Schneider D J, Nordt T K, Sobel B E
Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri 63110.
Diabetes. 1992 Jul;41(7):890-5. doi: 10.2337/diab.41.7.890.
In patients with non-insulin-dependent diabetes mellitus, concentrations in plasma of insulin and its precursors, proinsulin and split proinsulin, are increased. Because increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) occur also, we hypothesized that proinsulin and split proinsulin may augment endothelial cell PAI-1 expression, thereby potentially attenuating endogenous fibrinolysis and accelerating atherosclerosis. Proinsulin increased PAI-1 activity in conditioned media of endothelial cells as did split proinsulin, paralleled by increased expression of PAI-1 mRNA. These effects of proinsulin were not dependent on its conversion to insulin nor on its interactions with the insulin receptor. The proinsulin stimulation of PAI-1 expression was not attenuated by either anti-insulin receptor antibodies or a 100-fold excess of insulin. Furthermore, proinsulin-mediated increases in PAI-1 expression were not inhibited by a 500-fold excess of insulinlike growth factor I. In addition, inhibition of tyrosine kinase, which mediates many of the diverse effects of insulin and insulinlike growth factor I, did not attenuate the effect of proinsulin. These results indicate that proinsulin augments PAI-1 expression, potentially contributing to vasculopathy in patients with non-insulin-dependent diabetes mellitus.
在非胰岛素依赖型糖尿病患者中，血浆中胰岛素及其前体（胰岛素原和裂解胰岛素原）的浓度会升高。由于纤溶酶原激活物抑制剂-1（PAI-1）的浓度也会升高，我们推测胰岛素原和裂解胰岛素原可能会增强内皮细胞PAI-1的表达，从而可能减弱内源性纤维蛋白溶解并加速动脉粥样硬化。胰岛素原和裂解胰岛素原一样，均可增加内皮细胞条件培养基中的PAI-1活性，同时PAI-1 mRNA的表达也会增加。胰岛素原的这些作用既不依赖于其转化为胰岛素，也不依赖于其与胰岛素受体的相互作用。胰岛素原对PAI-1表达的刺激作用既不会被抗胰岛素受体抗体减弱，也不会被100倍过量的胰岛素减弱。此外，500倍过量的胰岛素样生长因子I也不会抑制胰岛素原介导的PAI-1表达增加。另外，介导胰岛素和胰岛素样生长因子I多种不同作用的酪氨酸激酶的抑制作用，也不会减弱胰岛素原的作用。这些结果表明，胰岛素原会增强PAI-1的表达，这可能是导致非胰岛素依赖型糖尿病患者血管病变的原因之一。
