Glucose tasting depletes intracellular calcium stores and impairs macrophage functionality

Hyperglycemia or increased blood glucose concentrations is a characteristic and one of the diagnostic criteria for <i>Diabetes mellitus</i> 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.