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Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18-55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise.
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Dieta Reductora , Ejercicio Físico/fisiología , Lipocalina 2/sangre , Adulto , Atletas , Femenino , Humanos , Lipocalina 2/metabolismo , MasculinoRESUMEN
OBJECTIVE: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and SNS activity in individuals with low sodium intake and differing categories of metabolic risk along the glucose continuum. We hypothesized that low sodium intake is associated with (1) impairment of endothelial function and (2) higher SNS activity in individuals with higher metabolic risk. RESEARCH DESIGN AND METHODS: In this prospective observational study, participants (n=54) with low sodium intake (single 24 hours urine sodium excretion <150 mmol/24 hours) were categorized based on oral glucose tolerance testing as: normal glucose tolerance (NGT, n=10), impaired glucose tolerance (IGT, n=15), treatment naive type 2 diabetes (T2D-) (n=12) or treated type 2 diabetes (T2D+) (n=17). We assessed endothelial function using pulse amplitude tonometry (PAT) derived reactive hyperemic index and PAT ratio; arterial stiffness via augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; glycosylated hemoglobin A1c (HbA1c) and lipid profile. RESULTS: Mean (SD) sodium excretion was 110.6 (26) mmol/24 hours. Compared with NGT, IGT and T2D-, the T2D+ group had lower MSNA (p=0.005), PAT ratio (p=0.04) and baroreflex sensitivity (p=0.0002) and an augmented heart rate (p=0.02). The T2D+ group had appropriate mean (SD) glycemic (HbA1c 7.2 (1.72)%), total cholesterol (4.2 (1.0) mmol/L), low-density lipoprotein (2.2 (1.0) mmol/L) and blood pressure (systolic 136 (13), diastolic 78 (12)) (mm Hg) control. CONCLUSIONS: Individuals with T2D+ have impaired endothelial and baroreflex function, despite low sodium intake, appropriately managed cardiometabolic risk factors and lower SNS activity, compared with others along the glucose continuum. Whether low sodium intake is associated with modulation of the sympathovascular profile in T2D requires further investigation.
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Diabetes Mellitus Tipo 2/fisiopatología , Endotelio/fisiopatología , Sodio en la Dieta , Sistema Nervioso Simpático/fisiopatología , Anciano , Femenino , Intolerancia a la Glucosa/fisiopatología , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Manometría , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND/PURPOSE: Sympathetic nervous system activation in obesity is associated with impaired cardiovascular and metabolic function. Animal studies have shown a direct link between sympathetic nervous activation and bone health but little is known about this link in humans. This study examined whether sympathetic activation may impact bone health in overweight adults. METHODS: This cross sectional study included 96 overweight or obese middle-aged adults (51 males, mean body mass index: 32.8â¯kg/m2, mean age: 55.3â¯years). Multivariate linear regression models evaluated associations between whole body and leg bone mineral density (BMD) and bone mineral content (BMC) derived from dual-energy X-ray absorptiometry and muscle sympathetic nervous system activity (MSNA) measured by microneurography. RESULTS: Older age, male sex and higher weight were associated with higher leg and body BMC and BMD. After adjustment for age, sex and weight, MSNA was significantly inversely associated with total BMC (pâ¯=â¯0.012) and with leg BMC (pâ¯<â¯0.01) but was not associated with either total or leg BMD (pâ¯=â¯0.159 and pâ¯=â¯0.063 respectively). When the analysis was sex specific, the relationships between MSNA and total and leg BMC were only significant in males. CONCLUSIONS: Our study indicates that in middle aged overweight or obese males, sympathetic activation may have a deleterious effect on bone mineral content.
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Densidad Ósea , Sobrepeso/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Anciano , Animales , Índice de Masa Corporal , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.
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Desnervación/métodos , Atrofia de Múltiples Sistemas/fisiopatología , Insuficiencia Autonómica Pura/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Anciano , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Atrofia de Múltiples Sistemas/metabolismo , Norepinefrina/sangre , Insuficiencia Autonómica Pura/sangre , Insuficiencia Autonómica Pura/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
OBJECTIVE: High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. APPROACH AND RESULTS: Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. CONCLUSIONS: WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943.
