Defects in oxygen supply to skeletal muscle of prediabetic ZDF rats

Abstract

In humans, prediabetes is characterized by marked increases in plasma insulin and near normal blood glucose levels as well as microvascular dysfunction of unknown origin. Using the extensor digitorum longus muscle of 7-wk inbred male Zucker diabetic fatty rats fed a high-fat diet as a model of prediabetes, we tested the hypothesis that hyperinsulinemia contributes to impaired O₂ delivery in skeletal muscle. Using in vivo video microscopy, we determined that the total O₂ supply to capillaries in the extensor digitorum longus muscle of prediabetic rats was reduced to 64% of controls with a lower O₂ supply rate per capillary and higher O₂ extraction resulting in a decreased O₂ saturation at the venous end of the capillary network. These findings suggest a lower average tissue Po₂ in prediabetic animals. In addition, we determined that insulin, at concentrations measured in humans and Zucker diabetic fatty rats with prediabetes, inhibited the O₂-dependent release of ATP from rat red blood cells (RBCs). This inability to release ATP could contribute to the impaired O₂ delivery observed in rats with prediabetes, especially in light of the finding that the endothelium-dependent relaxation of resistance arteries from these animals is not different from controls and is not altered by insulin. Computational modeling confirmed a significant 8.3-mmHg decrease in average tissue Po₂ as well as an increase in the heterogeneity of tissue Po₂, implicating a failure of a regulatory system for O₂ supply. The finding that insulin attenuates the O₂-dependent release of ATP from RBCs suggests that this defect in RBC physiology could contribute to a failure in the regulation of O₂ supply to meet the demand in skeletal muscle in prediabetes.