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.
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