HGP

人类基因组计划

• 批准号: 7608045
• 负责人: MEREDITH A HAWKINS
• 金额: $ 3.21万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608045
• 关键词: Affect; Age; Atherosclerosis; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Diabetes Mellitus; Effectiveness; Elevation; Fasting; Funding; Glucose; Glycosylated hemoglobin A; Grant; Hour; Human; Hyperglycemia; Hyperinsulinism; Infusion procedures; Institution; Insulin; Metabolic; Nicotinic Acids; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Patients; Plasminogen Activator Inhibitor 1; Research; Research Personnel; Resources; Source; Time; United States National Institutes of Health; Up-Regulation; day; diabetic; falls; non-diabetic; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our clinical endeavors this past year have focused on the time-dependent effects of free fatty acids on glucose effectiveness in humans with type 2 Diabetes Mellitus and the effects of free fatty acids on PAI-1 Levels and the rapid reverse in type 2 diabetes mellitus. Increased PAI-1 levels in type 2 diabetes mellitus contribute to increased atherosclerosis. Reproducing the diabetic milieu of hyperinsulinemia, hyperglycemia and elevated FFA in nondiabetic (ND) subjects rapidly elevated PAI-1 levels by 2-fold (Diabetes 47:290, 1998). We examined whether correction of these parameters could normalize PAI-1 levels in T2DM, and which of these factors could be responsible for the induction of PAI-1. Variable insulin infusions, which normalized fasting glucose (100 mg/dl) and FFA levels (450 mM) and reduced insulin needs (insulin 20uU/ml) over 72h in n=5 T2DM patients (HbA1C =10.71.1%, age=51.85.1 years, BMI=26.81.6 kg/m2), also corrected PAI-1 levels (16.22.1 vs. fasting = 55.46.1). To determine which factor(s) could be responsible for elevating PAI-1 levels, we acutely reproduced T2DM metabolic parameters during insulin (40 mU/m2.min) clamp studies in 15 nondiabetic subjects (age=29.83.2 years, BMI=27.31.7 kg/m2), with hyperinsulinemia alone (HI; insulin 80 U/ml), hyperglycemia (HG; 180 mg/dl) or high FFA (HF; 900 mM) for 5h. HI reduced PAI-1 from 35.16.3 (fasting) to 17.72.1 (5hHI). Elevating FFA prevented this decrease (HF: PAI-1=38.41.9). However, HG did not raise PAI-1 above HI levels (21.42.6). Finally, we acutely lowered FFA levels overnight in n=16 T2DM patients (HbA1C =10.71.7%, age=48.52.5 years, BMI=32.71.7 kg/m2). There was no significant lowering of PAI-1 levels following 10 hour infusions of nicotinic acid (NA) alone (FFA=25958, PAI-1=44.38.3), insulin alone (FFA=28552, PAI-1=48.57.2), or NA and insulin (FFA=9918, PAI-1=47.78.3). Thus, correcting the T2DM milieu for 3 days markedly reduced PAI-1. Increased FFA levels acutely reproduce typical T2DM fasting PAI-1 levels in nondiabetics, suggesting this is the mechanism for PAI-1 elevations in T2DM. Since FFA levels fell in the presence of high insulin, insulin may lower circulating PAI-1 via FFA lowering. However, lowering FFA failed to affect PAI-1 levels overnight in T2DM, indicating more time was required to reverse chronic upregulation of PAI-1.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在过去的一年里，我们的临床工作主要集中在2型糖尿病患者中游离脂肪酸对葡萄糖有效性的时间依赖效应，以及游离脂肪酸对PAI-1水平的影响以及2型糖尿病患者的快速逆转。 2型糖尿病患者PAI-1水平升高导致动脉粥样硬化加重。在非糖尿病(ND)受试者中再现高胰岛素血症、高血糖和FFA升高的糖尿病环境，使PAI-1水平迅速增加2倍(糖尿病47：290,1998)。我们研究了这些参数的校正是否可以使T2 DM患者的PAI-1水平正常化，以及这些因素中的哪些因素可能导致PAI-1的诱导。在n=5名T2 DM患者(HbA1C=10.71.1%，年龄=51.85.1岁，BMI=26.81.6 kg/m2)中，可变胰岛素输注使空腹血糖(100 mg/dl)和游离脂肪酸(450 MM)水平正常化，并在72小时内减少胰岛素需求(胰岛素20uU/ml)，也校正了PAI-1水平(16.22.1对空腹=55.46.1)。为了确定哪个因素(S)可能导致PAI-1水平升高，我们在15名非糖尿病受试者(年龄=29.83.2岁，体重指数=27.31.7 kg/m2)进行胰岛素(40 mU/m2·min)钳夹试验期间，快速复制T2 DM代谢参数，其中单纯高胰岛素血症(HI；胰岛素80U/ml)、高血糖(HG；180 mg/dl)或高FFA(HF；900 mm)持续5h。HI使PAI-1从35.16.3(空腹)降至17.72.1(5hHI)。升高FFA可阻止这种下降(HF：PAI-1=38.41.9)。但HG并未使PAI-1水平高于HI水平(21.42.6)。最后，我们显著降低了16例T2 DM患者过夜的FFA水平(HbA1C=10.71.7%，年龄=48.52.5岁，BMI=32.71.7 kg/m2)。单独输注烟酸(NA)(FFA=25958，PAI-1=44.38.3)、单纯胰岛素(FFA=28552，PAI-1=48.57.2)或NA+胰岛素(FFA=9918，PAI-1=47.78.3)10h后，PAI1水平无明显下降。 因此，纠正T2 DM环境3天可显著降低PAI-1。在非糖尿病患者中，FFA水平的升高可以很好地再现典型的T2 DM患者空腹PAI-1水平，提示这是T2 DM患者PAI-1水平升高的机制。由于FFA水平在高胰岛素存在时降低，胰岛素可能通过降低FFA来降低循环PAI-1。然而，降低FFA未能在夜间影响T2 DM患者的PAI-1水平，这表明需要更多的时间来逆转PAI-1的慢性上调。