Panahloo, Arshia; (1998) Plasminogen activator inhibitor-1 and cardiovascular risk. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Subjects with diabetes mellitus suffer from widespread premature atherosclerosis especially coronary heart disease. Diminished fibrinolysis, attributed to increased concentrations of plasminogen activator inhibitor-1 (PAI-1), may explain in part the accelerated atherosclerosis and thrombosis observed in diabetic subjects. In this thesis the determinants of PAI-1 in non-insulin-dependent diabetic subjects (NIDDM) and subjects post myocardial infarction were studied, with special focus on proinsulin-like molecules, cytokines and PAI-1 gene-environment interactions. PAI-1 activity was examined in a cross-sectional study of 146 NIDDM subjects using specific assays of insulin and intact and des 31,32 proinsulin, and measures of insulin resistance, relating these measurements to serum lipids and hypoglycaemic therapy. Proinsulin levels were higher on sulphonylurea therapy, but no difference in PAI-1 activity was observed. The importance of proinsulin in relation to serum PAI-1 was however highlighted by a cross-over study, where the role of 4 months therapy with sulphonylurea or insulin on PAI-1 was studied. There were no differences observed in glycaemic control, insulin sensitivity or lipids, but sulphonylurea therapy was associated with higher levels of PAI-1 antigen and proinsulin compared to insulin. In a cross-sectional study, a difference in PAI-1 activity according to a common insertion (5G)/ deletion (4G) polymorphism in the promoter region of the PAI-1 gene was demonstrated. In this study serum triglyceride, and its interaction with the promoter 4G/5G polymorphism were important determinants of PAI-1 activity. PAI-1 gene-environment interactions and the role of cytokines, were explored by studying subjects during the course of acute myocardial infarction and after six month follow-up. Acutely, proinsulin emerges as an important determinant of PAI-1 activity. Non-survivors had higher PAI-1 activity day one post infarction compared to survivors. At six months, subjects with the 4G/4G polymorphism had higher PAI-1 antigen compared to 5G/5G subjects, there were no differences observed in levels of proinsulin-like molecules or cytokines.

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