-induced endothelial adaptation is not clear. Here, we hypothesize that nutrients interact with exercise to influence endothelial function and chronic disease risk.

Tracking Biomarker Responses to Exercise in Hypertension.

PURPOSE OF REVIEW: Strong evidence is evolving that physical exercise prevents hypertension and reduces blood pressure in patients with pre- and manifest HTN. Yet, identifying and confirming the effectiveness of exercise are challenging. Herein, we discuss conventional and novel biomarkers such as extracellular vesicles (EVs) which may track responses to HTN before and after exercise. RECENT FINDINGS: Evolving data shows that improved aerobic fitness and vascular function as well as lowered oxidative stress, inflammation, and gluco-lipid toxicity are leading biomarkers considered to promote HTN, but they explain only about a half of the pathophysiology. Novel biomarkers such as EVs or microRNA are providing additional input to understand the complex mechanisms involved in exercise therapy for HTN patients. Conventional and novel biomarkers are needed to fully understand the integrative "cross-talk" between tissues to regulate vasculature physiology for blood pressure control. These biomarker studies will lead to more specific disease markers and the development of even more personalized therapy in this field. However, more systematic approaches and randomized controlled trials in larger cohorts are needed to assess exercise effectiveness across the day and with different exercise types.

Insulin infusion decreases medium-sized extracellular vesicles in adults with metabolic syndrome.

Elevated extracellular vesicles (EVs) are associated with glucose dysmetabolism. However, the effects of insulin on EVs and subsequent relationships with insulin sensitivity, substrate oxidation, and inflammation are unknown. We tested the hypothesis that insulin would lower EVs and relate to insulin action. Fifty-one sedentary adults (54.8 ± 1.0 yr; V̇o2peak : 22.1 ± 0.6 mL/kg/min) with metabolic syndrome (MetS) and obesity (36.4 ± 0.65 kg/m2) underwent a 2-h euglycemic-hyperinsulinemic clamp (5 mmol/L; 40 mU/m2/min). Count and size (medium: 200-624 nm; larger: 625-1,000 nm) for total particle count, endothelial- (CD105+), leukocyte- (CD45+), platelet- (CD41+), and tetraspanin- (TX+: CD9/CD81/CD63), as well as platelet endothelial cell adhesion molecule- (CD31+) derived EVs were determined before and following the clamp using Full Spectrum Profiling (FSPM). Size and MESF (molecules of equivalent soluble fluorochrome) data were generated using FCMPASS Software. Fat and carbohydrate oxidation, in addition to high-sensitivity c-reactive protein (hsCRP), were measured to understand insulin effects and associations between EVs, metabolic flexibility, and inflammation. Despite low metabolic insulin sensitivity (M-Value = 2.56 ± 0.17 mg/kg/min), insulin increased carbohydrate (P = 0.015) and decreased fat oxidation (P = 0.048) and hsCRP (P = 0.016) compared with fasting. Insulin also decreased total particle count (P < 0.001), attributable to decreased medium-sized CD105+ (P = 0.052) and CD45+ EVs (P < 0.001). Elevated fasting insulin was associated with reduced insulin-stimulated changes in all EVs phenotypes (P < 0.001). Interestingly, fasting EVs were associated with increased fasting carbohydrate oxidation (all P < 0.05). These findings suggest that insulin decreases medium-sized EVs in conjunction with metabolic flexibility under euglycemic conditions in adults with MetS. More research is needed to determine how therapies alter EV phenotype/size and consequent cardiometabolic risk.NEW & NOTEWORTHY This study is one of the first to investigate the effects of insulin on medium and larger extracellular vesicles (EVs) in relation to metabolic insulin sensitivity and fuel use in adults with metabolic syndrome. Our data suggest that insulin infusion decreases the concentration of total particle counts, mainly due to reductions in medium-sized EVs. Furthermore, EVs, predominantly medium-sized, are inversely associated with metabolic flexibility.

