GPR142 Agonists Stimulate Glucose-Dependent Insulin Secretion via Gq-Dependent Signaling

Abstract

GPR142 is an islet-enriched G protein-coupled receptor that has been investigated as a novel therapeutic target for the treatment of type 2 diabetes by virtue of its insulin secretagogue activity. However, the signaling pathways downstream of GPR142 and whether its stimulation of insulin release is glucose-dependent remain poorly characterized. In this study, we show that both native and synthetic GPR142 agonists can activate Gq as well as Gi signaling when GPR142 is recombinantly expressed in HEK293 cells. However, in primary pancreatic islets, a native cellular system, the insulin secretagogue activity of GPR142 agonists only requires Gq activation. In addition, our results show that stimulation of insulin secretion by GPR142 in pancreatic islets is strictly glucose-dependent.

GPR142 prompts glucagon-like Peptide-1 release from islets to improve β cell function

“…As such, compound A increased glucagon secretion in human islets by 73% in the presence of low ambient glucose (2.8 mM), ( Figure 1 D). Insulin secretion under this condition was not affected ( Figure 1 D), consistent with our previous report that this GPR142 action was strictly glucose-dependent [16] . In primary mouse islets, compound A increased glucagon secretion under both low (2.8 mM) and high (11.1 mM) glucose conditions ( Figure 1 E) to 2.7 ∼ 3.8-fold of control treatment, indicative that the GPR142 effect on glucagon is glucose-independent.…”

“…To examine the function of GPR142 in α cells, we probed the effect of receptor activation on glucagon secretion using the synthetic agonist N-[(3-methylimidazol-4-yl)methyl]-1-[5-methyl-4-(2-thienyl)pyrimidin-2-yl]-5-propyl-pyrazole-4-carboxamide [14] (example 49), hereafter referred to as compound A. We've previously shown that compound A triggered GPR142-specific signaling in vitro [16] , improved glucose tolerance, and increased secretion of insulin and incretins in vivo, all in a GPR142-dependent manner [1] . Furthermore, in vitro counter-screening of compound A in assays encompassing 17 other GPCRs, 18 enzymes, and 3 ion channels did not reveal meaningful activities at concentrations ≥10 μM (data not shown), confirming that compound A is a highly selective GPR142 agonist.…”

GPCR-Mediated Signaling of Metabolites

“…b-hydroxyoctanoate is produced by hepatocytes during b-oxidation to act as a signaling metabolite on HCA3 expressed on for example adipocytes (Figure 5). the enteroendocrine cells, local concentrations of aromatic amino acids derived from digestion of dietary proteins will most likely be high enough to act as physiological stimulators of gut hormone secretion (Wang et al, 2016a) (Figure 1). However, this is not the case in the islets.…”

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

“…All of these compounds were developed based on the understanding that the receptor is activated by tryptophan, an essential amino acid that is the biologic precursor to serotonin (Wurtman and Anton-Tay, 1969), and niacin (Ikeda et al, 1965). GPR142 is highly expressed on pancreatic b-cells and signals via Ga q (Wang et al, 2016a). Activation of the receptor enhances glucose-stimulated insulin release from pancreatic b-cells, but it is not known whether GPR142 has any further role beyond glycemic control.…”