Strategies of Unloading the Failing Heart from Metabolic Stress

We propose a unifying perspective of heart failure in patients with type 2 diabetes mellitus. The reasoning is as follows: cellular responses to fuel overload include dysregulated insulin signaling, impaired mitochondrial respiration, reactive oxygen species formation and the accumulation of certain metabolites, collectively termed glucolipotoxicity. As a consequence, cardiac function is impaired with intracellular calcium cycling and diastolic dysfunction as an early manifestation. In this setting, increasing glucose uptake by insulin or insulin sensitizing agents only worsens the disrupted fuel homeostasis of the heart.