Fibrinogen kinetics and protein turnover in hypertension: Effects of insulin

Abstract 

Background and Aim

Hyperfibrinogenemia, a cardiovascular risk factor, is frequent in hypertension and largely unexplained. In this study, we measured fibrinogen production and whole-body protein turnover under both basal and hyperinsulinemic states, in hypertensive [H] and control [C] subjects, using a leucine stable isotope tracer and precursor-product relationships.

Methods and results

Since hypertension is often a feature of the “metabolic”, insulin resistance syndrome, which in turn affects both fibrinogen kinetics and whole-body protein turnover, we selected hypertensive subjects without the metabolic syndrome. Following basal measurements, an euglycemic, ≈euaminoacidemic, hyperinsulinemic clamp was performed, with plasma insulin raised to 700–900pmol/L. In H, rates of the fractional and absolute synthesis (FSR and ASR, respectively) of fibrinogen were 30%–40% greater (p<0.05 or less) than in C in both states, whereas leucine turnover was normal. Hyperinsulinemia did not modify fibrinogen synthesis in either group with respect to baseline, whereas it suppressed leucine appearance from endogenous proteolysis by ≈40% to same extent in both groups. Amino acid clearance was similar in both the H and C subjects. In H, the insulin-mediated glucose disposal (M) was ≈25% lower, (although insignificantly) than in controls, showing no overall insulin resistance. There was an inverse correlation between M and fibrinogen FSR during the clamp.

Conclusions

In essential hypertension fibrinogen production is increased, is not further stimulated by insulin, and is inversely related to insulin sensitivity at high-physiological insulin concentrations. Amino acid disposal and basal as well as insulin-responsive protein degradation rates are instead normal.

Keywords: Insulin sensitivity, Fibrinogen FSR and ASR, Leucine, Stable isotopes, Euglycemic clamp, Amino acid clearance