Worksite Wellness Interventions on Vascular Function, Insulin Sensitivity , HDL

针对血管功能、胰岛素敏感性、HDL 的工作现场健康干预

• 批准号: 8149510
• 负责人: Richard Cannon
• 金额: $ 118.7万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149510
• 关键词: Blood Vessels; High Density Lipoproteins; Intervention; Workplace; insulin sensitivity

Obesity disproportionately affects women, and contributes to their increasing rate of type 2 diabetes and cardiovascular disease. Although adiposity increases the risk of diabetes, the contribution of fitness to impaired glucose homeostasis, especially in an increasingly sedentary workforce, is unknown.We propose that exercise fitness may contribute to glucose homeostasis in overweight and obese women who have impaired insulin sensitivity. To determine the contribution of fitness, we measured adiposity, exercise fitness, insulin sensitivity and non-insulin-mediated glucose metabolism in sedentary overweight and obese women employed at the National Institutes of Health.Seventy non-diabetic women BMI, 33.36.2 kg/m2; age, 4510 years, (meanSD) were enrolled. Adiposity was assessed by waist circumference (WC) and by dual-energy X-ray absorptiometry (DXA) measurements of truncal fat and lean body mass (LBM). Exercise fitness was measured by peak oxygen consumption (VO2 peak) during graded treadmill exercise using the Bruce Protocol. To minimize the impact of excess adipose tissue in the obese, VO2 peak was normalized to LBM to better estimate the contribution of exercising skeletal muscle to O2 uptake. We also measured exercise duration, respiratory exchange ratio (RER: measure of the relative contribution of fat to carbohydrate as an energy source for exercising muscle) and anaerobic threshold (AT: index of lactate accumulation). Insulin sensitivity (SI) and glucose effectiveness (SG: measure of non-insulin-mediated glucose disposal) were determined by the minimal model. Multivariate analysis was performed to determine predictors of SI. SI, SG, exercise duration, AT and RER were compared by tertiles of VO2 peak.Multiple regression analysis for predicting SI (range: 0.49 to 13.90 L.U-1.min-1) using stepwise modeling with age (23 to 66 years), WC (77.2 to 145.7 cm), truncal fat (31.3 to 58.5%), and VO2 peak (25.9 to 72.1 ml/kg LBM/min) revealed truncal fat (R2= 0.18, P<0.001) and VO2 peak (R2= 0.25, P<0.02) as independent predictors of SI. Women in the lowest tertile of VO2 peak (34.53.8 ml/kg LBM/min) had significantly lower exercise duration (337107 vs. 48882 seconds), AT (1.40.2 vs. 1.60.3 L/min) and RER (1.050.1 vs. 1.150.1) (all P<0.02), compared with women in the highest tertile of VO2 peak (54.36.0 ml/kg LBM/min). Furthermore, the lowest tertile indicated significantly lower SG (0.010.006 vs. 0.020.007 min-1) and SI (2.451.26 vs. 4.652.49 L. U-1.min-1) compared the highest tertile (P<0.001).Conclusion Although adiposity is associated with diminished insulin sensitivity in sedentary overweight and obese women, poor fitness is also a major factor. In addition, reduced non-insulin-mediated glucose metabolism by skeletal muscle may contribute to impaired glucose homeostasis in poorly fit women. Recent studies suggest that some patients with, or at risk for, atherosclerosis may have dysfunctional high-density lipoprotein (HDL) despite normal cholesterol content. An HDL-associated enzymeparaoxonase 1 (PON1)protects lipoproteins from oxidation by degrading oxidized lipids including oxidized cholesteryl esters and phospholipids.We assessed the hypothesis that anti-oxidant properties of HDL might be abnormal due to reduced activity of PON1 in women at risk for atherosclerosis because of sedentary lifestyle, obesity, and diminished insulin sensitivity. Forty-nine non-diabetic overweight and obese women (23 Caucasian, 26 African American) were enrolled in a worksite wellness program at the National Institutes of Health. Adiposity was assessed by BMI and by waist circumference. PON1 activity was assessed by the rate of cleavage of phenyl acetate by arylesterase/paraoxonase, resulting in phenol formation measured by absorbance at 270 nm. Insulin sensitivity (SI) was determined by the minimal model. To determine whether PON1 activity might preserve HDL in an intact state, the Oxygen Radical Absorbance Capacity (ORAC) assay was used to test the susceptibility of HDL to oxidant stress, and was assessed by measuring the capacity of HDL isolated from serum to inhibit oxygen radicals produced by 2,2-azobis(2-amidino-propane) dihydrochloride every minute over 2 hours. Data were analyzed by comparing measurements from women in the lowest tertile of SI (more insulin resistant) to those from women in the highest tertile of SI (more insulin sensitive). Data are reported as mean values SD. Women in the lowest tertile of SI (SI<2.54 L.U-1.min-1) were similar in age to women in the highest tertile of SI (SI>4.00 L.mU-1.min-1) (44 13 vs. 44 11 years, P=0.91), but were significantly more obese (BMI 38.8 8.3 vs. 29.7 3.1 kg/m2, P<0.001 and waist circumference 115.5 20.0 vs. 99.2 11.5 cm, P=0.008). Women in the lowest tertile of SI had marginally lower HDL cholesterol levels compared with women in the highest tertile (54 18 vs. 64 17 mg/dL, P=0.12). PON1 activity was significantly reduced in women with the lowest tertile of SI compared with women in the highest tertile (120.2 19.8 vs. 144.6 29.7 kU/L, P=0.01). For the cohort, PON1 activity was significantly associated with resistance of HDL to oxidation as measured by ORAC normalized to HDL cholesterol content (r=0.39, P<0.01). We conclude that reduced HDL-associated PON1 activity may be associated with diabetes risk, as women who were more obese and insulin resistant had significantly lower enzyme activity than women who were less obese and more insulin sensitive. Furthermore, the correlation between PON1 activity and susceptibility of HDL to oxidation suggests that PON1 is an important determinant of overall HDL anti-oxidant capacity.

