Abstract
Background
Insulin resistance is associated with impaired fibrinolysis and increased cardiovascular risk. Elevated plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, has been associated with insulin resistance and hyperinsulinemia. However, whether PAI-1 elevation stems from hyperinsulinemia or requires intact downstream insulin signaling remains unclear. We compared blood levels of certain metabolic factors in several groups of patients with severe insulin resistance. One group had insulin receptor mutations (INSR), characterized by receptor-level signaling binding defects, while another groups of patients had lipodystrophy (LD), characterized by severe insulin resistance with relatively preserved/overstimulated downstream pathways, and the final group consisted of healthy volunteers (HV).
Methods
We performed a cross-sectional analysis of adults ≥18 years with pathogenic INSR variants (n=10), non-HIV lipodystrophy (n=15), or healthy controls (n=14). Patients were age and sex matched. Plasma was collected at baseline, 30 and 120 minutes following a 75-g oral glucose tolerance test (OGTT). Total and active PAI-1, tissue plasminogen activator (tPA), PAI-1–tPA complex, plasmin, plasminogen, fibrin, fibrin monomer, fibrinogen, thrombin, and urokinase were measured by ELISA. Insulin and glucose were measured concurrently. Between-group and within-group differences and associations with insulin were evaluated using regression models.
Results
At baseline, patients with LD demonstrated significantly higher total PAI-1, active PAI-1, tPA, and PAI-1–tPA complex concentrations compared with INSR patients and healthy volunteers. Despite severe hyperinsulinemia, INSR patients demonstrated fibrinolytic factor concentrations similar to the healthy volunteers. During the oral glucose tolerance test, total and active PAI-1 decreased from baseline to 120 minutes in LD despite increasing insulin and glucose, whereas active PAI-1 increased in INSR. Correlational analysis showed that changes in insulin did not consistently predict changes in most fibrinolytic components.
Discussion: Patients with lipodystrophy demonstrated marked elevations in PAI-1 and related fibrinolytic factors, whereas patients with receptor-level insulin resistance had profiles similar to healthy controls despite severe hyperinsulinemia. These findings suggest that hyperinsulinemia is insufficient to explain PAI-1 elevation and that preserved or overactive post-receptor insulin signaling may contribute to impaired fibrinolysis in insulin-resistant states. Further investigation of insulin signaling pathways regulating PAI-1 should utilize larger cohorts and analyze non-plasma paracrine changes. This may help clarify mechanisms contributing to increased cardiovascular risk in insulin resistance.