RELATIONSHIP OF HEPATIC AND PERIPHERAL INSULIN-RESISTANCE WITH PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN PIMA-INDIANS

Plasminogen activator inhibitor-1 (PAI-1) is related to insulin resist ance and several components of the insulin resistance syndrome, and PA I-1 levels are elevated in subjects with non-insulin-dependent diabete s mellitus. Many Pima Indians are obese, insulin-resistant, and hyperi nsulinemic, and they have high rates of diabetes but a low risk of isc hemic heart disease. In contrast to whites and Asians, PAI-1 activity is similar between nondiabetic and diabetic Pima Indians. We therefore examined the association of PAI-1 with hepatic and peripheral insulin action measured using the hyperinsulinemic-euglycemic clamp. To inves tigate if insulin per se has any effect on PAI-1 in vivo, we also asse ssed the effects of endogenous (during a 75-g oral glucose load) and e xogenous (during hyperinsulinemic clamp) insulin on PAI-1 antigen. Twe nty-one (14 men and seven women; mean age, 26.3 +/- 4.8 years) Pima In dians underwent a 75-g oral glucose tolerance test (OGTT) and a sequen tial hyperinsulinemic-euglycemic clamp. Peripheral insulin action was measured as absolute glucose uptake (M value) and normalized to estima ted metabolic body size (EMBS). Hepatic insulin action was measured as percent suppression of basal hepatic glucose output during hyperinsul inemia. PAI-1 antigen was determined using a two-site enzyme-linked im munosorbent assay that detects only free PAI-1. PAI-1 antigen concentr ations were significantly related to body mass index ([BMI] r(s) = .54 , P = .012), waist (r(s) = .52, P = .016) and thigh (r(s) = .63, P = . 002) circumference, and fasting plasma insulin concentration (r(s) = . 59, P = .004). PAI-1 antigen concentrations were not significantly ass ociated with peripheral glucose uptake (M value) during either low-dos e (r(s) = -.01, P = NS) or high-dose (r(s) = -.11, P = NS) insulin inf usion. PAI-1 antigen was negatively correlated with basal hepatic gluc ose output (P = -.57, P = .013) and percent suppression of hepatic glu cose output during hyperinsulinemia (r(s) = -.69, P = .005). However, this relationship was largely due to the confounding effects of BMI, w aist and thigh girth, fasting insulin, and 2-hour postload glucose con centrations, and was not significant when controlled for these variabl es (partial r(s) = -.30, P = NS). There was no significant relationshi p of PAI-1 antigen concentration with glucose storage or glucose oxida tion. Despite a threefold increase in plasma insulin concentrations du ring the OGTT, there were no significant changes in PAI-1 antigen conc entrations (median, 57, 61, 55, and 44 ng/mL at 0, 60, 120, and 180 mi nutes, respectively; P = NS by ANOVA). During the hyperinsulinemic cla mp, mean plasma insulin concentrations at the end of low-dose (240 pmo l/m(2)/min) and high-dose (2,400 pmol/m(2)/min) infusions were 1,005 a nd 14,230 pmol/L, respectively. However, PAI-1 antigen concentrations at the end of low-dose and high-dose insulin infusions were similar to those at baseline (median, 63, 43, and 58 ng/mL, respectively; P = NS by ANOVA). PAI-1 antigen in Pima Indians is related to several compon ents of the insulin resistance syndrome. However, direct measurement o f insulin resistance indicates that hepatic but not peripheral insulin resistance is related to PAI-1 antigen. Neither endogenous nor exogen ous hyperinsulinemia for short periods had any significant effect on P AI-1 antigen concentrations. Short-term hyperinsulinemia is unlikely t o be an important regulator of PAI-1 in Pima Indians. The relationship of PAI-1 antigen to hepatic insulin resistance is largely dependent o n the relationship of PAI-1 to indices of obesity and fasting insulin concentrations. Copyright (C) 1996 by W.B. Saunders Company