Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man

Abstract

Increased plasma plasminogen activator inhibitor-1 (PAI-1) has been implicated in the development of vascular disease. In type 2 diabetes mellitus high PAI-1 levels are associated with increased plasma concentrations of free fatty acids (FFA) and triacylglycerol indicating an association or a causal relationship. To answer that question, the effect of FFA/triacylglycerol on plasma PAI-1 was examined. Ten healthy male volunteers were studied for 6 h during infusion of triacylglycerol [1.5 ml/min]/heparin [0.2 IU/(kg.min)] (LIP; n=10), saline only (SAL; n=10), and saline/heparin (HEP; n=5). Plasma insulin concentrations were kept constant at approximately 35 pmol/l by intravenous somatostatin-insulin infusions and there was no significant change in plasma glucose levels during any of the study protocols. LIP increased plasma triacylglycerol and FFA approximately 3- (p < 0.001) and approximately 8- (p < 0.000001) fold, respectively, within 90 min. Baseline plasma PAI-1 measured by a bio-immunoassay was similar in HEP (11.4 +/- 2.8 ng/ml), SAL (16.6 +/- 3.6 ng/ml), and LIP studies (15.2 +/- 3.4 ng/ml). Since studies were initiated in the morning, PAI-1 decreased (p < 0.025) over time following its normal diurnal variation to 6.4 +/- 2.0 ng/ml and 4.0 +/- 2.4 ng/ml at 360 min in SAL and HEP, respectively. During LIP, however, PAI-1 increased to approximately 2.6 fold higher levels than during SAL at 360 min (16.4 +/- 4.0 ng/ml, p < 0.01). While tissue plasminogen activator (tPA) and adipsin, an adipocyte derived protease, were unaffected by LIP, changes in soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly correlated (p = 0.02) with those seen for PAI-1. This suggests that hyperlipidemia independent of insulin and plasma glucose levels stimulates vascular tissue and in turn might induce an increase in plasma PAI-1. PAI-1 then could contribute to the development of atherothrombotic vascular disease.

How does blood glucose control with metformin influence intensive insulin protocols? Evidence for involvement of oxidative stress and inflammatory cytokines

“…48 Furthermore if fat-emulsion (in parenteral nutrition) and heparin are infused concurrently, a marked increase in plasma PAI-1 is evoked. 49 Results from the present study are consistent with reduction of hypercoagulation and predisposition to thrombosis and this beneficial effect was observed in both protocols.…”

Overactivation of S6 Kinase 1 as a Cause of Human Insulin Resistance During Increased Amino Acid Availability

“…Plasma FFA concentrations were determined with a microfluorimetric method (Wako, Richmond, VA). Plasma immunoreactive insulin, C-peptide, glucagon, and growth hormone were measured by commercially available radioimmunoassays (7,8,15,16,20) (insulin, Pharmacia, Uppsala, Sweden; C-peptide, Cis, Gif-Sur-Yvette, France; glucagon, Linco, St. Charles, MO; growth hormone, Sorin Biomedica, Saluggia, Italy). Plasma cortisol was determined following extraction and charcoal-dextran separation by radioimmunoassay (21).…”

Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes

“…This suggests that hepatic triglyceride storage may be directly associated with myocardial triglyceride storage and thus with an impairment in myocardial oxidative glucose metabolism. In addition, in T2DM patients increased levels of circulating FFA concentration are associated with an increment in PAI-1 level, partly contributing to the hypercoagulable state in these patients (27). This suggests that, in addition to the impaired myocardial metabolism, there is an increased risk for atherothrombotic incidents associated with impaired FFA suppressibility, which may partly contribute to the cardiovascular complications.…”