Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine L-cells. Enhancing GLP-1 action is an important target for prevention and treatment of type 2 diabetes. Several approaches (GLP-1 analogs, dipeptidyl peptidase IV inhibitors) are being used to develop therapeutic agents using GLP-1 action for the treatment of diabetes. However, an alternative approach is to increase endogenous GLP-1 secretion through modulation of the secretory mechanism in intestinal L cells by pharmaceutical agents or dietary ingredients. In the present study, we demonstrate that curcumin, a yellow pigment isolated from the rhizomes of Curcuma longa L, significantly increases GLP-1 secretion in GLUTag cells, and we clarified the structure-activity relationship using curcumin derivatives. Also, concerning the secretory mechanism, the significant increase in GLP-1 secretion by curcumin involved the Ca2+-Ca2+/calmodulin-dependent kinase II pathway, and was independent of extracellular signal-regulated kinase, PKC, and the cAMP/PKA-related pathway. These findings provide a molecular mechanism for GLP-1 secretion mediated by foods or drugs, and demonstrate a novel biological function of curcumin in regards to GLP-1 secretion. (c) 2013 Elsevier Inc. All rights reserved.