Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance - The Insulin Resistance Atherosclerosis Study (IRAS)

Hyperinsulinemia is associated with the development of coronary heart disea se. However, the underlying mechanisms are still poorly understood. Hyperco agulability and impaired fibrinolysis are possible candidates linking hyper insulinism with atherosclerotic disease, and it has been suggested that pro insulin rather than insulin is the crucial pathophysiological agent. The ai m of-this study was to investigate the relationship of insulin and its prec ursors to markers of coagulation and fibrinolysis in a large triethnic popu lation. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32 -33 spit proinsulin) was found consistently across varying states of glucos e tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; an d r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remain ed highly significant even after accounting for insulin sensitivity as meas ured by a frequently sampled intravenous glucose tolerance test. In a stepw ise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precu rsors was significant in the overall population (r=0.20 for insulin and pro insulin; each P<0.001) but showed a more inconsistent pattern in subgroup a nalysis and after adjustments for demographic and metabolic variables. Step wise multiple regression analysis showed that proinsulin (split products) b ut not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitiv ity was independently associated with higher PAI-1 and fibrinogen levels. I n summary, we were able to demonstrate an independent relationship of 2 cru cial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precur sors. These findings may have important clinical implications in the risk a ssessment and prevention of macrovascular disease, not only in patients wit h overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.