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Restricción Calórica , Terapia por Ejercicio , Lipoproteínas HDL/sangre , Síndrome Metabólico/terapia , Pérdida de Peso , Biomarcadores/sangre , Proteínas de Transferencia de Ésteres de Colesterol/sangre , HDL-Colesterol/sangre , Terapia Combinada , Femenino , Humanos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Tamaño de la Partícula , Fosfolípidos/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Esfingolípidos/sangre , Células THP-1 , Factores de Tiempo , Resultado del TratamientoRESUMEN
Background: A diet rich in fat, in particular saturated fat (SF), may be linked to cardiovascular disease development, possibly due to a detrimental effect of fat on endothelial function (EF). Objective: We aimed to determine whether the habitual SF intake [as a ratio to total fat (the sum of saturated, polyunsaturated, and monounsaturated fat)] might influence endothelial function in young, overweight but otherwise healthy adults. Design: Sixty-nine young adults (49 males, mean age: 23 ± 1 years, mean BMI: 29.1 ± 0.8 kg/m2) were classified into three tertiles according to their habitual SF intake consumption (low SF: <39%, medium SF 39.1-43.7%, and high SF: >43.7% of total fat). Endothelial function was assessed using digital amplitude tonometry. Results: The three groups of individuals were comparable for total energy intake and calories from: fat, protein, and carbohydrates. There was no difference in anthropometric and hemodynamic variables among the groups. Those in the high SF group presented with impaired endothelial function [reactive hyperemia index (RHI): high SF: 1.60 ± 0.08 compared to 2.23 ± 0.16 in the medium SF and 2.12 ± 0.14 in the low SF group, P < 0.01]. Regression analysis, including gender, age, ethnicity, body mass index indicated that the ratio of SF to total fat was an independent predictor of the RHI (P < 0.05). Conclusion: The habitual consumption of a diet high in SF in relation to polyunsaturated and monounsaturated fat was strongly associated with impaired endothelial function in young overweight adults, potentially contributing to increased risk of developing cardiovascular disease.
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OBJECTIVE: Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both. METHODS: Young (18-30 years) male subjects with overweight (BMI > 25 kg/m2 ) were allocated to a WL program (n = 10), a moxonidine treatment course (M; n = 10, 0.4 mg/d), a combination of both (WL + M; n = 11), or to a control (C) group (n = 6) for 6 months. Muscle sympathetic nerve activity (MSNA), endothelial function, renal function (Cockcroft-Gault formula), and the metabolic profile were assessed before and after intervention. RESULTS: WL occurred in the WL and WL + M groups (-7.6 ± 1.9 kg, P < 0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL + M groups (by â¼10 bursts/min, P < 0.001, and by â¼9 mm Hg, P < 0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL + M group, decreased total cholesterol (-0.78 ± 0.23 mmol/L, P < 0.001), decreased low-density lipoprotein cholesterol (-0.49 ± 0.16 mmol/L, P < 0.01), decreased insulin (-6.5 ± 2.8 mmol/L, P < 0.05), and attenuated glomerular hyperfiltration (-19 ± 5 mL/min, P < 0.01) occurred. CONCLUSIONS: The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight.
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Antihipertensivos/uso terapéutico , Restricción Calórica/métodos , Enfermedades Cardiovasculares/prevención & control , Imidazoles/uso terapéutico , Pérdida de Peso/efectos de los fármacos , Adolescente , Adulto , Antihipertensivos/farmacología , Humanos , Imidazoles/farmacología , Masculino , Adulto JovenRESUMEN
Background: Neck circumference (NC) is a predictor of cardiometabolic risk. The objective of this study was to explore the relationship of NC to muscle sympathetic nerve activity (MSNA) within an overweight and obese population. Methods: The study design was a retrospective cross-sectional analysis. Un-medicated persons (72 men, 53 postmenopausal women) aged 56 ± 1 years (mean ± SEM) with body mass index (BMI) 32.8 ± 0.4 kg/m2, were studied. NC was measured together with traditional anthropometric measures, supine blood pressure, fasting blood lipids, insulin, and glucose. Insulin sensitivity was assessed by homeostasis model (HOMA-IR) and Matsuda Insulin Sensitivity Index (ISI) derived from 75-g oral glucose tolerance test. Resting multiunit MSNA was recorded by microneurography in the peroneal nerve and expressed as burst frequency and burst incidence. Results: Men within the highest tertile of NC had significantly higher fasting and post-glucose plasma insulin levels (insulin AUC0-120), HOMA-IR, non-esterified fatty acids, MSNA (45 ± 2 vs. 36 ± 2 bursts per min; 69 ± 3 vs. 58 ± 3 bursts per 100 hb) and heart rate, and lower Matsuda ISI compared to men in the lowest tertile (P all <0.05). In stepwise regression analyses, NC alone explained 12%, and together with insulin AUC0-120 it accounted for 22%, of the variance in MSNA in men. In women, NC was associated with anthropometric measures but not with MSNA or metabolic indices. Conclusions: Among overweight and obese men, NC was independently associated with elevated MSNA and hyperinsulinemia, and thus may be relevant to cardiometabolic risk prediction. The biological basis of gender differences merits further elucidation.
