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Purpose People characterized as late chronotype have elevated type 2 diabetes and cardiovascular disease risk compared to early chronotype. It is unclear how chronotype is associated with insulin sensitivity, metabolic flexibility, or plasma TCA cycle intermediates concentration, amino acids (AA), and/or beta-oxidation. Methods The Morning-Eveningness Questionnaire (MEQ) was used to classify adults with metabolic syndrome (ATP III Criteria) as either early (n=15 (13F), MEQ = 64.7±1.4) or late (n=19 (16F), MEQ = 45.5±1.3) chronotype. Fasting bloods determined hepatic (HOMA-IR) and adipose insulin resistance (Adipose-IR) while a 120 min euglycemic clamp (40 mU/m 2/min, 5 mmoL/L) was performed to test peripheral insulin sensitivity (glucose infusion rate (GIR)). Carbohydrate (CHOOX) and fat oxidation (FOX) as well as non-oxidative glucose disposal (NOGD) were also estimated (indirect calorimetry). Plasma TCA intermediates, AA, and acyl-carnitines were measured along with VO2max and body composition (DXA). Results There were no statistical differences in age, BMI, fat-free mass, VO2max or ATP III criteria between groups. Early chronotype, however, had higher peripheral insulin sensitivity (P=0.009) and lower HOMA-IR (P=0.02) and Adipose-IR (P=0.05) compared to late chronotype. Further, early chronotype had higher NOGD (P=0.008) and greater insulin-stimulated CHOOX (P=0.02). While fasting lactate (P=0.01), TCA intermediates (isocitrate, ꭤ-ketoglutarate, succinate, fumarate, malate (all P≤0.04)) and some AA (proline, isoleucine (P=0.003-0.05)) were lower in early chronotype, other AA (threonine, histidine, arginine (all P≤0.05)) and most acyl-carnitines were higher (P≤0.05) compared to late chronotype. Conclusions Greater insulin sensitivity and metabolic flexibility relates to plasma TCA concentration in early chronotype.

Objective: This crossover study explored the impact of a single bout of exercise on insulin-stimulated responses in conduit arteries and capillaries.Methods: Twelve sedentary adults (49.5 [7.8] years; maximal oxygen consumption [VO 2 max]: 23.7 [5.4] mL/kg/min) with obesity (BMI 34.5 [4.3] kg/m 2 ) completed a control and exercise bout (70% VO 2 max to expend 400 kcal). Sixteen hours later, participants underwent a 2-hour euglycemic-hyperinsulinemic clamp (90 mg/dL; 40 mU/m 2 /min) to determine vascular and metabolic insulin sensitivity. Endothelial How to cite this article: Heiston EM, Liu Z, Ballantyne A, Kranz S, Malin SK. A single bout of exercise improves vascular insulin sensitivity in adults with obesity. Obesity (Silver Spring).

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% 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.

Metabolic Syndrome (MetS) raises cardiovascular disease risk. Extracellular vesicles (EVs) have emerged as important mediators of insulin sensitivity, although few studies on vascular function exist in humans. We determined the effect of insulin on EVs in relation to vascular function. Adults with MetS ( n = 51, n = 9 M, 54.8 ± 1.0 years, 36.4 ± 0.7 kg/m 2 , ATPIII: 3.5 ± 0.1 a.u., VO 2 max: 22.1 ± 0.6 ml/kg/min) were enrolled in this cross‐sectional study. Peripheral insulin sensitivity (M‐value) was determined during a euglycemic clamp (40 mU/m 2 /min, 90 mg/dl), and blood was collected for EVs (CD105+, CD45+, CD41+, TX+, and CD31+; spectral flow cytometry), inflammation, insulin, and substrates. Central hemodynamics (applanation tonometry) was determined at 0 and 120 min via aortic waveforms. Pressure myography was used to assess insulin‐induced arterial vasodilation from mouse 3rd order mesenteric arteries (100–200 μm in diameter) at 0.2, 2 and 20 nM of insulin with EVs from healthy and MetS adults. Adults with MetS had low peripheral insulin sensitivity (2.6 ± 0.2 mg/kg/min) and high HOMA‐IR (4.7 ± 0.4 a.u.) plus Adipose‐IR (13.0 ± 1.3 a.u.). Insulin decreased total/particle counts ( p < 0.001), CD45+ EVs ( p = 0.002), AIx75 ( p = 0.005) and Pb ( p = 0.04), FFA ( p < 0.001), total adiponectin ( p = 0.006), ICAM ( p = 0.002), and VCAM ( p = 0.03). Higher M‐value related to lower fasted total EVs ( r = −0.40, p = 0.004) while higher Adipose‐IR associated with higher fasted EVs ( r = 0.42, p = 0.004) independent of VAT. Fasting CD105+ and CD45+ derived total EVs correlated with fasting AIx75 ( r = 0.29, p < 0.05) and Pb ( r = 0.30, p < 0.05). EVs from MetS participants blunted insulin‐induced vasodilation in mesenteric arteries compared with increases from healthy controls across insulin doses (all p < 0.005). These data highlight EVs as potentially novel mediators of vascular insulin sensitivity and disease risk.