肥胖对妇女的影响不成比例，并导致其2型糖尿病和心血管疾病的增加。尽管肥胖增加了糖尿病的风险，但尚不清楚适应性对葡萄糖稳态受损的贡献，尤其是在越来越久坐的劳动力中。为了确定适应性的贡献，我们测量了在美国国立卫生研究院久坐的超重和肥胖妇女中，肥胖，胰岛素敏感性和非胰岛素介导的葡萄糖代谢。年龄为4510岁，（平均值）被录取。肥胖是通过腰围（WC）和双能X射线吸收法（DXA）测量的截短脂肪和瘦体重（LBM）评估的。使用Bruce方案在分级跑步机运动过程中通过峰值氧（VO2峰）来测量运动适应性。为了最大程度地减少肥胖中过量脂肪组织的影响，将VO2峰标准化为LBM，以更好地估计锻炼骨骼肌对O2摄取的贡献。我们还测量了运动持续时间，呼吸道交换比（RER：脂肪对碳水化合物作为运动肌肉的能源的相对贡献）和厌氧阈值（AT：乳酸堆积的索引）。通过最小模型确定胰岛素敏感性（SI）和葡萄糖有效性（SG：非胰岛素介导的葡萄糖处置的度量）。进行多变量分析以确定SI的预测指标。使用VO2峰的三位数比较SI，SG，运动持续时间，AT和RER。使用逐步建模（23至66岁），WC（77.2至145.7 cm），truncal Fat（71.3至5％），使用逐步建模（范围：0.49至13.90 l.u-1.min-1）。 ML/kg lbm/min）显示截短脂肪（R2 = 0.18，p <0.001）和Vo2峰（R2 = 0.25，p <0.02）是Si的独立预测指标。 VO2峰值最低三重的女性（34.53.8 mL/kg lbm/min）的运动持续时间明显较低（337107 vs. 48882秒），为（1.40.2 vs. 1.60.3 l/min）vs.1.60.3 l/min）和RER（1.050.1 vs. 1.050.1 vs. 1.150.1 vs. 1.150.1）（所有p <0.02），vus ver（54. vu），vu n of vues ny vu n of vu n of wive（vu）。 ML/kg lbm/min）。此外，最低的三位一体表明SG明显降低SG（0.010.006 vs. 0.020.007 min-1）和SI（2.451.26 vs. 4.652.49 L. U-1.min-1）比较了最高的第三次（P <0.001）。 尽管肥胖与久坐的超重和肥胖女性的胰岛素敏感性降低有关，但适应性差也是一个主要因素。此外，骨骼肌降低的非胰岛素介导的葡萄糖代谢可能会导致较差的女性葡萄糖稳态受损。 最近的研究表明，尽管胆固醇含量正常，但有些患有或面临动脉粥样硬化风险的患者可能患有功能失调的高密度脂蛋白（HDL）。 An HDL-associated enzymeparaoxonase 1 (PON1)protects lipoproteins from oxidation by degrading oxidized lipids including oxidized cholesteryl esters and phospholipids.We assessed the hypothesis that anti-oxidant properties of HDL might be abnormal due to reduced activity of PON1 in women at risk for atherosclerosis because of sedentary lifestyle,肥胖，胰岛素敏感性降低。 四十九个非糖尿病性超重和肥胖女性（23名高加索人，26名非裔美国人） 参加了美国国立卫生研究院的工作场所健康计划。肥胖是通过BMI和腰围评估的。通过芳基酯酶/二氧蛋白酶通过乙酸苯基苯酯的裂解速率评估PON1活性，从而导致酚形成通过270 nm的吸光度测量。胰岛素灵敏度（SI）由最小模型确定。为了确定PON1活性是否可以保持完整状态，使用氧自由基吸收能力（ORAC）测定法来测试HDL对HDL对氧化剂胁迫的敏感性，并通过测量从血清中分离出的HDL的能力来评估2-2-氮杂型（2-2-氮杂）（2-2-氨基抗体）的HDL能力。通过比较Si（抗胰岛素耐药性更高）中女性中女性的测量值（较低的胰岛素敏感性）（胰岛素敏感更敏感）的女性来分析数据。数据报告为平均值SD。 Si（Si <2.54 l.u-1.min-1）中最低三位数的女性年龄与Si最高三重（Si> 4.00 l.mu-1.min-1）的女性相似（44 13 vs. 44 11年11年，P = 0.91），但肥胖（BMI 38.8 8.3 vs.29.7 3.1 kg/perception bere of Pripper） 115.5 20.0 vs. 99.2 11.5厘米，p = 0.008）。与三位一体的女性相比，SI最低三位数的女性的HDL胆固醇水平略低（54 18 vs. 64 17 mg/dl，p = 0.12）。与第三位最高的女性相比，SI最低的女性PON1活性显着降低（120.2 19.8 vs. 144.6 29.7 KU/L，P = 0.01）。对于队列，PON1活性与HDL对氧化的抗性显着相关，这是通过对HDL胆固醇含量标准化的ORAC测量的（r = 0.39，p <0.01）。我们得出的结论是，降低与HDL相关的PON1活性可能与糖尿病的风险有关，因为肥胖和耐胰岛素的女性比肥胖和对胰岛素更敏感的女性的酶活性明显低。此外，PON1活性与HDL对氧化的易感性之间的相关性表明PON1是总HDL抗氧化能力的重要决定因素。