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AIMS: Elevated serum uric acid (SUA) is often present in conditions associated with increased cardiovascular risk yet it is not recognized as a marker of risk. We evaluated whether SUA was associated with evidence of early markers of cardiovascular risk factor including subclinical early organ damage, sympathetic tone and metabolic profile in a healthy population with a high prevalence of obesity. MATERIAL AND METHODS: Data from 281 patients (175 women and 106 men, mean age: 35.5â±â0.8 years, mean BMI: 33.2â±â0.5âkg/m) were retrieved from a database. All participants were healthy, nonsmoker and free of medication. Available data included metabolic profile, muscle sympathetic nervous activity (MSNA, microneurography), endothelial function (pulse amplitude tonometry, augmentation index), estimated glomerular filtration rate (eGFR) and echocardiography. RESULTS: With participants grouped into sex-adjusted tertiles of SUA, those in the third tertile of SUA had increased waist circumference, worse metabolic profile (fasting glucose, total cholesterol, triglycerides and HDL), elevated MSNA, decreased endothelial function, increased augmentation index and decreased eGFR compared with those in the first tertile of SUA. In multiple regression analysis adjusted for age, sex, BMI and ethnicity, SUA was independently associated with waist circumference, low-density lipoprotein, triglycerides, augmentation index, MSNA and eGFR, providing a combined adjusted Râ=â0.599 or 60% of the overall variance. CONCLUSION: In a healthy population with a high proportion of obesity, SUA is associated with measures of metabolic, end-organ damage and sympathetic tone indicating the potential value of SUA as a marker of early cardiovascular disease development.
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Obesidad , Ácido Úrico/sangre , Adulto , Biomarcadores/sangre , Enfermedades Cardiovasculares/epidemiología , Colesterol/sangre , Femenino , Humanos , Masculino , Obesidad/epidemiología , Obesidad/fisiopatología , Triglicéridos/sangre , Circunferencia de la CinturaRESUMEN
Background: Asian subjects are at increased cardio-metabolic risk at comparatively lower body mass index (BMI) compared with white subjects. Sympathetic nervous system activation and dyslipidemia, both characteristics of increased adiposity, appear to be related. We therefore analyzed the association of muscle sympathetic nerve activity (MSNA) with the plasma lipidomic profile in young adult Asian and white subjects. Methods: Blood samples were collected from 101 participants of either Asian or white background (age, 18 to 30 years; BMI, 28.1 ± 5.9 kg/m2). Lipids were extracted from plasma and analyzed using electrospray ionization-tandem mass spectrometry. MSNA was quantified using microneurography. The association of MSNA and obesity with lipid species was examined using linear regression analysis. Results: The plasma concentrations of total dihydroceramide, ceramide, GM3 ganglioside, lysoalkylphosphatidylcholine, alkenylphosphatidylethanolamine, and lysophosphatidylinositol were elevated in the Asian subjects relative to the white subjects. After adjustment for confounders, diacylglycerols and triacylglycerols, cholesterol esters, phosphatidylinositols, phosphatidylethanolamines, and phosphatidylglycerols bore significant associations with MSNA but only in the Asian subjects. These associations remained significant after further adjustment for the participants' degree of insulin resistance and appeared not to be related to differences in diet macronutrient content between groups. Conclusions: The lipidomic profile differs between Asian and white subjects. There exists a strong relationship between certain lipid species and MSNA. The association is stronger in Asian subjects, despite their lower BMI. This study demonstrates an association between circulating lipids and central sympathetic outflow. Whether the stronger association between the lipid profile and sympathetic activation underpins the apparent greater risk posed by increased adiposity in Asian individuals merits further attention.