Role of Blood Pressure Responses to Exercise and Vascular Insulin Sensitivity with Nocturnal Blood Pressure Dipping in Metabolic Syndrome.

INTRODUCTION: Nocturnal systolic blood pressure (SBP) dipping is independently related to cardiovascular disease risk, but it is unclear if vascular insulin sensitivity associates with SBP dipping in patients with metabolic syndrome (MetS). METHODS: Eighteen adults with MetS (ATP III criteria 3.3 ± 0.6; 53.2 ± 6.5 years; body mass index 35.8 ± 4.5 kg/m2) were categorized as "dippers" (≥10% change in SBP; n = 4 F/3 M) or "non-dippers" (<10%; n = 9 F/2 M). Twenty-four-hour ambulatory blood pressure was recorded to assess SBP dipping. A euglycemic-hyperinsulinemic clamp (40 mU/m2/min, 90 mg/dL) with ultrasound (flow mediated dilation) was performed to test vascular insulin sensitivity. A graded, incremental exercise test was conducted to estimate sympathetic activity. Heart rate (HR) recovery after exercise was then used to determine parasympathetic activity. Metabolic panels and body composition (DXA) were also tested. RESULTS: Dippers had greater drops in SBP (16.63 ± 5.2 vs. 1.83 ± 5.6%, p < 0.01) and experienced an attenuated rise in both SBPslope (4.7 ± 2.3 vs. 7.2 ± 2.5 mm Hg/min, p = 0.05) and HRslope to the incremental exercise test compared to non-dippers (6.5 ± 0.9 vs. 8.2 ± 1.7 bpm/min, p = 0.03). SBP dipping correlated with higher insulin-stimulated flow-mediated dilation (r = 0.52, p = 0.03), although the relationship was no longer significant after covarying for HRslope (r = 0.42, p = 0.09). CONCLUSION: Attenuated rises in blood pressure and HR to exercise appear to play a larger role than vascular insulin sensitivity in SBP dipping in adults with MetS.

Early chronotype with metabolic syndrome favours resting and exercise fat oxidation in relation to insulin-stimulated non-oxidative glucose disposal.

NEW FINDINGS: What is the central question of this study? Chronotype reflects differences in circadian-mediated metabolic and hormonal profiles. But, does resting and/or exercise fuel use differ in early versus late chronotype as it relates to insulin sensitivity? What are the main finding and its importance? Early chronotypes with metabolic syndrome utilized more fat during rest and exercise independent of aerobic fitness when compared with late chronotypes. Early chronotypes were also more physically active throughout the day. Greater fat use was related to non-oxidative glucose disposal. These findings suggest that early chronotypes have differences in fuel selection that associate with type 2 diabetes risk. ABSTRACT: Early chronotypes (ECs) are often insulin-sensitive, in part, due to physical activity behaviour. It is unclear, however, if chronotypes differ in resting and/or exercise fuel oxidation in relation to insulin action. Using the Morningness-Eveningness Questionnaire (MEQ), adults with metabolic syndrome (ATP III criteria) were classified as EC (MEQ = 63.7 ± 0.9, n = 24 (19F), 54.2 ± 1.2 years) or late chronotype (LC; MEQ = 47.2 ± 1.4, n = 27 (23F), 55.3 ± 1.5 years). Carbohydrate (CHO) and fat oxidation (FOX, indirect calorimetry) were determined at rest, 55% and 85% V ̇ O 2 max ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{max}}}$ , along with heart rate and rating of perceived exertion. Physical activity patterns (accelerometers), body composition (DXA) and insulin sensitivity (clamp, 40 mU/m2 /min, 90 mg/dl) with an indirect calorimetry for non-oxidative glucose disposal (NOGD) were also determined. While demographics were similar, ECs had higher V ̇ O 2 max ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{max}}}$ (P = 0.02), NOGD (P < 0.001) and resting FOX (P = 0.02) than LCs. Both groups increased CHO reliance during exercise at 55% and 85% V ̇ O 2 max ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{max}}}$ (test effect, P < 0.01) from rest, although ECs used more fat (group effect, P < 0.01). ECs had lower sedentary behaviour and more physical activity during morning/midday (both, P < 0.05). FOX at 55% V ̇ O 2 max ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{max}}}$ correlated with V ̇ O 2 max ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{max}}}$ (r = 0.425, P = 0.004) whereas FOX at 85% V ̇ O 2 max ${\dot{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{max}}}$ related to NOGD (r = 0.392, P = 0.022). ECs with metabolic syndrome used more fat in relation to insulin-stimulated NOGD.

