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.
Highlights
Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells is one type of incretin and stimulates glucose-dependent insulin secretion and proliferation of pancreatic β-cells [1–PLOS ONE | DOI:10.1371/journal.pone.0126157 May 11, 2015Delphinidin 3-rutinoside (D3R) Stimulates GLP-1 Secretion via calmodulin-dependent kinaseII (CaMKII) Pathway3]
As we recently demonstrated that CaMKII activation is involved in GLP-1 secretion in GLUTag cells treated with curcumin [20], we speculated that D3R-stimulated GLP-1 secretion proceeds by a similar mechanism
We demonstrated that the anthocyanin D3R significantly stimulates GLP-1 secretion in GLUTag cells through increased Ca2+-CaMKII pathway activation, which may be mediated by GPR40/120 (Fig 6)
Summary
Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells is one type of incretin and stimulates glucose-dependent insulin secretion and proliferation of pancreatic β-cells [1–PLOS ONE | DOI:10.1371/journal.pone.0126157 May 11, 2015D3R Stimulates GLP-1 Secretion via CaMKII Pathway3]. Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells is one type of incretin and stimulates glucose-dependent insulin secretion and proliferation of pancreatic β-cells [1–. D3R Stimulates GLP-1 Secretion via CaMKII Pathway. Due to its established role in the metabolic response, glucose homeostasis, GLP1 is an important factor in the treatment and prevention of type 2 diabetes. Several therapeutic approaches to enhance GLP-1 action are being studied and include the use of GLP-1 analogs, which improve glycemic control in type 2 diabetes patients [4, 5]. As circulating GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-4) through cleavage of the N-terminal region of intact GLP-1 [6, 7], DPP-4 inhibitors are promising therapeutic agents for extending the half-life of endogenously secreted GLP-1. Several DPP-4 antagonists have been identified that ameliorate hyperglycemia in type 2 diabetes patients [8, 9]
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