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Asiático , Metabolismo de los Lípidos , Músculo Esquelético/inervación , Sistema Nervioso Simpático/fisiopatología , Población Blanca , Glucemia/metabolismo , Ceramidas/metabolismo , Ésteres del Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Diglicéridos/metabolismo , Femenino , Gangliósidos/metabolismo , Humanos , Resistencia a la Insulina , Lisofosfolípidos/metabolismo , Masculino , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Triglicéridos/metabolismo , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: We aimed to examine the effect of interrupting 7 h prolonged sitting with brief bouts of walking or resistance activities on 22 h glucose homeostasis (including nocturnal-to-following morning hyperglycaemia) in adults with type 2 diabetes. METHODS: This study is an extension of a previously published randomised crossover trial, which included 24 inactive overweight/obese adults with type 2 diabetes (14 men; 62 ± 6 years) who completed three 7 h laboratory conditions, separated by 6-14 day washout periods: SIT: (1) prolonged sitting (control); (2) light-intensity walking (LW): sitting plus 3 min bouts of light-intensity walking at 3.2 km/h every 30 min; (3) simple resistance activities (SRA): sitting plus 3 min bouts of simple resistance activities (alternating half-squats, calf raises, brief gluteal contractions and knee raises) every 30 min. In the present study, continuous glucose monitoring was performed for 22 h, encompassing the 7 h laboratory trial, the evening free-living period after leaving the laboratory and sleeping periods. Meals and meal times were standardised across conditions for all participants. RESULTS: Compared with SIT, both LW and SRA reduced 22 h glucose [SIT: 11.6 ± 0.3 mmol/l, LW: 8.9 ± 0.3 mmol/l, SRA: 8.7 ± 0.3 mmol/l; p < 0.001] and nocturnal mean glucose concentrations [SIT: 10.6 ± 0.4 mmol/l, LW: 8.1 ± 0.4 mmol/l, SRA: 8.3 ± 0.4 mmol/l; p < 0.001]. Furthermore, mean glucose concentrations were sustained nocturnally at a lower level until the morning following the intervention for both LW and SRA (waking glucose both -2.7 ± 0.4 mmol/l compared with SIT; p < 0.001). CONCLUSIONS/INTERPRETATION: Interrupting 7 h prolonged sitting time with either LW or SRA reduced 22 h hyperglycaemia. The glycaemic improvements persisted after these laboratory conditions and nocturnally, until waking the following morning. These findings may have implications for adults with relatively well-controlled type 2 diabetes who engage in prolonged periods of sitting, for example, highly desk-bound workers. TRIAL REGISTRATION: anzctr.org.au ACTRN12613000576729 FUNDING: : This research was supported by a National Health and Medical Research Council (NHMRC) project grant (no. 1081734) and the Victorian Government Operational Infrastructure Support scheme.
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Diabetes Mellitus Tipo 2/sangre , Ejercicio Físico/fisiología , Anciano , Glucemia/metabolismo , Estudios Cruzados , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posprandial , Postura/fisiología , Caminata/fisiologíaRESUMEN
BACKGROUND AND AIMS: Plasma sphingolipids including ceramides, and gangliosides are associated with insulin resistance (IR) through effects on insulin signalling and glucose metabolism. Our studies of subjects with metabolic syndrome (MetS) showed close relationships between IR and sympathetic nervous system (SNS) activity including arterial norepinephrine (NE). We have therefore investigated possible associations of IR and SNS activity with complex lipids that are involved in both insulin sensitivity and neurotransmission. METHODS: We performed a cross-sectional assessment of 23 lipid classes/subclasses (total 339 lipid species) by tandem mass spectrometry in 94 overweight untreated subjects with IR (quantified by HOMA-IR, Matsuda index and plasma insulin). RESULTS: Independently of IR parameters, several circulating complex lipids associated significantly with arterial NE and NEFA (non-esterified fatty acids) and marginally with heart rate (HR). After accounting for BMI, HOMA-IR, systolic BP, age, gender, and correction for multiple comparisons, these associations were significant (p < 0.05): NE with ceramide, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine and free cholesterol; NEFA with mono- di- and trihexosylceramide, GM3 ganglioside, sphingomyelin, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine, phosphatidylinositol and free cholesterol; HR marginally (p = or <0.1>0.05) with ceramide, GM3 ganglioside, sphingomyelin, lysophosphatidylcholine, phosphatidylinositol, lysophosphatidylinositol and free cholesterol. Multiple subspecies of these lipids significantly associated with NE and NEFA. None of the IR biomarkers associated significantly with lipid classes/subclasses after correction for multiple comparisons. CONCLUSIONS: This is the first demonstration that arterial norepinephrine and NEFA, that reflect both SNS activity and IR, associate significantly with circulating complex lipids independently of IR, suggesting a role for such lipids in neural mechanisms operating in MetS.
