Parallel Variations of Plasma Insulin, Triglyceride and Plasminogen Activator Inhibitor 1 (Pai 1) Levels in Obese Non Diabetic Subjects

Abstract

We had shown in non diabetic healthy subjects with Body Mass Index (BMI) varying largely, a significant correlation (r) between PAI activity levels and BMI : (r=0.66) and insulinemia (r=0.52).PAI levels were then studied in non diabetic Obese women (0)(n=50) and in age matched healthy women with normal BMI (N) (m ± SEM) = 0 versus N : BMI : 33.4± 0.8/ 20.2± 0.8 ; plasma insulin (Ins -uu/ml) : 22.7±1.5/12±1; Triglyceride(TG-mmol/1):1.240.09/0.8±0.1.The low value of euglobulin fibrinolytic activity (EFA) in Obese was due to high levels of PAI 1 : 0 versus N : EFA (mm) : 5.2 ±0.3/ 9 ±0.3 ; PAI activity (PAIact.- Verheijen's method-u/ml) :14 ± 2.1/5.04 ±0.6 -(p 0.01). In 10 0 and 10 N PAIact and PAI 1 antigen (PAI 1 Ag- Kruithof's method-ng/ml) were determined in parallel : 0 versus N : PAIact.: 29.4±3.8/ 5.8±0.9 ; PAI 1 Ag : 100±14.2/19.7 ±1.7, (p0.01). In Obesegroup correlations between, PAIact. and BMI (r=0.51), and insulin (r=0.69) and Triglyceride (r=0.48) were significant (p 0.01).When in Obese subjects, insulinemia was decreased by 24 hours Fast (n=10) or by 15 days Metformin treatment (1.7g/day) (n=9), PAI activity (measured on fibrin plates)decreased significantly in a parallel way : compared to initial values -after 24 hours Fast =Ins : 75 %, PAIact. 73% -after Metformin treatment=Ins :75%, PAIact. :57%, TG :73%.From these results, a direct action of insulin on the synthesis cells of PAI 1 could be evoked. An effect of Triglyceride levels cannot be excluded, the variation of Triglyceride, insulin, PAI levels being parallel.As hyperinsulinemia, hypertriglyceridemia are risk factors for atherothrombosis, as there is a link between insulin, triglyceride, PA Inhibitor 1 levels, the pathogenic role of hyperinsulinemia and hypertriglyceridemia in the development of atherothrombosis could be in part mediated by plasma hypofibrinolysis due to high level of PAI 1.

Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta.

“…In obese humans, elevations in plasma PAI-l levels appear to correlate with insulin (13,15). Insulin has been reported to stimulate PAI-l production by cultured human hepatocytes (47), suggesting that increased hepatic synthesis of PAI-l may account for its elevation in obese subjects.…”

“…Significant correlations have been established between PAl-1 levels and obesity (13), noninsulindependent diabetes (14), hyperinsulinemia (15), and hypertriglyceridemia (15,16). Moreover, PAI-1 activity was shown to be increased in patients with coronary artery disease (CAD) (17), although no such relationship could be demonstrated when hyperlipidemic or diabetic subjects were excluded from consideration (18).…”

Interaction of non-esterified fatty acid and insulin in control of triacylglycerol secretion by Hep G2 cells

“…Prospective population studies in Framingham (Kannel & McGee, 1979;Abbot & Carroll, 1984) and Paris (Cambien et al, 1986) have indicated that elevated triacylglycerol concentration is an independent risk factor for the development of cardiovascular disease. The concentration of triacylglycerol in plasma from fasted non-diabetic people is positively correlated with that of insulin (Olefsky et al, 1974;Orchard et al, 1983;Laasko et al, 1987;Juhan-Vague et al, 1987). Insulin is a potent stimulator of both fatty acid (Salmon & Hems, 1973;Diamant & Shafrir, 1975;Kirk et al, 1976;Amatruda et al, 1983) and triacylglycerol (Durrington et al, 1982;Dich et al, 1983;Wang et al, 1988) synthesis.…”

Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries.

“…The PAI-1 and GAPDH mRNA autoradiographic signals were quantitated by scanning densitometry, and the densitometric value for PAl-1 mRNA was normalized to that of GAPDH as detailed in Methods. The normalized data for the 16 samples analyzed is shown in Fig. 2.…”

“…These include obesity (14), noninsulin-dependent diabetes (15), hyperinsulinemia (16), and hypertriglyceridemia (11,16). Recently, PAI-1 was found to be predictive of coronary atherosclerosis in patients with glucose intolerance and presenting with previous myocardial infarction (17 (20 ,u) containing 0.6 x 106 cpm of radiolabeled probe (see below) and yeast tRNA at 2.5 mg/ml was then added, and the slides were hybridized for 16 hr at 55°C.…”