Abstract
Hyperglycemia or increased blood glucose concentrations is a characteristic and one of the diagnostic criteria for Diabetes mellitus and critically contributes to the onset of secondary diseases. We investigated the effect of hyperglycemia on macrophage activation and functionality, demonstrating enhanced priming toward inflammatory cytokines in hyperglycemic macrophages. Additionally, increased glucose concentrations depleted intracellular Ca2+ stores by promoting Ca2+ release from the ER. We identified taste receptors on macrophages as sensors for hyperglycemia, mediating Ca2+ release into the cytosol by activating the IP3 receptor and inhibiting SERCA. Dysregulated Ca2+ homeostasis correlated with taste receptor expression and hyperglycemia in both murine and human cohorts. Consequently, glucose-induced Ca2+ depletion resulted in altered macrophage functionality, such as ER stress and impaired cell migration. These findings reveal glucose-induced perturbations in Ca2+ signaling and homeostasis and demonstrate a regulatory role of taste receptors in macrophages, enhancing our understanding of immune cell dysfunction in diabetes.