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Lípidos/sangre , Síndrome Metabólico/sangre , Obesidad/sangre , Sistema Nervioso Simpático/metabolismo , Transmisión Sináptica , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Ceramidas/sangre , Estudios Transversales , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Resistencia a la Insulina , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Norepinefrina/sangre , Obesidad/diagnóstico , Obesidad/fisiopatología , Fosfolípidos/sangre , Esfingolípidos/sangre , Sistema Nervioso Simpático/fisiopatología , Espectrometría de Masas en TándemRESUMEN
Background and Purpose: Elevated sympathetic nervous system (SNS) activity is a characteristic of obesity and type 2 diabetes (T2D) that contributes to target organ damage and cardiovascular risk. In this study we examined whether baseline metabolic status influences the degree of sympathoinhibition attained following equivalent dietary weight loss. Methods: Un-medicated obese individuals categorized as normal glucose tolerant (NGT, n = 15), impaired glucose tolerant (IGT, n = 24), and newly-diagnosed T2D (n = 15) consumed a hypocaloric diet (29% fat, 23% protein, 45% carbohydrate) for 4-months. The three groups were matched for baseline age (56 ± 1 years), body mass index (BMI, 32.9 ± 0.7 kg/m2), and gender. Clinical measurements included whole-body norepinephrine kinetics, muscle sympathetic nerve activity (MSNA, by microneurography), spontaneous cardiac baroreflex sensitivity (BRS), and oral glucose tolerance test. Results: Weight loss averaged -7.5 ± 0.8, -8.1 ± 0.5, and -8.0 ± 0.9% of body weight in NGT, IGT, and T2D groups, respectively. T2D subjects had significantly greater reductions in fasting glucose, 2-h glucose and glucose area under the curve (AUC0-120) compared to NGT and IGT (group effect, P <0.001). Insulinogenic index decreased in IGT and NGT groups and increased in T2D (group × time, P = 0.04). The magnitude of reduction in MSNA (-7 ± 3, -8 ± 4, -15 ± 4 burst/100 hb, respectively) and whole-body norepinephrine spillover rate (-28 ± 8, -18 ± 6, and -25 ± 7%, respectively), time effect both P <0.001, did not differ between groups. After adjustment for age and change in body weight, Δ insulin AUC0-120 was independently associated with reduction in arterial norepinephrine concentration, whilst Δ LDL-cholesterol and improvement in BRS were independently associated with decrease in MSNA. Conclusions: Equivalent weight loss through hypocaloric diet is accompanied by similar sympathoinhibition in matched obese subjects with different baseline glucose tolerance. Attenuation of hyperinsulinemia and hyperlipidemia, rather than glycemic indices, is associated with reduction in SNS activity following weight loss intervention.
