Insulin Inhibits Low pO2‐Induced ATP Release from Human Erythrocytes (RBCs): Implications for Vascular Control in Pre‐Diabetes

Abstract

RBCs release ATP when exposed to low O2 tension (pO2). This ATP participates in the matching of O2 supply with need in skeletal muscle by stimulating increases in blood flow to areas with increased O2 demand. Here we investigate the hypothesis that hyperinsulinemia, as occurs in pre‐diabetes, inhibits ATP release from RBCs exposed to low pO2, impairing this cell's ability to stimulate vasodilation in response to reduced extraluminal pO2. RBCs were exposed to low O2 (14 ± 1 mm Hg) in the absence and presence of insulin (1 nM). Insulin attenuated ATP release from 16 ± 4 to 8 ± 3 nmoles/4x108 RBCs (n=6, P<0.01). To determine a functional consequence of this action of insulin, we examined the ability of isolated skeletal muscle arterioles perfused with buffer containing RBCs to dilate in response to decreased extraluminal pO2 (21 ± 4 mm Hg, n=10). In vessels perfused with untreated RBCs, low extraluminal pO2 resulted in a 9 ± 3% increase in diameter (P<0.05). In contrast, when RBCs were treated with insulin, the vessels failed to dilate in response to low pO2. These studies show that insulin inhibits ATP release from RBCs in response to reduced pO2 and impairs their ability to stimulate dilation of skeletal muscle arterioles. These results suggest that the hyperinsulinemia of pre‐diabetes could hinder the matching of O2 supply with need in skeletal muscle. Funded by AHA Fellowship (MH), ADA grant RA‐133, NIH grants HL‐64180 and HL‐89094.