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GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.

Lin HV, Efanov AM, Fang X, Beavers LS, Wang X, Wang J, Gonzalez Valcarcel IC, Ma T - PLoS ONE (2016)

Bottom Line: In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids.In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142.In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.

ABSTRACT
GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Effects of amino acids on insulin secretion in isolated pancreatic islets.(A-C) Islets isolated from Gpr142KO mice and WT littermate controls were incubated in the presence of L-Tryptophan (A), L-Phenylalanine (B), Exendin-4, or L-Arginine (C) for 1 hour, and insulin concentrations in the culture media were measured and expressed as fold change compared to control treatment (11.1 mM glucose). For each experiment, islets were isolated from 8–10 mice, pooled, then plated for treatment. Data are mean ± SEM. N = 5 replicates per treatment group. *,**: p<0.05, 0.01 KO vs. WT; ###: p<0.001 WT islets treatment group vs. 11.1mM glucose control group; ^^,^^^: KO islets p<0.01, 0.001 treatment group vs. 11.1mM glucose control group. (D) Islets isolated from a non-diabetic human donor were incubated at 11.1mM glucose in the presence of varying concentrations of L-Tryptophan, and insulin concentrations in the culture media were measured. Data are mean ± SEM. N = 5 replicates per group. *,****: p<0.05, 0.0001 vs. control (no L-Trp).
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pone.0157298.g002: Effects of amino acids on insulin secretion in isolated pancreatic islets.(A-C) Islets isolated from Gpr142KO mice and WT littermate controls were incubated in the presence of L-Tryptophan (A), L-Phenylalanine (B), Exendin-4, or L-Arginine (C) for 1 hour, and insulin concentrations in the culture media were measured and expressed as fold change compared to control treatment (11.1 mM glucose). For each experiment, islets were isolated from 8–10 mice, pooled, then plated for treatment. Data are mean ± SEM. N = 5 replicates per treatment group. *,**: p<0.05, 0.01 KO vs. WT; ###: p<0.001 WT islets treatment group vs. 11.1mM glucose control group; ^^,^^^: KO islets p<0.01, 0.001 treatment group vs. 11.1mM glucose control group. (D) Islets isolated from a non-diabetic human donor were incubated at 11.1mM glucose in the presence of varying concentrations of L-Tryptophan, and insulin concentrations in the culture media were measured. Data are mean ± SEM. N = 5 replicates per group. *,****: p<0.05, 0.0001 vs. control (no L-Trp).

Mentions: Since GPR142 is highly enriched in pancreatic islets, we then studied if GPR142 regulates insulin secretion. We utilized islets from wild type (WT) control mice and Gpr142knockout (KO) mice that were confirmed to have receptor expression below the limit of detection by quantitative PCR (Fig 1D). L-Trp dose-dependently stimulated the release of insulin in WT islets in the presence of 11.1 mM glucose (Fig 2A). Importantly, this response was significantly blunted in KO islets (Fig 2A), indicating that GPR142 is a key mediator of the insulin secretagogue activity of L-Trp. L-Trp also robustly stimulated insulin secretion in human primary islets at concentrations similar to those in murine islets (Fig 2D). As of L-Phe, its effect on insulin secretion in WT murine islets was more modest and was not significantly different in islets isolated from Gpr142 mice (Fig 2B) altogether making unclear if GPR142 mediates L-Phe’s insulin secretagogue response ex vivo.


GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.

Lin HV, Efanov AM, Fang X, Beavers LS, Wang X, Wang J, Gonzalez Valcarcel IC, Ma T - PLoS ONE (2016)

Effects of amino acids on insulin secretion in isolated pancreatic islets.(A-C) Islets isolated from Gpr142KO mice and WT littermate controls were incubated in the presence of L-Tryptophan (A), L-Phenylalanine (B), Exendin-4, or L-Arginine (C) for 1 hour, and insulin concentrations in the culture media were measured and expressed as fold change compared to control treatment (11.1 mM glucose). For each experiment, islets were isolated from 8–10 mice, pooled, then plated for treatment. Data are mean ± SEM. N = 5 replicates per treatment group. *,**: p<0.05, 0.01 KO vs. WT; ###: p<0.001 WT islets treatment group vs. 11.1mM glucose control group; ^^,^^^: KO islets p<0.01, 0.001 treatment group vs. 11.1mM glucose control group. (D) Islets isolated from a non-diabetic human donor were incubated at 11.1mM glucose in the presence of varying concentrations of L-Tryptophan, and insulin concentrations in the culture media were measured. Data are mean ± SEM. N = 5 replicates per group. *,****: p<0.05, 0.0001 vs. control (no L-Trp).
© Copyright Policy
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pone.0157298.g002: Effects of amino acids on insulin secretion in isolated pancreatic islets.(A-C) Islets isolated from Gpr142KO mice and WT littermate controls were incubated in the presence of L-Tryptophan (A), L-Phenylalanine (B), Exendin-4, or L-Arginine (C) for 1 hour, and insulin concentrations in the culture media were measured and expressed as fold change compared to control treatment (11.1 mM glucose). For each experiment, islets were isolated from 8–10 mice, pooled, then plated for treatment. Data are mean ± SEM. N = 5 replicates per treatment group. *,**: p<0.05, 0.01 KO vs. WT; ###: p<0.001 WT islets treatment group vs. 11.1mM glucose control group; ^^,^^^: KO islets p<0.01, 0.001 treatment group vs. 11.1mM glucose control group. (D) Islets isolated from a non-diabetic human donor were incubated at 11.1mM glucose in the presence of varying concentrations of L-Tryptophan, and insulin concentrations in the culture media were measured. Data are mean ± SEM. N = 5 replicates per group. *,****: p<0.05, 0.0001 vs. control (no L-Trp).
Mentions: Since GPR142 is highly enriched in pancreatic islets, we then studied if GPR142 regulates insulin secretion. We utilized islets from wild type (WT) control mice and Gpr142knockout (KO) mice that were confirmed to have receptor expression below the limit of detection by quantitative PCR (Fig 1D). L-Trp dose-dependently stimulated the release of insulin in WT islets in the presence of 11.1 mM glucose (Fig 2A). Importantly, this response was significantly blunted in KO islets (Fig 2A), indicating that GPR142 is a key mediator of the insulin secretagogue activity of L-Trp. L-Trp also robustly stimulated insulin secretion in human primary islets at concentrations similar to those in murine islets (Fig 2D). As of L-Phe, its effect on insulin secretion in WT murine islets was more modest and was not significantly different in islets isolated from Gpr142 mice (Fig 2B) altogether making unclear if GPR142 mediates L-Phe’s insulin secretagogue response ex vivo.

Bottom Line: In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids.In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142.In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.

ABSTRACT
GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus