Early chronotype favors appetite and reduced later day caloric intake among adults with obesity.

Late chronotype (LC) is related to obesity and altered food intake throughout the day. But whether appetite perception and gut hormones differ among chronotypes is unclear. Thus, we examined if early chronotype (EC) have different appetite responses in relation to food intake than LC. Adults with obesity were categorized using the Morningness-Eveningness Questionnaire (MEQ) as either EC (n = 21, 18F, MEQ = 63.9 ± 1.0, 53.7 ± 1.2 yr, 36.2 ± 1.1 kg/m2) and LC (n = 28, 24F, MEQ = 47.2 ± 1.5, 55.7 ± 1.4 yr, 37.1 ± 1.0 kg/m2). Visual analog scales were used during a 120 min 75 g oral glucose tolerance test (OGTT) at 30 min intervals to assess appetite perception, as well as glucose, insulin, GLP-1 (glucagon-like polypeptide-1), GIP (glucose-dependent insulinotrophic peptide), PYY (protein tyrosine tyrosine), and acylated ghrelin. Dietary intake (food logs), resting metabolic rate (RMR; indirect calorimetry), aerobic fitness (maximal oxygen consumption (VO2max)), and body composition dual-energy X-ray absorptiometry (DXA) were also assessed. Age, body composition, RMR, and fasting appetite were similar between groups. However, EC had higher satisfaction and fullness as well as reduced desires for sweet, salty, savory, and fatty foods during the OGTT (P <0.05). Only GIP tAUC0-120 min was elevated in EC versus LC (p = 0.01). Daily dietary intake was similar between groups, but EC ate fewer carbohydrates (p = 0.05) and more protein (p = 0.01) at lunch. Further, EC had lower caloric (p = 0.03), protein (p = 0.03) and fat (p = 0.04) intake during afternoon snacking compared to LC. Dietary fat was lower, and carbohydrates was higher, in EC than LC (p = 0.05) at dinner. Low glucose and high insulin as well as GLP-1 tAUC60-120 min related to desires for sweet foods (p < 0.05). Taken together, EC had more favorable appetite and lower caloric intake later in the day compared with LC.

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.

Nutritional Aspects to Cardiovascular Diseases and Type 2 Diabetes Mellitus.

PURPOSE OF REVIEW: In this narrative review, we discuss the current evidence related to the role of dietary interventions to prevent and treat type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We also propose alternative therapeutic strategies other than weight loss in this population, namely, improvements in cardiorespiratory fitness and its determinants. RECENT FINDINGS: While weight loss has been consistently associated with the prevention of T2DM and improvements in glycemic control in those with established diseases, its role in preventing and treating CVD is less clear. In fact, in this setting, improvements in diet quality have provided greater benefits, suggesting that this might represent an alternative, or an even more effective strategy than energy-restriction. Improvements in diet quality, with and without caloric restriction have been shown to improve CVD risk and to prevent the development of T2DM in individuals at risk; however, with regard to glycemic control in patients with T2DM, any dietary intervention resulting in significant weight loss may produce clinically meaningful benefits. Finally, dietary interventions with and without energy restriction that can improve cardiorespiratory fitness, even in absence of weight loss in patients with obesity, should be encouraged.

Physical Activity During Breast Cancer Therapy Associates With Preserved Exercise Capacity and Cardiac Function (WF97415).

Background: Cancer treatment increases cardiovascular disease risk, but physical activity (PA) may prevent cardiovascular disease. Objectives: This study examined whether greater PA was associated with better submaximal exercise capacity and cardiac function during cancer therapy. Methods: Participants included 223 women with stage I to III breast cancer (BC) before and 3 months after undergoing treatment and 126 control participants. Leisure-time PA (LTPA) was reported using the Godin-Shephard LTPA questionnaire. Cardiac function was assessed by cardiac magnetic resonance. Submaximal exercise capacity was determined by 6-minute walk distance. Results: BC participants reported similar baseline LTPA scores (24.7; 95% CI: 21.7-28.0) as control participants (29.4; 95% CI: 25.0-34.2). The BC group declined to 16.9 (95% CI: 14.4-19.6) at 3 months relative to 30.8 (95% CI: 26.2-35.8) in control participants. Among BC participants, more LTPA was related to better exercise capacity (ß ± SE: 7.1 ± 1.6; 95% CI: 4.0-10.1) and left ventricular (LV) circumferential strain (-0.16 ± 0.07; 95% CI: -0.29 to -0.02). Increased LTPA over the 3 months was associated with decreased likelihood of treatment-induced cardiac dysfunction according to LV circumferential strain classifications (OR: 0.98; 95% CI: 0.97-0.998). BC participants reporting insufficient LTPA according to PA guidelines exhibited deteriorations in exercise capacity (adjusted mean difference ± SE: -29 ± 10 m; P = 0.029), LV end-systolic volume (5.8 ± 1.3 mL; P < 0.001), LV ejection fraction (-3.2% ± 0.8%; P = 0.002), and LV circumferential strain (2.5% ± 0.5%; P < 0.001), but BC participants meeting LTPA guidelines did not exhibit these adverse changes. Conclusions: PA declined during BC therapy; however, PA participation was associated with attenuated declines in exercise capacity and cardiac function that are often observed in this population. (Understanding and Predicting Breast Cancer Events After Treatment [WF97415 UPBEAT]; NCT02791581).

ß-Aminoisobutyric Acid Relates to Favorable Glucose Metabolism through Adiponectin in Adults with Obesity Independent of Prediabetes.

ß-Aminoisobutyric acid (BAIBA) is secreted by skeletal muscle and promotes insulin sensitivity, fat oxidation, and anti-inflammation. While BAIBA is purportedly lower in individuals with obesity, no work has examined if prediabetes (PD) differentially impacts BAIBA concentrations in people with obesity. Methods. Adults were classified as normal glucose tolerant (NGT; n = 22 (20F); 48.0 ± 2.4 yrs; 36.9 ± 1.2 kg/m2) or PD (n = 23 (18F); 54.2 ± 1.6 yrs; 38.4 ± 1.2 kg/m2) based on ADA criteria. A 180-minute 75 g OGTT was used to estimate fasting (HOMA-IR (liver)) and postprandial (Matsuda index (muscle)) insulin sensitivity as well as ß-cell function (disposition index (DI), glucose-stimulated insulin secretion adjusted for insulin sensitivity). Body composition and fasting measures of BAIBA, fat oxidation (indirect calorimetry), and adipokines were determined. Results. NGT and PD had similar BAIBA concentrations (1.4 ± 0.1 vs. 1.2 ± 0.1 µM, P = 0.23) and fat oxidation (P = 0.31), despite NGT having lower fasting (92.2 ± 1.2 vs. 104.1 ± 3.2 mg/dL, P = 0.002) and tAUC180min glucose (P < 0.001) compared to PD. Moreover, NGT had higher postprandial insulin sensitivity (P = 0.01) and higher total phase DIliver (P = 0.003) and DImuscle (P = 0.001). Increased BAIBA was associated with adiponectin (r = 0.37, P = 0.02), adiponectin/leptin ratio (r = 0.39, P = 0.01), and lower glucose and insulin at 180 minutes (r = -0.31, P = 0.03 and r = -0.39, P = 0.03, respectively). Adiponectin also correlated with lower glucose at 180 minutes (r = -0.45, P = 0.005), and mediation analysis showed that BAIBA was no longer a significant predictor of glucose at 180 minutes after controlling for adiponectin (P = 0.08). Conclusion. While BAIBA did not differ between NGT and PD, higher BAIBA is related to favorable glucose metabolism, possibly through an adiponectin-related mechanism. Additional work is required to understand how exercise and/or diet impact BAIBA in relation to type 2 diabetes risk.

Extracellular vesicles and insulin-mediated vascular function in metabolic syndrome.

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/m2 , ATPIII: 3.5 ± 0.1 a.u., VO2 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/m2 /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.

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.

Aortic waveform responses to insulin in late versus early chronotype with metabolic syndrome.