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OBJECTIVE: Prolonged sitting is increasingly recognized as a ubiquitous cardiometabolic risk factor, possibly distinct from lack of physical exercise. We examined whether interrupting prolonged sitting with brief bouts of light-intensity activity reduced blood pressure (BP) and plasma noradrenaline in type 2 diabetes (T2D). METHODS: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men; meanâ±âSD; 62â±â6 years) consumed standardized meals during 3â×â8âh conditions: uninterrupted sitting (SIT); sittingâ+âhalf-hourly bouts of walking (3.2âkm/h for 3-min) (light-intensity walking); and sittingâ+âhalf-hourly bouts of simple resistance activities for 3âmin (SRAs), each separated by 6-14 days washout. Resting seated BP was measured hourly (mean of three recordings, ≥20-min postactivity). Plasma noradrenaline was measured at 30-min intervals for the first hour after meals and hourly thereafter. RESULTS: Compared with SIT, mean resting SBP and DBP were significantly reduced (Pâ<â0.001) for both light-intensity walking (meanâ±âSEM; -14â±â1/-8â±â1âmmHg) and SRA (-16â±â1/-10â±â1âmmHg), with a more pronounced effect for SRA (Pâ<â0.05 versus light-intensity walking). Similarly, mean plasma noradrenaline was significantly reduced for both light-intensity walking (-0.3â±â0.1ânmol/l) and SRA (-0.6â±â0.1ânmol/l) versus SIT, with SRA lower than light-intensity walking (Pâ<â0.05). Mean resting heart rate was lowered by light-intensity walking (-3â±â1âbpm; Pâ<â0.05), but not SRA (-1â±â1âbpm). CONCLUSION: Interrupting prolonged sitting with brief bouts of light-intensity walking or SRA reduces resting BP and plasma noradrenaline in adults with T2D, with SRA being more effective. Given the ubiquity of sedentary behaviors and poor adherence to structured exercise, this approach may have important implications for BP management in patients with T2D.
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Presión Sanguínea , Diabetes Mellitus Tipo 2/fisiopatología , Norepinefrina/sangre , Obesidad/fisiopatología , Postura/fisiología , Entrenamiento de Fuerza , Caminata/fisiología , Anciano , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicaciones , Descanso/fisiologíaRESUMEN
OBJECTIVE: To determine whether interrupting prolonged sitting with brief bouts of light-intensity walking (LW) or simple resistance activities (SRA) improves postprandial cardiometabolic risk markers in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men 62 ± 6 years old) underwent the following 8-h conditions on three separate days (with 6-14 days washout): uninterrupted sitting (control) (SIT), sitting plus 3-min bouts of LW (3.2 km · h(-1)) every 30 min, and sitting plus 3-min bouts of SRA (half-squats, calf raises, gluteal contractions, and knee raises) every 30 min. Standardized meals were consumed during each condition. Incremental areas under the curve (iAUCs) for glucose, insulin, C-peptide, and triglycerides were compared between conditions. RESULTS: Compared with SIT, both activity-break conditions significantly attenuated iAUCs for glucose (SIT mean 24.2 mmol · h · L(-1) [95% CI 20.4-28.0] vs. LW 14.8 [11.0-18.6] and SRA 14.7 [10.9-18.5]), insulin (SIT 3,293 pmol · h · L(-1) [2,887-3,700] vs. LW 2,104 [1,696-2,511] and SRA 2,066 [1,660-2,473]), and C-peptide (SIT 15,641 pmol · h · L(-1) [14,353-16,929] vs. LW 11,504 [10,209-12,799] and SRA 11,012 [9,723-12,301]) (all P < 0.001). The iAUC for triglycerides was significantly attenuated for SRA (P < 0.001) but not for LW (SIT 4.8 mmol · h · L(-1) [3.6-6.0] vs. LW 4.0 [2.8-5.1] and SRA 2.9 [1.7-4.1]). CONCLUSIONS: Interrupting prolonged sitting with brief bouts of LW or SRA attenuates acute postprandial glucose, insulin, C-peptide, and triglyceride responses in adults with T2D. With poor adherence to structured exercise, this approach is potentially beneficial and practical.