Acute exercise improves glucose and TAG metabolism in young and older adults following high-fat, high-carbohydrate meal intake.

A single high-fat, high-carbohydrate meal (HFHC) results in elevated postprandial glucose (GLU), triglycerides (TAG) and metabolic load index (MLI; TAG (mg/dl) + GLU (mg/dl)) that contributes to chronic disease risk. While disease risk is higher in older adults (OA) compared to younger adults (YA), the acute effects of exercise on these outcomes in OA is understudied. Twelve YA (age 23.3 ± 3.9 yrs, n = 5 M/7 F) and 12 OA (age 67·7 ± 6.0 yrs, n = 8 M/4 F) visited the laboratory in random order to complete a HFHC with no exercise (NE) or acute exercise (EX) condition. EX was performed 12 hours prior to HFHC at an intensity of 65 % of maximal heart rate to expend 75 % of the kcals consumed in HFHC (Marie Callender's Chocolate Satin Pie; 12 kcal/kgbw; 57 % fat, 37 % CHO). Blood samples were taken at 0, 30, 60, 90 minutes, and then every hour until 6 hours post-meal. TAG levels increased to a larger magnitude in OA (Δ∼61 ± 31 %) compared to YA (Δ∼37 ± 34 %, P < 0·001), which were attenuated in EX compared to NE (P < 0·05) independent of age. There was no difference in GLU between OA and YA after the HFM, however, EX had attenuated GLU independent of age (NE: Δ∼21 ± 26 %; EX: Δ∼12 ± 18 %, P = 0·027). MLI was significantly lower after EX compared to NE in OA and YA (P < 0·001). Pre-prandial EX reduced TAG, GLU and MLI post-HFHC independent of age.

Insulin stimulation reduces aortic wave reflection in adults with metabolic syndrome.

Adults with metabolic syndrome (MetS) have increased fasting arterial stiffness and altered central hemodynamics that contribute, partly, to increased cardiovascular disease (CVD) risk. Although insulin affects aortic wave reflections in healthy adults, the effects in individuals with MetS are unclear. We hypothesized that insulin stimulation would reduce measures of pressure waveforms and hemodynamics in people with MetS. Thirty-five adults with obesity (27 women; 54.2 ± 6.0 yr; 37.1 ± 4.8 kg/m2) were selected for MetS (ATP III criteria) following an overnight fast. Pulse wave analysis was assessed using applanation tonometry before and after a 2-h euglycemic-hyperinsulinemic clamp (90 mg/dL, 40 mU/m2/min). Deconvolution analysis was used to decompose the aortic waveform [augmentation index corrected to heart rate of 75 beats/min (AIx@75); augmentation pressure (AP)] into backward and forward pressure components. Aerobic fitness (V̇o2max), body composition (DXA), and blood biochemistries were also assessed. Insulin significantly reduced augmentation index (AIx@75, 28.0 ± 9.6 vs. 23.0 ± 9.9%, P < 0.01), augmentation pressure (14.8 ± 6.4 vs. 12.0 ± 5.7 mmHg, P < 0.01), pulse pressure amplification (1.26 ± 0.01 vs. 0.03 ± 0.01, P = 0.01), and inflammation [high-sensitivity C-reactive protein (hsCRP): P = 0.02; matrix metallopeptidase 7 (MMP-7): P = 0.03] compared to fasting. In subgroup analyses to understand HTN influence, there were no insulin stimulation differences on any outcome. V̇o2max, visceral fat, and blood potassium correlated with fasting AIx@75 (r = -0.39, P = 0.02; r = 0.41, P = 0.03; r = -0.53, P = 0.002). Potassium levels were also associated with insulin-mediated reductions in AP (r = 0.52, P = 0.002). Our results suggest insulin stimulation improves indices of aortic reflection in adults with MetS.NEW & NOTEWORTHY This study is one of the first to investigate the effects of insulin on central and peripheral hemodynamics in adults with metabolic syndrome. We provide evidence that insulin infusion reduces aortic wave reflection, potentially through a reduction in inflammation and/or via a potassium-mediated vascular response.