Late chronotype (LC) correlates with reduced metabolic insulin sensitivity and cardiovascular disease. It is unclear if insulin action on aortic waveforms and inflammation is altered in LC versus early chronotype (EC). Adults with metabolic syndrome (n = 39, MetS) were classified as either EC (Morning-Eveningness Questionnaire [MEQ] = 63.5 ± 1.2) or LC (MEQ = 45.5 ± 1.3). A 120 min euglycemic clamp (40 mU/m2 /min, 90 mg/dL) with indirect calorimetry was used to determine metabolic insulin sensitivity (glucose infusion rate [GIR]) and nonoxidative glucose disposal (NOGD). Aortic waveforms via applanation tonometry and inflammation by blood biochemistries were assessed at 0 and 120 min of the clamp. LC had higher fat-free mass and lower VO2 max, GIR, and NOGD (between groups, all p ≤ 0.05) than EC. Despite no difference in 0 min waveforms, both groups had insulin-stimulated elevations in pulse pressure amplification with reduced AIx75 and augmentation pressure (AP; time effect, p ≤ 0.05). However, EC had decreased forward pressure (Pf; interaction effect, p = 0.007) with insulin versus rises in LC. Although LC had higher tumor necrosis factor-α (TNF-α; group effect, p ≤ 0.01) than EC, both LC and EC had insulin-stimulated increases in TNF-α and decreases in hs-CRP (time effect, both p ≤ 0.01). Higher MEQ scores related to greater insulin-stimulated reductions in AP (r = -0.42, p = 0.016) and Pf (r = -0.41, p = 0.02). VO2 max correlated with insulin-mediated reductions in AIx75 (r = -0.56, p < 0.01) and AP (r = -0.49, p < 0.01). NOGD related to decreased AP (r = -0.44, p = 0.03) and Pf (r = -0.43, p = 0.04) during insulin infusion. LC was depicted by blunted forward pressure waveform responses to insulin and higher TNF-α in MetS. More work is needed to assess endothelial function across chronotypes.

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.

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.

Insulin Sensitivity and Metabolic Flexibility Parallel Plasma TCA Levels in Early Chronotype With Metabolic Syndrome.

CONTEXT: 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. OBJECTIVE: This study examined these metabolic associations with chronotype. METHODS: The Morningness-Eveningness Questionnaire (MEQ) was used to classify adults with metabolic syndrome (ATP III criteria) as either early (n = 15 [13F], MEQ = 64.7 ±â€…1.4) or late (n = 19 [16F], MEQ = 45.5 ±â€…1.3) chronotype. Fasting bloods determined hepatic (HOMA-IR) and adipose insulin resistance (Adipose-IR) while a 120-minute euglycemic clamp (40 mU/m2/min, 5 mmoL/L) was performed to test peripheral insulin sensitivity (glucose infusion rate). Carbohydrate (CHOOX) and fat oxidation (FOX), as well as nonoxidative glucose disposal (NOGD), were also estimated (indirect calorimetry). Plasma tricarboxylic acid cycle (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 with 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, α-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 with late chronotype. CONCLUSION: Greater insulin sensitivity and metabolic flexibility relates to plasma TCA concentration in early chronotype.

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.

Statins for Cardiac and Vascular Protection During and After Cancer Therapy.

PURPOSE OF REVIEW: Although cancer treatments have increased overall survival rates, the cardiovascular consequences of cancer therapy place patients at an increased risk of adverse outcomes. This manuscript presents data accumulated to date regarding cardiovascular outcomes relating to the administration of 3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitor (or statin) therapy in individuals receiving potentially cardiotoxic cancer treatments. RECENT FINDINGS: Retrospective observational studies in humans and randomized controlled trials in animals suggest that statins may reduce cancer-specific and all-cause mortality. Further, statins may attenuate cancer therapy-induced declines in left ventricular ejection fraction (LVEF) and increases in blood pressure. Observational studies suggest a potential attenuation in LVEF decline in patients with cancer and primary or secondary indications to receive a statin for prevention of cardiovascular events. Large randomized clinical trials are warranted to understand the efficacy and potential impacts of statin class, dosage, and duration on cardiovascular outcomes in patients treated for cancer.

