Abstract
Imperatorin, a dietary furocoumarin, is found not only in medicinal plants, but also in popular culinary herbs, such as parsley and fennel. Recently, imperatorin has been shown to activate GPR119 in cells. Another GPR, GPR131, also called TGR5 or G-protein-coupled bile acid receptor 1 (GPBAR1), is known to regulate glucose metabolism. Additionally, TGR5 activation increases glucagon-like peptide (GLP-1) secretion to lower blood sugar levels in animals. Therefore, the present study aims to determine whether the effects of imperatorin on GLP-1 secretion are mediated by TGR5. First, we transfected cultured Chinese hamster ovary cells (CHO-K1 cells) with the TGR5 gene. Glucose uptake was confirmed in the transfected cells using a fluorescent indicator. Moreover, NCI-H716 cells, which secrete GLP-1, were used to investigate the changes in calcium concentrations and GLP-1 levels. In addition, streptozotocin (STZ)-induced type 1-like diabetic rats were used to identify the effects of imperatorin in vivo. Imperatorin dose-dependently increased glucose uptake in CHO-K1 cells expressing TGR5. In STZ diabetic rats, similar to the results in NCI-H716 cells, imperatorin induced a marked increase of GLP-1 secretion that was reduced, but not totally abolished, by a dose of triamterene that inhibited TGR5. Moreover, increases in GLP-1 secretion induced by imperatorin and GPR119 activation were shown in NCI-H716 cells. We demonstrated that imperatorin induced GLP-1 secretion via activating TGR5 and GPR119. Therefore, imperatorin shall be considered as a TGR5 and GPR119 agonist.
Highlights
Diabetes mellitus (DM) is a metabolic disorder that is characterized by pancreatic islet dysfunction [1].The prevalence of DM is markedly increased in clinical settings [2]
For the first time, we demonstrate that imperatorin can activate Takeda G-protein-coupled receptor 5 (TGR5) and G-protein-coupled receptor 119 (GPR119) sites to promote glucagon-like peptide-1 (GLP-1) secretion
The exogenous TGR5 gene was successfully transfected into CHO-K1 cells and confirmed by Western blots (Figure 1a)
Summary
Diabetes mellitus (DM) is a metabolic disorder that is characterized by pancreatic islet dysfunction [1].The prevalence of DM is markedly increased in clinical settings [2]. Many parameters, including decreased insulin secretion due to pancreatic dysfunction, inadequate. Nutrients 2017, 9, 1192 hepatic glucose production and peripheral insulin resistance, are involved in the development of. Enteroendocrine cells in the intestinal mucosa release hormones that stimulate insulin secretion from the endocrine pancreas, reducing blood glucose levels; this process is known as the incretin effect [5,6]. Two types of incretins, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been identified in humans. GLP-1 is primarily produced and released by L-cells located in the distal ileum, whereas GIP is secreted by enteroendocrine K-cells in the proximal gut. GLP-1 has become a new target for T2DM therapeutics [5]. Two strategies have been widely applied in clinical practice to treat T2DM, namely
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