Mood, Psychological, and Behavioral Factors of Health-Related Quality of Life Throughout Recovery From Sport Concussion.

OBJECTIVE: To measure alterations in mood, psychological, and behavioral factors in collegiate athletes throughout recovery from sport concussion (SC) compared with matched controls. SETTING: University research laboratory. PARTICIPANTS: Twenty (55% female) division I collegiate athletes with SC (19.3 ± 1.08 years old, 1.77 ± 0.11 m, 79.6 ± 23.37 kg) and 20 (55% female) uninjured matched controls (20.8 ± 2.17 years old, 1.77 ± 0.10 m, 81.9 ± 23.45 kg). DESIGN: Longitudinal case control. MAIN MEASURES: Self-reported concussion-related symptoms, anxiety, resilience, stigma, sleep disturbance, fatigue, and appetite were assessed at 3 time points in the SC group: T1 (≤72 hours of SC), T2 (7 days after T1), and TF (after symptom resolution). Control participants were evaluated at similar intervals. Group and group-by-sex differences were assessed using repeated-measures analyses of variance. Post hoc analyses were performed with Tukey's honestly significant difference (HSD) and paired-sample t tests. RESULTS: The SC group had greater sleep disturbance than controls at T1 (P = .001; d = 1.21) and endorsed greater stigma at all time points (P ≤ .03; d ≥ 0.80). Stigma (F(2) = 3.68; P = 0.03; η2p = 0.12), sleep disturbance (F(2) = 5.27; P = .008; η2p = 0.15), and fatigue (F(2) = 3.46; P = .04; η2p = 0.11) improved throughout recovery in those with SC only. No differences were observed between males and females (P > .05). CONCLUSION: Sleep disturbance and stigma were negatively affected by SC, highlighting potential areas for clinical interventions to maximize recovery in males and females.

Exercise improves adiposopathy, insulin sensitivity and metabolic syndrome severity independent of intensity.

NEW FINDINGS: What is the central question of this study? What are the effects of work-matched continuous versus high-intensity interval training for 2 weeks on adiposopathy and cardiometabolic risk in obese adults with prediabetes? What is the main finding and its importance? Independent of intensity, short-term exercise improves adiposopathy and insulin sensitivity. While both exercise intensities reduced fasting leptin concentrations and metabolic syndrome severity, only interval training elevated total adiponectin. In contrast to previous work, neither condition altered high-molecular weight adiponectin. Collectively, these data suggest that short-term exercise can improve adipokine profiles, which may aid in reducing cardiometabolic risk prior to clinically meaningful weight loss in adults with prediabetes. ABSTRACT: Individuals with prediabetes who are overweight and obese are at an increased risk of developing endocrine disruption of fat tissue, known as adiposopathy. While short-term exercise improves adipokine profiles, the effects of exercise intensity when matched for energy expenditure on adiposopathy are unknown. We hypothesized that high-intensity exercise would elicit greater changes in adiposopathy compared to moderate exercise. Twenty-eight overweight and obese adults (age: 60.9 ± 8.4 years; BMI: 33.0 ± 5.4 kg m-2 ) with prediabetes were randomized to twelve 60-min sessions of either moderate-continuous (CONT; n = 14) or high-intensity interval (INT; n = 14) exercise training. Total and high molecular weight (HMW) adiponectin and leptin were collected to assess adiposopathy (ratio of total adiponectin to leptin; A/L). Insulin sensitivity (SIIS ) was determined using a 75 g oral glucose tolerance test before and after training. Cardiometabolic risk factors were measured and a z-score was calculated to determine metabolic syndrome (MetS) severity. CONT and INT increased A/L (P < 0.01) and decreased leptin (P < 0.01) and MetS severity (P = 0.04). Neither intervention altered circulating levels of HMW adiponectin (P = 0.76) and only INT increased total adiponectin levels (P = 0.02). Both intensities increased insulin sensitivity (P < 0.01), which was associated with improvements in A/L (r = 0.47, P = 0.01). Additionally, increases in A/L tended to relate to decreased MetS severity (r = -0.36, P = 0.09). Short-term exercise intensity, when matched for energy expenditure, does not differentially affect improvements in adiposopathy in overweight and obese adults with prediabetes. Further, 12 bouts of exercise improved insulin sensitivity and MetS severity, suggesting that improving adipokine profiles may aid in reducing cardiometabolic risk.

