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.

肥胖对女性的影响尤为严重，并导致她们患 2 型糖尿病和心血管疾病的比例不断增加。尽管肥胖会增加患糖尿病的风险，但健身对血糖稳态受损的影响尚不清楚，尤其是在久坐不动的劳动力中。我们认为，运动健身可能有助于胰岛素敏感性受损的超重和肥胖女性的血糖稳态。为了确定健康的贡献，我们测量了美国国立卫生研究院雇用的久坐超重和肥胖女性的肥胖、运动健康、胰岛素敏感性和非胰岛素介导的葡萄糖代谢。70 名非糖尿病女性 BMI，33.36.2 kg/平方米；登记年龄为 4510 岁（平均值标准差）。通过腰围 (WC) 和双能 X 射线吸收测定法 (DXA) 测量躯干脂肪和去脂体重 (LBM) 来评估肥胖程度。运动健康度是通过使用布鲁斯方案进行分级跑步机运动期间的峰值耗氧量（VO2 峰值）来测量的。为了最大限度地减少肥胖者体内多余脂肪组织的影响，将 VO2 峰值标准化为 LBM，以更好地估计锻炼骨骼肌对 O2 吸收的贡献。我们还测量了运动持续时间、呼吸交换比（RER：衡量脂肪与碳水化合物作为锻炼肌肉能量来源的相对贡献）和无氧阈值（AT：乳酸积累指数）。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理的测量）由最小模型确定。进行多变量分析以确定 SI 的预测因子。 SI、SG、运动持续时间、AT 和 RER 通过 VO2 峰值的三分位数进行比较。使用年龄（23 至 66 岁）逐步建模来预测 SI（范围：0.49 至 13.90 L.U-1.min-1）的多元回归分析， WC（77.2 至 145.7 厘米）、躯干脂肪（31.3 至 58.5%）和 VO2 峰值（25.9 至 72.1 ml/kg LBM/min）显示躯干脂肪（R2= 0.18，P<0.001）和 VO2 峰值（R2= 0.25，P<0.02）是 SI 的独立预测因子。 VO2 峰值最低三分位数（34.53.8 ml/kg LBM/min）的女性的运动持续时间（337107 秒 vs. 48882 秒）、AT（1.40.2 vs. 1.60.3 L/min）和 RER（1.050）显着较低.1 vs. 1.150.1)（所有 P<0.02），与 VO2 最高三分位数的女性相比峰值（54.36.0 ml/kg LBM/min）。此外，与最高三分位数相比，最低三分位数表明 SG（0.010.006 vs. 0.020.007 min-1）和 SI（2.451.26 vs. 4.652.49 L. U-1.min-1）显着较低（P< 0.001).结论 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，但健康状况不佳也是一个主要因素。此外，骨骼肌非胰岛素介导的葡萄糖代谢减少可能会导致体质不佳的女性葡萄糖稳态受损。 最近的研究表明，一些患有动脉粥样硬化或有动脉粥样硬化风险的患者尽管胆固醇含量正常，但高密度脂蛋白（HDL）可能功能失调。 HDL 相关酶对氧磷酶 1 (PON1) 通过降解氧化脂质（包括氧化胆固醇酯和磷脂）来保护脂蛋白免遭氧化。我们评估了以下假设：在有动脉粥样硬化风险的女性中，由于 PON1 活性降低，HDL 的抗氧化特性可能会异常。由于久坐的生活方式、肥胖和胰岛素敏感性降低。 49 名非糖尿病超重和肥胖女性（23 名白种人，26 名非裔美国人）接受了 参加了美国国立卫生研究院的工作场所健康计划。肥胖程度通过 BMI 和腰围来评估。通过芳基酯酶/对氧磷酶切割乙酸苯酯的速率来评估 PON1 活性，从而通过 270 nm 处的吸光度测量苯酚的形成。胰岛素敏感性（SI）由最小模型确定。为了确定 PON1 活性是否可以使 HDL 保持完整状态，使用氧自由基吸收能力 (ORAC) 测定来测试 HDL 对氧化应激的敏感性，并通过测量从血清中分离的 HDL 抑制氧自由基的能力来进行评估2,2-偶氮二(2-脒基-丙烷)二盐酸盐在2小时内每分钟产生一次。通过比较 SI 最低三分位数（胰岛素抵抗程度更高）的女性与 SI 最高三分位数（胰岛素更敏感）女性的测量值来分析数据。数据以平均值SD 报告。 SI 最低三分位 (SI<2.54 L.U-1.min-1) 中的女性与 SI 最高三分位 (SI>4.00 L.mU-1.min-1) 中的女性年龄相似（44 13 vs. 44 11 岁，P=0.91），但肥胖程度明显更高（BMI 38.8 ± 8.3 vs. 29.7 ± 3.1 kg/m2， P<0.001，腰围 115.5 ± 20.0 vs. 99.2 ± 11.5 cm，P=0.008）。与 SI 最高三分位数的女性相比，SI 最低三分位数的女性 HDL 胆固醇水平略低（54·18 与 64·17 mg/dL，P=0.12）。与 SI 最高三分位数的女性相比，SI 最低三分位数的女性 PON1 活性显着降低（120.2 19.8 vs. 144.6 29.7 kU/L，P=0.01）。对于该队列，PON1 活性与 HDL 抗氧化性显着相关，根据 ORAC 标准化为 HDL 胆固醇含量进行测量（r=0.39，P<0.01）。我们得出的结论是，HDL 相关的 PON1 活性降低可能与糖尿病风险相关，因为肥胖和胰岛素抵抗的女性的酶活性显着低于肥胖程度较低和胰岛素敏感的女性。此外，PON1 活性与 HDL 氧化敏感性之间的相关性表明，PON1 是 HDL 整体抗氧化能力的重要决定因素。