Cardiac contraction-induced GLUT4 translocation requires dual signaling input

•AMPK and PKD1 are each required for contraction-stimulated glucose import.•Simultaneous activation of two signaling pathways creates a dual signaling input.•The necessity for dual signaling input refines subsequent metabolic responses.

Contraction-induced translocation of glucose transporter type-4 (GLUT4) to the sarcolemma is essential to stimulate cardiac glucose uptake during increased energy demand. As such, this process is a target for therapeutic strategies aiming at increasing glucose uptake in insulin-resistant and/or diabetic hearts. AMP-activated protein kinase (AMPK) and its upstream kinases form part of a signaling axis essential for contraction-induced GLUT4 translocation. Recently, activation of protein kinase-D1 (PKD1) was also shown to be as obligatory for contraction-induced GLUT4 translocation in cardiac muscle. However, contraction-induced PKD1 activation in this context occurs independently from AMPK signaling, suggesting that contraction-induced GLUT4 translocation requires the input of two separate signaling pathways. Necessity for dual input would more tightly couple GLUT4 translocation to stimuli that are inherent to cardiac contraction.