HIV SYNDROME X & PROTEASE INHIBITORS: HUMAN STUDIES

这一建议是基于这样的前提，即HIV/AIDS患者的胰岛素作用差异很大，并且蛋白酶抑制剂(PI)的不良影响发生在既往存在胰岛素抵抗的人身上。另据推测，合并感染丙型肝炎病毒(丙型肝炎病毒)的患者更容易患上2型糖尿病。为了验证这些假设，我们将测定150名个体的葡萄糖耐量、脂蛋白、胰岛素对肌肉和脂肪组织的作用、胰岛素分泌功能和血浆中可溶细胞黏附分子的浓度，其中125名HIV/AIDS患者(50%合并丙型肝炎病毒感染)即将开始接受PIS治疗，25名仅接受丙型肝炎病毒治疗的患者。这些研究的结果将：1)确定这些患者治疗前胰岛素作用和分泌的变化；2)检验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)风险因素流行的假设；3)比较艾滋病毒/艾滋病患者中丙型肝炎病毒阳性和丙型肝炎病毒阴性患者的CHD和2型糖尿病的风险因素。所有基线测量将在PIS治疗三个月后重复进行。这些数据将为PI对相关变量的影响提供前瞻性评估，并检验以下假设：1)基线状态下胰岛素抵抗和高胰岛素血症的个体越多，PI的不良影响就越大：2)PI的脂解作用导致血浆FFA浓度全天升高，这与PI治疗患者的胰岛素作用减弱和血脂紊乱密切相关；以及3)合并感染丙型肝炎病毒的患者将加剧2型糖尿病危险因素的增加。然后，将对艾滋病毒/艾滋病患者进行研究，看看是否用单不饱和(MF)/多不饱和(PF)取代饱和脂肪(SF)，而不是碳水化合物(CHO)，更有可能最大限度地缓解PI治疗患者继发于胰岛素抵抗、高胰岛素血症和较低的低密度脂蛋白-胆固醇浓度的异常。具体地说，患者将在两个随机分配的四周饮食时段(除以两周的冲洗期)后接受研究，饮食中含有(按卡路里百分比计算)15%的蛋白质。55%的Cho和30%的脂肪，或者15%，40%的Cho和45%的脂肪。在这两种饮食中，SF将不到卡路里的10%，并且MF/PF比率保持不变。从上午8点到下午4点，每小时测量一次空腹和餐后血糖、胰岛素、游离脂肪酸、甘油三酯和脂蛋白据推测，所有的CHD危险因素都将在55%的CHO饮食中得到强调。这些研究的结果将有助于解释为什么PI治疗会发生不愉快的代谢和临床事件，并确定最有可能降低这些患者患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.