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Diabetes Mellitus Tipo 2/terapia , Terapia por Ejercicio/métodos , Obesidad/terapia , Entrenamiento de Fuerza , Caminata , Anciano , Glucemia/metabolismo , Péptido C/metabolismo , Estudios Cruzados , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Insulina/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/metabolismo , Sobrepeso/complicaciones , Sobrepeso/metabolismo , Sobrepeso/terapia , Periodo Posprandial , Postura , Conducta Sedentaria , Triglicéridos/metabolismoRESUMEN
BACKGROUND: The consumption of advanced glycation end products (AGEs) has increased because of modern food processing and has been linked to the development of type 2 diabetes in rodents. OBJECTIVE: We determined whether changing dietary AGE intake could modulate insulin sensitivity and secretion in healthy, overweight individuals. DESIGN: We performed a double-blind, randomized, crossover trial of diets in 20 participants [6 women and 14 men; mean ± SD body mass index (in kg/m(2)): 29.8 ± 3.7]. Isoenergetic- and macronutrient-matched diets that were high or low in AGE content were alternately consumed for 2 wk and separated by a 4-wk washout period. At the beginning and end of each dietary period, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test were performed. Dietary, plasma and urinary AGEs N()-(carboxymethyl)lysine (CML), N()-(carboxyethyl)lysin (CEL), and methylglyoxal-derived hydroimadazolidine (MG-H1) were measured with the use of mass spectrometry. RESULTS: Participants consumed less CML, CEL, and MG-H1 during the low-AGE dietary period than during the high-AGE period (all P < 0.05), which was confirmed by changes in urinary AGE excretion. There was an overall difference in insulin sensitivity of -2.1 mg · kg(-1) · min(-1) between diets (P = 0.001). Insulin sensitivity increased by 1.3 mg · kg(-1) · min(-1) after the low-AGE diet (P = 0.004), whereas it showed a tendency to decrease by 0.8 mg · kg(-1) · min(-1) after the high-AGE diet (P = 0.086). There was no difference in body weight or insulin secretion between diets (P = NS). CONCLUSIONS: A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity. Hence, a restriction in dietary AGE content may be an effective strategy to decrease diabetes and cardiovascular disease risks in overweight individuals. This trial was registered at clinicaltrials.gov as NCT00422253.
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Dieta , Productos Finales de Glicación Avanzada/administración & dosificación , Resistencia a la Insulina/fisiología , Sobrepeso/dietoterapia , Adulto , Glucemia/análisis , Estudios Cruzados , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Productos Finales de Glicación Avanzada/sangre , Productos Finales de Glicación Avanzada/orina , Humanos , Imidazolidinas/sangre , Imidazolidinas/orina , Insulina/sangre , Lisina/análogos & derivados , Lisina/sangre , Lisina/orina , Masculino , Persona de Mediana Edad , Piruvaldehído/sangre , Piruvaldehído/orinaRESUMEN
BACKGROUND: Clinical practice guidelines globally recommend lifestyle modification including diet and exercise training as first-line treatment for obesity. The clinical benefits of exercise training in adults with obesity is well-documented; however, there is no strong evidence for the effectiveness of exercise training for weight loss in class II and class III obesity. The purpose of the randomised controlled trial described in this protocol article is to examine the effect of exercise training, in addition to a very low energy diet (VLED), in clinically severe obese women for changes in body composition, physical function, quality of life, and markers of cardiometabolic risk. METHODS/DESIGN: Sixty women, aged 18-50 years with a body mass index (BMI) greater than 34.9 kg.m(2) and at least one obesity-related co-morbidity, will be recruited for this 12-month study. Participants will be randomised to either exercise plus energy restriction (n = 30), or energy restriction alone (n = 30). All participants will follow an energy-restricted individualised diet incorporating a VLED component. The exercise intervention group will also receive exercise by supervised aerobic and resistance training and a home-based exercise programme totalling 300 minutes per week. Primary outcome measures include body composition and aerobic fitness. Secondary outcome measures include: physical function, cardiometabolic risk factors, quality of life, physical activity, and mental health. All outcome measures will be conducted at baseline, 3, 6 and 12 months. DISCUSSION: Previous research demonstrates various health benefits of including exercise training as part of a healthy lifestyle at all BMI ranges. Although clinical practice guidelines recommend exercise training as part of first-line treatment for overweight and obesity, there are few studies that demonstrate the effectiveness of exercise in class II and class III obesity. The study aims to determine whether the addition of exercise training to a VLED provides more favourable improvements in body composition, physical function, quality of life, and markers of cardiometabolic risk for women with clinically severe obesity, compared to VLED alone. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12611000694910 ). Date registered: 4 July 2011.
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Restricción Calórica , Obesidad Mórbida/dietoterapia , Entrenamiento de Fuerza , Adolescente , Adulto , Composición Corporal , Protocolos Clínicos , Terapia Combinada , Femenino , Humanos , Salud Mental , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Obesidad Mórbida/fisiopatología , Obesidad Mórbida/psicología , Aptitud Física , Calidad de Vida , Proyectos de Investigación , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Victoria , Pérdida de Peso , Adulto JovenRESUMEN
BACKGROUND: The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program. METHODS: Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m(2), underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry. RESULTS: Weight loss averaged -8.3 ± 0.6% of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9%, P = 0.04) and exogenous insulin clearance (by 12 ± 5%, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by -12 ± 5%, whole-body norepinephrine spillover rate by -14 ± 8%, and MSNA by -9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = -0.63, P = 0.01) which explained 40% of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64% of the variance. CONCLUSIONS: Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850.