A single bout of exercise improves vascular insulin sensitivity in adults with obesity.

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 [VO2 max]: 23.7 [5.4] mL/kg/min) with obesity (BMI 34.5 [4.3] kg/m2 ) completed a control and exercise bout (70% VO2 max to expend 400 kcal). Sixteen hours later, participants underwent a 2-hour euglycemic-hyperinsulinemic clamp (90 mg/dL; 40 mU/m2 /min) to determine vascular and metabolic insulin sensitivity. Endothelial and capillary functions were assessed by brachial artery flow-mediated dilation and contrast-enhanced ultrasound, respectively. Metabolized glucose infusion rate, substrate oxidation (indirect calorimetry), nonoxidative glucose disposal (NOGD), and inflammation were also determined. RESULTS: Exercise increased insulin-stimulated preocclusion diameter (p = 0.01) and microvascular blood flow (condition effect: p = 0.04) compared with control. Furthermore, exercise improved metabolic insulin sensitivity by 21%, which paralleled rises in NOGD (p = 0.05) and decreases in soluble receptors for advanced glycation end products (condition effect: p = 0.01). Interestingly, changes in NOGD were related to increased insulin-stimulated microvascular blood flow (r = 0.57, p = 0.05). CONCLUSIONS: A single bout of exercise increases vascular insulin sensitivity in adults with obesity. Additional work is needed to determine vascular responses following different doses of exercise in order to design lifestyle prescriptions for reducing chronic disease risk.

Both intermuscular fat and LVEF decline promote heart failure symptoms in cancer survivors.

BACKGROUND: Approximately 20% of cancer survivors treated with chemotherapy experience worsening heart failure (HF) symptoms post-cancer treatment. While research has predominantly investigated the role of cardiotoxic treatments, much less attention has focused on other risk factors, such as adiposity. However, emerging data in cancer survivors indicates that adiposity may also impact a variety of cardiovascular outcomes. METHODS: In a prospective study of 62 patients diagnosed with cancer followed for 24 months from cancer diagnosis through to survivorship (post-cancer treatment), we ascertained baseline fat depots including intermuscular fat (IMF) of the erector spinae muscles; and pre- and post-cancer treatment left ventricular ejection fraction (LVEF) and HF symptoms at baseline and 24-months, respectively. Linear regression was used to model independent variables in relation to HF symptoms at 24-months. RESULTS: Baseline IMF and LVEF change over 24-months significantly interacted to predict HF score at 24-months. The highest HF symptom score was observed for participants who experienced high IMF at baseline and a high decline in LVEF over 24-months (HF score = 11.0) versus all other categories of baseline IMF and LVEF change. CONCLUSIONS: Together IMF and LVEF decline may play an important role in the worsening of HF symptoms in cancer survivors. The finding that IMF at cancer diagnosis led to elevated HF scores post-treatment suggests that IMF may be a potential target for intervention studies.

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.

A Low-Calorie Diet with or without Exercise Reduces Postprandial Aortic Waveform in Females with Obesity.

