Proapoptotic and antiapoptotic effects of hyperglycemia: role of insulin signalingThis article is one of a selection of papers published in the special issue Bridging the Gap: Where Progress in Cardiovascular and Neurophysiologic Research Meet.

Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of insulin resistance, impaired contractile function, abnormal energy metabolism, cardiomyocyte and endothelial cell death, coronary heart disease, and heart failure. High blood glucose can, however, paradoxically protect the heart against a variety of insults, including ischemia, hypoxia, and calcium overload. To provide information on the underlying basis of these divergent actions of high glucose, the present study examined the hypothesis that the adverse effects of high glucose are linked to impaired insulin signaling, leading to a reduction in the levels of cytoprotective factors, and that the beneficial effects of high glucose occur in the absence of insulin and result in an improvement in Akt signaling. This hypothesis was evaluated by using an in vitro cardiomyocyte model that is amenable to manipulations in glucose and insulin. Prolonged exposure of the isolated neonatal cardiomyocyte to medium containing insulin and high glucose led to increased susceptibility to angiotensin II-mediated apoptosis, an effect associated with reduced levels of phospho-Akt and an increased Bax/Bcl-2 ratio. By contrast, exposure to high glucose levels in the absence of insulin rendered the cardiomyocyte resistant to angiotensin II-mediated apoptosis. Because the beneficial effects of high glucose were associated with elevations in phospho-Akt and Bcl-2 content, the cardioprotective activity of high glucose resembles the actions of insulin. Hence, the activation state of Akt is largely determined by the activity of insulin and other growth factors. Because high glucose diminishes insulin signaling, it reduces phospho-Akt levels and renders the cell susceptible to damaging insults. In the absence of insulin, however, the natural activity of high glucose is unmasked. As a result, Akt signaling is increased and the cell is rendered resistant to cell death.