Effect of Dietary Glycemic Index on Beta-cell Function

描述(申请人提供)：2型糖尿病是美国的一个主要健康问题，影响着数百万人。它是由于胰岛β细胞不能分泌足够的胰岛素而导致高血糖所致。糖耐量受损(IGT)的人血糖水平升高，发展为2型糖尿病的风险增加。这项研究的长期目标是更好地了解导致β细胞功能丧失和胰岛素分泌受损的因素。已有研究表明，高糖水平会导致氧化应激，从而损害β细胞的功能，而波动的高糖水平甚至比持续的高糖更会增加氧化应激。饮食中含有高血糖指数(GI)的食物会增加饮食的血糖负荷(GL)和餐后血糖水平。因此，高甘油三酯(HGL)饮食可能会增加血糖波动和氧化应激，从而潜在地损害β细胞。相反，低血糖(LGL)饮食可能是有益的。这项研究探索了一种假设，即血糖变异性增加会导致氧化应激增加，从而加剧IGT患者的β细胞功能障碍。具体目标1：确定在IGT受试者中，与基线对照饮食相比，高糖饮食是否恶化，低糖饮食是否改善胰岛细胞功能。具体目标2：确定在IGT受试者中，HGL饮食中血糖变异性增加是否与β细胞功能降低有关，反之，LGL饮食中血糖变异性降低是否与改善β细胞功能有关。具体目标3：通过确定1)氧化应激的系统标志物是否与β细胞功能相关；2)血糖变异性和β细胞功能之间的关系是否至少部分由氧化应激来解释；以及3)抗氧化剂N-乙酰半胱氨酸(NAC)防止HGL饮食中的β细胞功能下降，从而确定HGL饮食诱导的氧化应激是否介导了β细胞功能的下降。研究设计：这项研究将是一项针对IGT患者的随机、平行设计的喂养研究。受试者将被随机分配到3个不同的组(n=15/ARM)：1)LGL饮食(GI&lt；35)4周；2)HGL饮食(GI&GT；70)+安慰剂4周，每天两次；或3)HGL饮食(GI&GT；70)+NAC 600 mg，每天2次。受试者将在两周后以中等血糖负荷(GI 55-58)的基线对照饮食进行研究，以供比较，所有饮食将以相同的常量营养素组成(50%碳水化合物/30%脂肪/20%蛋白质)保持体重稳定。β细胞功能将通过频繁采样的静脉葡萄糖耐量测试和进餐测试来评估。血糖变异性将通过3天连续血糖监测系统进行评估，并通过果糖胺控制血糖。将测量空腹和餐后血浆硝基酪氨酸水平和24小时尿异前列腺素水平作为氧化应激的标志。

DESCRIPTION (provided by applicant): Type 2 diabetes is a major health problem in the United States affecting millions of people. It is caused by failure of the pancreatic beta-cells to secrete enough insulin resulting in high blood glucose levels. People with impaired glucose tolerance (IGT) have elevated glucose levels and are at increased risk for progressing to type 2 diabetes. The long-term objectives of this research are to better understand the factors that contribute to the loss of beta-cell function and impaired insulin secretion. High glucose levels have been shown to impair beta- cell function by causing oxidative stress, and oscillating high glucose levels increase oxidative stress even more than continuous high glucose. Diets containing foods with a high glycemic index (GI) increase the glycemic load (GL) of the diet and post-prandial glucose levels. Therefore, high GL (HGL) diets could be potentially damaging to the beta-cell by increasing glucose fluctuations and oxidative stress. Conversely, low GL (LGL) diets may be beneficial. The study explores the hypothesis that increased glycemic variability results in increased oxidative stress and thereby exacerbates beta-cell dysfunction in people with IGT. Specific Aim 1: Determine if a HGL diet worsens and a LGL diet improves beta-cell function compared to a baseline control diet in subjects with IGT. Specific Aim 2: Determine if increased glycemic variability on the HGL diet is associated with decreased beta- cell function and conversely if decreased glycemic variability on the LGL diet is associated with improved beta- cell function in subjects with IGT. Specific Aim 3: Determine if oxidative stress induced by a HGL diet mediates decreases in beta-cell function by determining if 1) systemic markers of oxidative stress are associated with beta-cell function; 2) if the relationship between glycemic variability and beta-cell function is at least partially explained by oxidative stress; and 3) the anti-oxidant N-acetylcysteine (NAC) prevents decreases in beta-cell function on a HGL diet. Study design: The study will be a randomized, parallel-design feeding study in men and women with IGT. Subjects will be randomly assigned to one of 3 separate arms (n=15/arm): 1) 4 weeks on a LGL diet (GI<35); 2) 4 weeks on a HGL diet (GI>70) + placebo twice daily; or 3) 4 weeks on a HGL diet (GI>70) + NAC 600 mg twice daily. Subjects will be studied after a 2 week baseline control diet with a moderate glycemic load (GI 55- 58) for comparison and all diets will be weight stable with the same macronutrient composition (50% carbohydrate/30% fat/20% protein). Beta-cell function will be assessed by both a frequently sampled intravenous glucose tolerance test and a meal test. Glycemic variability will be assessed by a 3 day Continuous Glucose Monitoring System and glycemic control by fructosamine. Fasting and post-meal plasma nitrotyrosine levels and 24 hour urine isoprostane levels will be measured as markers of oxidative stress.