PURPOSE: Arterial stiffness is considered a predictor of cardiovascular disease. Females have higher values of arterial stiffness than males, suggesting a greater risk of heart-related complications. Although a low-calorie diet (LCD) reduces fasting arterial stiffness, in part through weight loss, it is unknown if interval exercise (INT) adds to the benefit of LCD on fasting and postprandial arterial stiffness in females with obesity. METHODS: Twenty-five females (47 ± 2.6 yr, 37.6 ± 1.3 kg·m-2) were randomized to 13 d of LCD (n = 12; mixed meals of ~1200 kcal·d-1) or LCD + INT (n = 13; 60 min·d-1 of supervised 3-min intervals at 90% HRpeak and 50% HRpeak). Arterial stiffness (augmentation index [AIx] and carotid-femoral pulse wave velocity [cfPWV]) and blood biochemistries were measured during a 75-g oral glucose tolerance test before and after the intervention to determine fasting and postprandial arterial stiffness as well as insulin sensitivity (simple index of insulin sensitivity [SIIS]) and inflammation (C-reactive protein, interleukin 8, and tumor necrosis factor alpha). RESULTS: Although LCD + INT increased V˙O2peak and HDL compared with LCD (P = 0.04 and P < 0.01, respectively), both interventions decreased body fat, LDL, total cholesterol, and triglycerides (all P < 0.01) and increased SIIS (P = 0.03). Despite no effect on fasting AIx (P = 0.27), LCD and LCD + INT decreased AIx60min (-7.4% ± 4.3% vs -7.0% ± 5.0%, P = 0.04) and tAUC120min (-663 ± 263 vs -457 ± 406, P = 0.03). There were no changes in fasting cfPWV (P = 0.91) or cfPWV120min (P = 0.62). Increased SIIS and decreased interleukin 8 were associated with reduced fasting AIx (r = -0.44, P = 0.03, and r = 0.40, P = 0.055), whereas decreased C-reactive protein correlated with reduced postprandial AIx60min (r = 0.43, P = 0.04). CONCLUSION: Independent of exercise, 13 d of LCD reduces postprandial AIx in females with obesity. Insulin sensitivity and inflammation correlated with improved arterial stiffness, suggesting unique mechanisms regulate fasted versus postprandial arterial stiffness.

Cellular and Functional Effects of Insulin Based Therapies and Exercise on Endothelium.

Endothelial dysfunction is a hallmark of type 2 diabetes that can have severe consequences on vascular function, including hypertension and changes in blood flow, as well as exercise performance. Because endothelium is also the barrier for insulin movement into tissues, it acts as a gatekeeper for transport and glucose uptake. For this reason, endothelial dysfunction is a tempting area for pharmacological and/or exercise intervention with insulin-based therapies. In this review, we describe the current state of drugs that can be used to treat endothelial dysfunction in type 2 diabetes and diabetes-related diseases (e.g., obesity) at the molecular levels, and also discuss their role in exercise.

Short-term interval exercise suppresses acylated ghrelin and hunger during caloric restriction in women with obesity.

Caloric restriction is suggested to increase hunger, in part, through complex interactions of hormones and behavior that contribute to challenges in long-term weight loss. Although intense exercise may attenuate appetite, no data exist testing the effects of interval exercise (INT) during a low-calorie diet (LCD) on appetite regulation. We hypothesized that LCD+INT would favorably influence satiety when compared with an energy-deficit matched LCD in women with obesity. Twenty-six women with obesity (47.3±2.4 yrs; 37.3 ± 1.2 kg/m2) were randomized to either LCD (n = 13; mixed meals of ~1200 kcal/d) or LCD+INT (n = 13; 60 min/d of supervised interval exercise at 90% HRpeak for 3 min and 50% HRpeak for 3 min) for 2 weeks. An additional 350kcal (shake) was provided to LCD+INT individuals post-exercise to equate energy availability between groups. Total PYY, acylated ghrelin and des-ghrelin were measured at 0, 30 and 60 min of a 75g OGTT before and after the intervention. Visual analog scales were also administered at 0 and 120 min of the OGTT to assess appetite perception. Food logs were recorded prior to and during the intervention to ensure caloric intake compliance. Compared with pre-intervention conditions, both interventions decreased food intake (P = 0.001) and body fat (P < 0.01). There was no effect on fasting PYY, but both LCD and LCD+INT increased post-prandial PYY iAUC (P < 0.001) relative to pre-intervention. LCD+INT maintained fasting acylated ghrelin (P = 0.06) and suppressed post-prandial acylated ghrelin iAUC (P = 0.04) compared to LCD. Neither intervention impacted circulating des- ghrelin before or following the OGTT. Interestingly, LCD+INT attenuated fasting hunger and maintained fullness compared with LCD (P = 0.05 and P = 0.06, respectively). Taken together, interval exercise favors acylated ghrelin suppression and perception of hunger during a LCD in women with obesity.