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Restricción Calórica , Dedos/irrigación sanguínea , Hiperinsulinismo/dietoterapia , Insulina/sangre , Hígado/metabolismo , Obesidad/dietoterapia , Resistencia Vascular , Pérdida de Peso , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Índice de Masa Corporal , Péptido C/sangre , Femenino , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/etiología , Hiperinsulinismo/fisiopatología , Cinética , Masculino , Manometría , Persona de Mediana Edad , Músculo Esquelético/inervación , Norepinefrina/sangre , Obesidad/sangre , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/fisiopatología , Pletismografía , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatología , Resultado del Tratamiento , VictoriaRESUMEN
The sympathetic nervous system (SNS) plays a key role in both cardiovascular and metabolic regulation; hence, disturbances in SNS regulation are likely to impact on both cardiovascular and metabolic health. With excess adiposity, in particular when visceral fat accumulation is present, sympathetic activation commonly occurs. Experimental investigations have shown that adipose tissue releases a large number of adipokines, cytokines, and bioactive mediators capable of stimulating the SNS. Activation of the SNS and its interaction with adipose tissue may lead to the development of hypertension and end-organ damage including vascular, cardiac, and renal impairment and in addition lead to metabolic abnormalities, especially insulin resistance. Lifestyle changes such as weight loss and exercise programs considerably improve the cardiovascular and metabolic profile of subjects with obesity and decrease their cardiovascular risk, but unfortunately weight loss is often difficult to achieve and sustain. Pharmacological and device-based approaches to directly or indirectly target the activation of the SNS may offer some benefit in reducing the cardiometabolic consequences of obesity. Preliminary evidence is encouraging, but more trials are needed to investigate whether sympathetic inhibition could be used in obesity to reverse or prevent cardiometabolic disease development. The purpose of this review article is to highlight the current knowledge of the role that SNS plays in obesity and its associated metabolic disorders and to review the potential benefits of sympathoinhibition on metabolic and cardiovascular functions.
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Enfermedades Cardiovasculares/etiología , Grasa Intraabdominal/fisiopatología , Obesidad/complicaciones , Sistema Nervioso Simpático/fisiopatología , Adipoquinas/metabolismo , Adiposidad , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Humanos , Mediadores de Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Inhibición Neural , Obesidad/metabolismo , Obesidad/fisiopatología , Obesidad/terapia , Pronóstico , Factores de Riesgo , Transducción de Señal , Sistema Nervioso Simpático/metabolismoRESUMEN
OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS. PARTICIPANTS AND METHODS: We examined multiunit and single-unit muscle SNS activity (by microneurography), HRV (time and frequency domain analysis) and endothelial function [ischaemic reactive hyperaemia index (RHI) using the EndoPAT device] in 19 overweight/obese women with PCOS (BMI: 31·3 ± 1·5 kg/m(2), age: 31·3 ± 1·6 years) and compared them with 21 control overweight/obese women (BMI: 33·0 ± 1·4 kg/m(2), age: 28·2 ± 1·6 years) presenting a similar metabolic profile (fasting total, HDL and LDL cholesterol, glucose, triglycerides, insulin sensitivity and blood pressure). RESULTS: Women with PCOS had elevated multiunit muscle SNS activity (41 ± 2 vs 33 ± 3 bursts per 100 heartbeats, P < 0·05). Single-unit analysis showed that vasoconstrictor neurons were characterized by elevated firing rate and probability and incidence of multiple spikes (P < 0·01 for all parameters). Women with PCOS also had impaired endothelial function (RHI: 1·77 ± 0·14 vs 2·18 ± 0·14, P < 0·05). HRV did not differ between the groups. CONCLUSION: Women with PCOS have increased sympathetic drive and impaired endothelial function independent of obesity and metabolic disturbances. Sympathetic activation and endothelial dysfunction may confer greater cardiovascular risk in women with PCOS.