HIV SYNDROME X & PROTEASE INHIBITORS: HUMAN STUDIES

这一建议是基于这样一个前提，即胰岛素的作用在HIV/AIDS患者中变化很大，蛋白酶抑制剂（Pis）的不良影响发生在已经存在胰岛素抵抗的个体中。也有假设认为，2型糖尿病更可能在合并感染丙型肝炎病毒（HCV）的患者中发展。为了验证这些假设，我们将测定150人的葡萄糖耐量、脂蛋白、胰岛素对肌肉和脂肪组织的作用、胰岛素分泌功能和可溶性细胞粘附分子的血浆浓度，其中125名HIV/AIDS患者（50%合并HCV）即将开始Pis治疗，25名仅HCV患者。这些研究的结果将：1)确定治疗前这些患者胰岛素作用和分泌的变化；2)验证先前存在的胰岛素抵抗和高胰岛素血症决定2型糖尿病和冠心病（CHD）危险因素的假设；3)比较hcv阳性和hcv阴性的HIV/AIDS患者中CHD和2型糖尿病的危险因素。所有基线测量将在Pis治疗后3个月重复。这些数据将为Pis对相关变量的影响提供前瞻性评估，并验证以下假设：1)基线时胰岛素抵抗和高胰岛素水平越高的个体，PI的不良影响越大；2)Pis的溶脂作用导致血浆FFA浓度升高，这与PI治疗患者胰岛素作用和血脂异常的降低密切相关；3) 2型糖尿病危险因素的增加将在合并HCV的患者中加剧。随后将对HIV/AIDS患者进行研究，看看用单不饱和脂肪(MF)/多不饱和脂肪（PF）而不是碳水化合物（CHO）代替饱和脂肪（SF）是否更有可能最大程度地减轻pi治疗患者继发于胰岛素抵抗和高胰岛素血症的异常，并降低ldl -胆固醇浓度。具体来说，患者将在两个随机分配的四周饮食期（分为两周的洗脱期）后进行研究，食用含有15%蛋白质的饮食（以卡路里百分比计）。55%的CHO和30%的脂肪，或者15%、40%的CHO和45%的脂肪。在两种饮食中，SF将低于卡路里的10%，并且MF/PF比率保持不变。从上午8点到下午4点，每隔一小时测量空腹和餐后血糖、胰岛素、游离脂肪酸、甘油三酯和脂蛋白。据推测，55%的CHO饮食会加重所有冠心病风险因素。这些研究的结果将有助于解释为什么不良代谢和临床事件发生在PI治疗中，并确定最有可能降低这些患者2型糖尿病和冠心病风险的饮食。

This proposal is based on the premise that insulin action varies widely in patients with HIV/AIDS, and that the untoward effects of protease inhibitors (Pis) occur in individuals with pre- existing insulin resistance. It is also postulated that type 2 diabetes, is more likely to develop in patients co-infected with hepatitis-C virus (HCV). To test these hypotheses we will determine glucose tolerance, lipoprotein, insulin action on muscle and adipose tissue, insulin secretory function, and plasma concentration of soluble cellular adhesion molecules in 150 individuals, 125 patients with HIV/AIDS (50 percent co-infected with HCV) in whom treatment with Pis is soon to be initiated, and 25 subjects with HCV only. The results of these studies will: 1) define the pre-treatment variation in insulin action and secretion in these patients; 2) test the hypothesis that pre- existing insulin resistance and hyperinsulinemia determines prevalence of risk factors for type 2 diabetes and coronary heart disease (CHD): and 3) compare risk factors for CHD and type 2 diabetes in HCV-positive and HCV-negative patients with HIV/AIDS. All baseline measurements will be repeated three months after treatment with Pis. These data will provide a prospective assessment of the effect of Pis on relevant variables, as well testing the hypotheses that: 1) the more insulin resistant and hyperinsulinemic an individual at baseline, the greater the untoward impact of PI: 2) the lipolytic effect of Pis results in day-long elevations in plasma FFA concentrations, that correlate closely with the decrease in insulin action and dyslipedemia in PI-treated patients; and 3) the increase in risk factors for type 2 diabetes will be accentuated in patients co-infected with HCV. Patients with HIV/AIDS will then be studied to see if replacing saturated fat (SF) with monounsaturated (MF)/polyunsaturated (PF), rather than carbohydrate (CHO), is more likely to maximally attenaute the abnormalities in PI-treated patients secondary to insulin resistance and hyperinsulinemia and lower LDL-cholesterol concentration. Specifically, patients will be studied after two randomly assigned dietary periods of four weeks (divided by a two-week washout period), consuming diets containing (as percent of calories) either 15 percent protein. 55 percent CHO and 30 percent fat, or, 15 percent, 40 percent CHO and 45 percent fat. SF will be less than 10 percent of calories in both diets, and the MF/PF ratio kept constant. Measurements will be made of fasting and postprandial plasma glucose, insulin, FFA, triglyceride, and lipoprotein at hourly intervals from 8 AM to 4 PM. It is postulated that all CHD risk factors will be accentuated on the 55 percent CHO diet. The results of these studies will help explain why untoward metabolic and clinical events occur with PI treatment, and define the diet most likely to decrease risk of type 2 diabetes and CHD in these patients.