The Anthocyanin Delphinidin 3-Rutinoside Stimulates Glucagon-Like Peptide-1 Secretion in Murine GLUTag Cell Line via the Ca2+/Calmodulin-Dependent Kinase II Pathway

PLoS One. 2015 May 11;10(5):e0126157. doi: 10.1371/journal.pone.0126157. eCollection 2015.

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from enteroendocrine L-cells. Although several nutrients induce GLP-1 secretion, there is little evidence to suggest that non-nutritive compounds directly increase GLP-1 secretion. Here, we hypothesized that anthocyanins induce GLP-1 secretion and thereby significantly contribute to the prevention and treatment of diabetes. Delphinidin 3-rutinoside (D3R) was shown to increase GLP-1 secretion in GLUTag L cells. The results suggested that three hydroxyl or two methoxyl moieties on the aromatic ring are essential for the stimulation of GLP-1 secretion. Notably, the rutinose moiety was shown to be a potent enhancer of GLP-1 secretion, but only in conjunction with three hydroxyl moieties on the aromatic ring (D3R). Receptor antagonist studies revealed that D3R-stimulates GLP-1 secretion involving inositol 1,4,5-trisphosphate receptor-mediated intracellular Ca2+ mobilization. Treatment of GLUTag cells with a Ca2+/calmodulin-dependent kinaseII (CaMKII) inhibitor (KN-93) abolished D3R-stimulated GLP-1 secretion. In addition, treatment of GLUTag cells with D3R resulted in activation of CaMKII. Pre-treatment of cells with a G protein-coupled receptor (GPR) 40/120 antagonist (GW1100) also significantly decreased D3R-stimulated GLP-1 secretion. These observations suggest that D3R stimulates GLP-1 secretion in GLUTag cells, and that stimulation of GLP-1 secretion by D3R is mediated via Ca2+-CaMKII pathway, which may possibly be mediated by GPR40/120. These findings provide a possible molecular mechanism of GLP-1 secretion in intestinal L-cells mediated by foods or drugs and demonstrate a novel biological function of anthocyanins in regards to GLP-1 secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthocyanins / pharmacology*
  • Benzoates / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cell Line
  • Cyclic AMP / metabolism
  • Glucagon-Like Peptide 1 / metabolism*
  • Mice
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects

Substances

  • Anthocyanins
  • Benzoates
  • GW1100
  • Pyrimidines
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2

Grant support

This study was supported in part by Grants-in-Aid for Scientific Research (Nos. 26450168 for TAT, and 26850088 for MK) from the Japan Society for Promotion of Science.