Postprandial augmentation index is reduced in adults with prediabetes following continuous and interval exercise training.

NEW FINDINGS: What is the central question of this study? We compared high-intensity interval versus continuous training on fasting and postprandial arterial stiffness in people with prediabetes. What is the main finding and its importance? We show, for the first time, that exercise improves the augmentation index during the postprandial state, but not the fasted state, in adults with prediabetes. However, the fasted augmentation index improved in relationship to exercise dose, as assessed by kilocalories per session. Collectively, these findings suggest that short-term exercise can improve arterial compliance in adults with prediabetes. Therefore, lifestyle interventions designed to reduce arterial stiffness could have considerable clinical impact. ABSTRACT: People with prediabetes have elevated risk for cardiovascular disease, in part, owing to arterial stiffness mediated by low insulin sensitivity. However, the effect the intensity and/or amount (i.e. kilocalories per session) of short-term exercise training on fasting and postprandial arterial stiffness is unknown. We tested the hypothesis that increased intensity and dose (i.e. amount) of exercise would be correlated with reduced fasting and postprandial arterial stiffness in obese adults with prediabetes. After randomization, 31 adults (age 61.4 ± 8.3 years, body mass index 32.1 ± 5.4 kg m-2 ) with prediabetes performed supervised continuous (CONT; n = 17; 70% of peak heart rate) or interval (INT; n = 14; 3 min at 50% of peak heart rate and 3 min at 90% of peak heart rate) cycling training for 60 min day-1 over 2 weeks. The amount of exercise was calculated using regression equations derived from oxygen uptake ( V ̇ O 2 ) and heart rate. Arterial stiffness [augmentation index (AI) and cartoid-femoral pulse wave velocity], insulin and glucose were determined during a 180 min 75 g oral glucose tolerance test (OGTT) and analysed by the total area under the curve (tAUC) pre- versus post-training. The simple index of insulin sensitivity, (SIIS )OGTT, was calculated; aerobic fitness (peak V ̇ O 2 ) and body mass were also assessed. Short-term training had no effect on weight but did improve peak V ̇ O 2 (P = 0.003), glucose tAUC180min (P = 0.01) and insulin sensitivity (P = 0.002), independent of intensity. The CONT and INT exercise significantly reduced AI 2 h postprandial (P = 0.008) and tAUC180min (P = 0.03). Reductions in fasted AI were related to exercise dose (trend: r = -0.37, P = 0.055). Increased peak V ̇ O 2 was linked to reduced fasted (r = -0.47, P = 0.01) and tAUC180min AI (r = -0.39, P = 0.05). Decreased AI tAUC180min was correlated with increased insulin sensitivity (r = -0.50, P = 0.009). Short-term CONT and INT training reduced postprandial arterial stiffness comparably in adults with prediabetes.

