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Scope: The prevalence of type 2 diabetes mellitus (T2DM) is increasing yearly worldwide. Glycemic control is the basis for the treatment of T2DM, as it can prevent the progress of associated complications. Spices possess various health beneficial effects on humans. The aim of this study is to search for spices that can promote glucose uptake and to elucidate the underlying molecular mechanism(s)., Methods and Results: Among 24 spice extracts, the extracts from black pepper and white pepper significantly increase glucose uptake in L6 myotubes. Piperine is found to be the active compound in these extracts. Treatment of myotubes with piperine induces the translocation of glucose transporter 4 (GLUT4) to the plasma membrane by phosphorylation of AMP-activated protein kinase (AMPK). Piperine increases the intracellular Ca 2+ level and reactive oxygen species (ROS) generation through transient receptor potential vanilloid channel 1 (TRPV1), followed by activation of Ca 2+ /calmodulin-dependent protein kinase kinase-beta (CaMKKβ) as the upstream events for AMPK phosphorylation. Furthermore, oral administration of piperine to Wistar rats at 0.01 and 0.1 mg kg -1 body weight decreases postprandial hyperglycemia accompanied by GLUT4 translocation and AMPK phosphorylation., Conclusion: Piperine in pepper prevents hyperglycemia by GLUT4 translocation through CaMKKβ/AMPK signaling via TRPV1-dependent increase in the intracellular Ca 2+ level and ROS generation., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)