Abstract

Human erythrocytes, by virtue of their ability to release ATP in response to physiological stimuli, have been proposed to participate in the regulation of local blood flow. A signal transduction pathway that relates these stimuli to ATP release has been described and includes the heterotrimeric G protein G_i and adenylyl cyclase (AC). In this cell, G_i activation results in increases in cAMP and, ultimately, ATP release. It has been reported that G_i expression is decreased in animal models of diabetes and in platelets of humans with type 2 diabetes. Here, we report that G_i2 expression is selectively decreased in erythrocytes of humans with type 2 diabetes and that this defect is associated with reductions in cAMP accumulation and ATP release in response to incubation of erythrocytes with mastoparan 7 (10 μmol/l), an activator of G_i. Importantly, this defect in ATP release correlates inversely with the adequacy of glycemic control as determined by levels of HbA_1c (A1C). These results demonstrate that in erythrocytes of humans with type 2 diabetes, both G_i expression and ATP release in response to mastoparan 7 are impaired, which is consistent with the hypothesis that this defect in erythrocyte physiology could contribute to the vascular disease associated with this clinical condition.