Non-invasive assessment of hepatic lipid subspecies matched with non-alcoholic fatty liver disease phenotype.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic fat accumulation. Increased hepatic saturated fats and decreased hepatic polyunsaturated fats may be particularly lipotoxic, contributing to metabolic dysfunction. We compared hepatic lipid subspecies in adults with and without NAFLD, and examined links with hallmark metabolic and clinical characteristics of NAFLD. METHODS AND RESULTS: Nineteen adults with NAFLD (total hepatic fat:18.8 ± 0.1%) were compared to sixteen adults without NAFLD (total hepatic fat: 2.1 ± 0.01%). 1H-MRS was used to assess hepatic lipid subspecies. Methyl, allylic, methylene, and diallylic proton peaks were measured. Saturation, unsaturation, and polyunsaturation indices were calculated. Whole-body phenotyping in a subset of participants included insulin sensitivity (40 mU/m2 hyperinsulinemic-euglycemic clamps), CT-measured abdominal adipose tissue depots, exercise capacity, and serum lipid profiles. Participants with NAFLD exhibited more saturated and less unsaturated hepatic fat, accompanied by increased insulin resistance, total and visceral adiposity, triglycerides, and reduced exercise capacity compared to controls (all P < 0.05). All proton lipid peaks were related to insulin resistance and hypertriglyceridemia (P < 0.05). CONCLUSION: Participants with NAFLD preferentially stored excess hepatic lipids as saturated fat, at the expense of unsaturated fat, compared to controls. This hepatic lipid profile was accompanied by an unhealthy metabolic phenotype.

IMPACT OF WEIGHT LOSS TRAJECTORY FOLLOWING RANDOMIZATION TO BARIATRIC SURGERY ON LONG-TERM DIABETES GLYCEMIC AND CARDIOMETABOLIC PARAMETERS.

Objective: It is unclear whether acute weight loss or the chronic trajectory of weight loss after bariatric surgery is associated with long-term type 2 diabetes mellitus (T2DM) glycemic improvement. This ancillary study of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial aimed to answer this question. Methods: In STAMPEDE, 150 patients with T2DM were randomized to bariatric surgery, and 96 had 5-year follow-up. Data post-Roux-en-Y gastric bypass (RYGB, n = 49) and sleeve gastrectomy (SG, n = 47) were analyzed. We defined percent weight loss in the first year as negative percent decrease from baseline weight to lowest weight in the first year. Percent weight regain was positive percent change from lowest weight in the first year to fifth year. Weight change was then correlated with cardiometabolic (CM) and glycemic outcomes at 5 years using Spearman rank correlations and multivariate analysis. Results: In both RYGB and SG, less weight loss in the first year positively correlated with higher 5-year glycated hemoglobin (HbA1c) (RYGB, ß = +0.13; P<.001 and SG, ß = 0.14; P<.001). In SG, greater weight regain from nadir positively correlated with higher HbA1c (ß = 0.06; P = .02), but not in RYGB. Reduced first-year weight loss was also correlated with increased 5-year triglycerides (ß = 1.81; P = .01), but not systolic blood pressure. Weight regain did not correlate with CM outcomes. Conclusion: Acute weight loss may be more important for T2DM glycemic control following both RYGB and SG as compared with weight regain. Clinicians should aim to assist patients with achieving maximal weight loss in the first year post-op to maximize long-term health of patients. Abbreviations: BMI = body mass index; HbA1c = glycated hemoglobin; RYGB = Roux-en-Y gastric bypass; SBP = systolic blood pressure; SG = sleeve gastrectomy; STAMPEDE = Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently; T2DM = type 2 diabetes mellitus; TG = triglyceride.

Impact of Exercise on Inflammatory Mediators of Metabolic and Vascular Insulin Resistance in Type 2 Diabetes.

The development of obesity is cornerstone in the etiology of metabolic and vascular insulin resistance and consequently exacerbates glycemic control. Exercise is an efficacious first-line therapy for type 2 diabetes that improves insulin action through, in part, reducing hormone mediated inflammation. Together, improving the coordination of skeletal muscle metabolism with vascular delivery of glucose will be required for optimizing type 2 diabetes and cardiovascular disease treatment.