Glycyrrhizic acid increases glucagon like peptide-1 secretion via TGR5 activation in type 1-like diabetic rats
Introduction
Diabetes mellitus (DM) is known as one of the metabolic disorders concomitant with hyperglycemia, mainly due to pancreatic dysfunction [1]. The prevalence of DM in clinics has markedly increased, and DM is predicted to affect approximately 439 million people by 2030 around the world [2]. Generally, DM includes two main subtypes, type 1 DM (T1DM) is mainly characterized by loss of functions in pancreatic β cells, associated with deficiency of insulin [3]; type 2 DM (T2DM) is diagnozed using the insulin resistance in addition to hyperglycemia and hyperlipidemia and has been classified as a common metabolic disorder [4]. Many parameters, including lower insulin secretion due to pancreatic dysfunction, inadequate glucose production in liver and insulin resistance in peripheral tissues, are introduced to mediate in the progress of T2DM [5]. Therefore, the development of therapeutic approaches is critically required.
After food intake, cells in intestinal mucosa may release the hormone incretin, which can induce insulin secretion to compensate the hyperglycemia [6], [7]. Basically, two types of incretin, glucose dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1), were involved. In recent studies, GLP-1 has been used as a new target for T2DM therapeutics [6]. Two strategies were introduced in clinics to treat T2DM, the application of GLP-1 analogs and/or the inhibitors of dipeptidylpeptidase-IV (DPP-4), the enzyme degrades both GLP-1 and GIP [6]. However, these strategies had limitations in clinical: GLP-1 analogs can only be administered by injection and the effectiveness of DPP-4 inhibitors is mild [8]. Therefore, improving insulin resistance or T2DM by using an herbal extract to activate the GLP-1 pathway has received increasing attention.
Glycyrrhizic acid (GA) is belonged to a triterpenoid saponin contained in the root of licorice and has been documented to show therapeutic activities against metabolic syndrome [9]. Glycyrrhizin has been shown to attenuate hyperglycemia in a rat model of DM [10]. Additionally, GA has been demonstrated to inhibit Advanced Glycation End (AGE) product accumulation and the expression of its receptor (RAGE) using the rats received high fat and fructose diet [11]. However, although the nuclear receptor PPARγ has been suggested as a possible target [9], the action mechanism(s) of GA remain unclear.
The bile acid binding receptor GPR 131 is also known as G-protein-coupled bile acid receptor 1 (GPBAR1), Takeda G-protein-coupled receptor 5 (TGR5), or M-BAR [12], [13], [14]. Activation of TGR5 increases cyclic adenosine monophosphate (cAMP) that may activate protein kinase A (PKA) and downstream signaling [12], [15]. Human NCI-H716 cells, similar to STC-1 and GLUTag [16], were widely used to examine the mechanisms underlying the secretion of GLP-1 [17]. Interestingly, TGR5 activation may enhance GLP-1 secretion in cultured NCI-H716 cells [18]. Therefore, a TGR5 agonist may be effective in T2DM-like animals [19].
The steroid-like structure of GA is similar to that of bile acid. Therefore, we are interested in understanding the role of TGR5 in GA-induced actions. First, the increased plasma GLP-1 by GA has been characterized in diabetic rats. Then, the effect of GA was inhibited by blocking TGR5 in cells and animals. Therefore, for the first time, we demonstrated that GA can promote GLP-1 secretion via TGR5 activation.
Section snippets
Materials
Glycyrrhizic acid ammonium salt (purity >70%) from Aldrich Sigma Chemical Co. (St. Louis, MO, USA) was dissolved in normal saline and triamterene (6-phenyl-2,4,7-pteridinotriamine; Aldrich Sigma Chemical Co.), an inhibitor of the TGR5 receptor [20] was prepared as the stock solution by dimethyl sulfoxide (DMSO). Additionally, sitagliptin phosphate (Merck, Cramlington, Northumberland, UK), an inhibitor of dipeptidyl peptidase-4 (DPP-4), was diluted in normal saline. The purity of glycyrrhizic
Effects of GA on the changes of plasma glucose in type 1-like diabetic rats
In STZ-induced diabetic rats, injection of GA attenuated the hyperglycemia in a dose-dependent manner (Fig. 1A). Moreover, plasma insulin levels in STZ-induced diabetic rats (5.35 ± 2.11 pmol/l, n = 8) have been markedly reduced compared to those in normal rats (141.4 ± 10.2 pmol/l, n = 8). However, GA at the highest dose failed to modify the plasma insulin levels in these diabetic rats (5.66 ± 1.39 pmol/l, n = 8). It means that endogenous insulin did not involve in the effect of GA in this animal model.
Discussion
GA is a main component of licorice and has shown hypoglycemic effects in the STZ diabetes model [10]. The present study demontrated that GA enhanced glucose-decreasing effect by elevation of circulating levels of GLP-1 in STZ-treated rats. The elevation in plasma GLP-1 by GA appears to be associated with TGR5 activation because the GLP-1 level was reduced by triamterene. Triamterene is a potassium-sparing diuretic and is used in clinic. Recently, it has been shown to inhibit TGR5 activation
Conclusion
Taken together, we demonstrated for the first time that GA could increase plasma GLP-1 level via TGR5 activation in tyep 1-like diabetic rats. Therefore, GA could have future applications in the clinic.
Conflict of interests
The authors declare no conflict of interests in this work.
Acknowledgements
We appreciate Ya-Pin Lin and Yi-Zhi Chen for their helpful contributions in this research. We also thank the professional company, American Journal Experts (AJE), for editing services. Budget of this report was mainly obtained from the Ministry of Science and Technology (MOST 104-2320-B-384-004-MY3) in Taiwan, the Republic of China.
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