TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity

Abstract

BackgroundPatients with diabesity have a significantly increased risk of developing cardiovascular disease. Therefore, therapy addressing the multiple metabolic abnormalities linked with diabesity and leading to further reduction of cardiovascular risk is highly desirable. Activation of the TGR5 receptor holds therapeutic potential for diabesity. In the present study, we evaluated the efficacy of TRC210258, a novel TGR5 agonist, in clinically relevant animal models of diabesity.MethodsA novel small molecule, TRC210258 (N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adenosine monophosphate (cAMP) assay and cAMP-responsive element reporter assay using cells overexpressing the human TGR5 receptor. The effect of TRC210258 on glucagon-like peptide-1 release was evaluated in vitro using a human enteroendocrine cell line. The effect of TRC210258 on energy expenditure and glycemic control was evaluated in high-fat diet-induced obese mice. Additionally, the effect of TRC210258 on dyslipidemic parameters was determined in high fat-fed hamsters.ResultsTRC210258 demonstrated potent TGR5 agonist activity, with enhanced glucagon-like peptide-1 release and energy expenditure. Treatment with TRC210258 resulted in better glycemic control and improved parameters of dyslipidemia such as plasma triglyceride, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol levels. Treatment with TRC210258 also improved emerging dyslipidemic cardiovascular risk parameters, including remnant cholesterol and triglyceride clearance.ConclusionThis study highlights the potential of TRC210258, a novel TGR5 agonist, to improve dyslipidemic cardiovascular risk beyond glycemic control in patients with type 2 diabetes.

Canavanine induces insulin release via activation of imidazoline I3 receptors

“…According to a previous method, CHO‐K1 cells were transiently transfected with human nischarin ( NISCH ), a mouse homologue of the human imidazoline receptor antisera‐selective (IRAS) protein and an expression vector (Origene, Rockville, MD, USA) using the TurboFect transfection reagent (Thermo Fisher Scientific, Pittsburgh, PA, USA). Twenty‐four hours after transfection, cells were incubated with the different concentrations of canavanine (0.01–1 μ mol/L) or agmatine (0.01–1 μ mol/L).…”

TGR5, Not Only a Metabolic Regulator

“…One of them has the highest activity in vitro (hTGR5 EC 50 = 0.28 nM, mTGR5 EC 50 = 0.92 nM). Zambad et al (2013) synthesized TRC210258 as a novel TGR5 agonist (Table 1). Zheng et al found small compound WB403 could activate TGR5 and promote GLP-1 secretion (Zheng et al, 2015).…”

Allantoin activates imidazoline I-3 receptors to enhance insulin secretion in pancreatic β-cells

“…According to the previous report [26], CHO-K1 cells were transiently transfected with human nischarin (NISCH) gene, also known as human imidazoline receptor antiseraselective (IRAS) protein, and an expression vector (Origene, Rockville, MD, USA) using the TurboFect transfection reagent (Thermo Fisher Scientific, USA). At 24 h later, the transfected cells were used to treat with allantoin or agmatine at indicated concentrations.…”