Effect of Dietary Glycemic Index on Beta-cell Function

描述（由申请人提供）：2型糖尿病是美国影响数百万人的主要健康问题。它是由胰腺细胞分泌胰岛素不足导致高血糖引起的。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。高葡萄糖水平已被证明通过引起氧化应激而损害β细胞功能，而振荡的高葡萄糖水平甚至比持续的高葡萄糖水平更能增加氧化应激。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）和餐后葡萄糖水平。因此，高GL饮食可能会增加葡萄糖波动和氧化应激，从而潜在地损害β细胞。相反，低GL （LGL）饮食可能有益。该研究探索了一种假设，即血糖变异性的增加导致氧化应激的增加，从而加剧了IGT患者的β细胞功能障碍。具体目标1：确定与基线对照饮食相比，IGT患者的高糖饮食是否恶化，低糖饮食是否改善β细胞功能。特定目标2：确定高糖饮食中血糖变异性的增加是否与β细胞功能的下降有关，相反，低糖饮食中血糖变异性的降低是否与IGT患者β细胞功能的改善有关。特异性目标3：通过确定氧化应激的全身标记物是否与β细胞功能相关，确定高糖饮食诱导的氧化应激是否介导β细胞功能下降；2)如果血糖变异性和β细胞功能之间的关系至少部分可以用氧化应激来解释；3)抗氧化剂n -乙酰半胱氨酸（NAC）可防止高糖饮食中β细胞功能的下降。研究设计：该研究将是一项随机、平行设计的IGT男性和女性喂养研究。受试者将被随机分配到3个独立组（n=15/组）之一：1)4周低脂饮食（GI<35）；2) 4周高糖饮食（GI指数70）+安慰剂，每日2次；或3)4周高糖饮食（GI值70）+ NAC 600毫克，每日两次。受试者将在2周的基线对照饮食后进行研究，该饮食具有中等血糖负荷（GI 55- 58），用于比较，所有饮食均为体重稳定且具有相同的常量营养素组成（50%碳水化合物/30%脂肪/20%蛋白质）。β细胞功能将通过频繁取样的静脉葡萄糖耐量试验和膳食试验来评估。血糖变异性将通过3天连续血糖监测系统和果糖胺控制血糖来评估。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将作为氧化应激的标志物进行测量。

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. PUBLIC HEALTH RELEVANCE: Understanding whether increased glycemic variability and oxidative stress are important in beta-cell dysfunction is critical for the development of effective strategies aimed at the prevention and treatment of type 2 diabetes. In addition, understanding the contribution of dietary glycemic load to beta-cell dysfunction in subjects with pre-diabetes can have a significant public health impact, including changes to dietary counseling and promotion of healthier eating patterns.