HGP

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 在过去的一年里，我们的临床工作集中在游离脂肪酸对2型糖尿病患者葡萄糖有效性的时间依赖性影响，以及游离脂肪酸对派-1水平的影响和2型糖尿病的快速逆转。 2型糖尿病患者派-1水平升高导致动脉粥样硬化增加。在非糖尿病（ND）受试者中再现高胰岛素血症、高血糖症和FFA升高的糖尿病环境使派-1水平迅速升高2倍（Diabetes 47：290，1998）。我们研究了这些参数的校正是否可以使T2 DM中的派-1水平正常化，以及这些因素中的哪些因素可能导致派-1的诱导。在n=5例T2 DM患者（HbA 1C = 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FFA水平（450 mM）正常化并在72小时内降低胰岛素需求（胰岛素20 uU/ml），也校正了派-1水平（16.22.1 vs.空腹= 55.46.1）。为了确定哪些因素可能导致派-1水平升高，我们在胰岛素治疗期间急性复制了T2 DM代谢参数。（40 mU/m2.min）钳夹研究，15例非糖尿病受试者（年龄= 29.8 ± 3.2岁，BMI= 27.3 ± 1.7 kg/m2），仅伴有高胰岛素血症（HI;胰岛素80 U/ml）、高血糖症（HG; 180 mg/dl）或高FFA（HF; 900 mM）5小时。HI使派-1从35.16.3（空腹）降至17.72.1（5 hHI）。升高FFA阻止了这种降低（HF：派-1=38.41.9）。然而，HG并没有使派-1升高到HI水平以上（21.42.6）。最后，我们在n=16例T2 DM患者（HbA 1C = 10.71.7%，年龄=48.52.5岁，BMI=32.71.7 kg/m2）中隔夜急性降低FFA水平。在单独的烟酸（NA）（FFA=25958，PAI-1=44.38.3）、单独的胰岛素（FFA = 28552，派-1 =48.57.2）或NA和胰岛素（FFA=9918，派-1 =47.78.3）输注10小时后，派-1水平没有显著降低。 因此，校正T2 DM环境3天显著降低派-1。FFA水平升高可急性重现非糖尿病患者中典型的T2 DM空腹派-1水平，表明这是T2 DM患者派-1升高的机制。由于FFA水平在高胰岛素存在下下降，胰岛素可通过降低FFA来降低循环派-1。然而，降低FFA未能影响T2 DM患者的派-1水平，表明需要更多的时间来逆转派-1的慢性上调。

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.