Abstract
G protein-coupled receptor (GPR) 119 is expressed in pancreatic β-cells and intestinal L cells, and is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, respectively. Therefore, the development of GPR119 agonists is a potential treatment for type 2 diabetes. We screened 1500 natural plant extracts for GPR119 agonistic actions and investigated the most promising extract, that from Angelica dahurica (AD), for hypoglycemic actions in vitro and in vivo. Human GPR119 activation was measured in GeneBLAzer T-Rex GPR119-CRE-bla CHO-K1 cells; intracellular cAMP levels and insulin secretion were measured in INS-1 cells; and GLP-1 release was measured in GLUTag cells. Glucose tolerance tests and serum plasma insulin levels were measured in normal C57BL6 mice and diabetic db/db mice. AD extract-treated cells showed significant increases in GPR119 activation, intracellular cAMP levels, GLP-1 levels and glucose-stimulated insulin secretion as compared with controls. In normal mice, a single treatment with AD extract improved glucose tolerance and increased insulin secretion. Treatment with multiple doses of AD extract or n-hexane fraction improved glucose tolerance in diabetic db/db mice. Imperatorin, phellopterin and isoimperatorin were identified in the active fraction of AD extract. Among these, phellopterin activated GPR119 and increased active GLP-1 and insulin secretion in vitro and enhanced glucose tolerance in normal and db/db mice. We suggest that phellopterin might have a therapeutic potential for the treatment of type 2 diabetes.
Highlights
Type 2 diabetes mellitus is a common metabolic disorder which is increasingly prevalent throughout the world [1]
The reporter activity was increased in a dose-dependent manner, suggesting that intracellular cAMP production was stimulated by Angelica dahurica (AD) extract treatment (Fig 1A)
We found that cAMP levels were significantly enhanced both in GLUTag and INS-1 cells after treatment with 100 μg/mL of AD extracts (Fig 1B), the dose which showed the highest activity in the reporter cell line
Summary
Type 2 diabetes mellitus is a common metabolic disorder which is increasingly prevalent throughout the world [1]. Type 2 diabetes is characterized by insulin resistance and hyperglycemia [2,3,4,5]. Angelica dahurica Extracts Stimulate GPR119 inadequate hepatic glucose production and peripheral insulin resistance, are involved in disease development, and many therapeutic approaches have been attempted to treat this metabolic syndrome [1, 6]. Incretin-based therapies such as glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors have been used for treating diabetic patients [7], but these drugs have shown clinically limited effects. GLP-1 analogs require intraperitoneal injections, and the efficacy of dipeptidyl peptidase-4 inhibitors is modest as their action is dependent on endogenous GLP-1 [8]
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