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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

Glucose tolerance tests after L-Tryptophan and L-Phenylalanine oral dosing in Gpr142KO mice and WT littermate controls.(A-D) Vehicle (15% HP-β-CD) or L-Trp (500 mg/kg), or (E-F) vehicle or L-Phe (500 mg/kg) was dosed orally at 20 ml/kg to 5hr daytime fasted mice 15 minutes prior to the glucose challenge. Glucose (2 g/kg) was injected i.p. (A-B, E-F) or given by oral gavage (C-D) at indicated time points. Tail blood glucose was monitored for 120 minutes after glucose injection. Animals used were male, 5–8 months of age, and maintained on standard chow diet. Data are mean ± SEM. N = 7 per group. *,**,***: p<0.05, 0.01, 0.001 treatment group vs. vehicle.
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pone.0157298.g003: Glucose tolerance tests after L-Tryptophan and L-Phenylalanine oral dosing in Gpr142KO mice and WT littermate controls.(A-D) Vehicle (15% HP-β-CD) or L-Trp (500 mg/kg), or (E-F) vehicle or L-Phe (500 mg/kg) was dosed orally at 20 ml/kg to 5hr daytime fasted mice 15 minutes prior to the glucose challenge. Glucose (2 g/kg) was injected i.p. (A-B, E-F) or given by oral gavage (C-D) at indicated time points. Tail blood glucose was monitored for 120 minutes after glucose injection. Animals used were male, 5–8 months of age, and maintained on standard chow diet. Data are mean ± SEM. N = 7 per group. *,**,***: p<0.05, 0.01, 0.001 treatment group vs. vehicle.

Mentions: We examined the effect of L-Trp and L-Phe on glycemia. Oral dosing of L-Trp suppressed glucose excursion in WT mice during intraperitoneal glucose tolerance test (IPGTT) and oral glucose tolerance test (OGTT) (Fig 3A and 3C). L-Trp had no significant effect on glucose excursion in KO mice (Fig 3B and 3D).Conversely, the effect of L-Phe on glucose excursion during IPGTT was clearly present in both WT and KO mice (Fig 3E and 3F). This finding demonstrates the existence of a novel GPR142-independent pathway that underlies in vivo effect of L-Phe on glucose disposal and warrants additional investigation.


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)

Glucose tolerance tests after L-Tryptophan and L-Phenylalanine oral dosing in Gpr142KO mice and WT littermate controls.(A-D) Vehicle (15% HP-β-CD) or L-Trp (500 mg/kg), or (E-F) vehicle or L-Phe (500 mg/kg) was dosed orally at 20 ml/kg to 5hr daytime fasted mice 15 minutes prior to the glucose challenge. Glucose (2 g/kg) was injected i.p. (A-B, E-F) or given by oral gavage (C-D) at indicated time points. Tail blood glucose was monitored for 120 minutes after glucose injection. Animals used were male, 5–8 months of age, and maintained on standard chow diet. Data are mean ± SEM. N = 7 per group. *,**,***: p<0.05, 0.01, 0.001 treatment group vs. vehicle.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4920590&req=5

pone.0157298.g003: Glucose tolerance tests after L-Tryptophan and L-Phenylalanine oral dosing in Gpr142KO mice and WT littermate controls.(A-D) Vehicle (15% HP-β-CD) or L-Trp (500 mg/kg), or (E-F) vehicle or L-Phe (500 mg/kg) was dosed orally at 20 ml/kg to 5hr daytime fasted mice 15 minutes prior to the glucose challenge. Glucose (2 g/kg) was injected i.p. (A-B, E-F) or given by oral gavage (C-D) at indicated time points. Tail blood glucose was monitored for 120 minutes after glucose injection. Animals used were male, 5–8 months of age, and maintained on standard chow diet. Data are mean ± SEM. N = 7 per group. *,**,***: p<0.05, 0.01, 0.001 treatment group vs. vehicle.
Mentions: We examined the effect of L-Trp and L-Phe on glycemia. Oral dosing of L-Trp suppressed glucose excursion in WT mice during intraperitoneal glucose tolerance test (IPGTT) and oral glucose tolerance test (OGTT) (Fig 3A and 3C). L-Trp had no significant effect on glucose excursion in KO mice (Fig 3B and 3D).Conversely, the effect of L-Phe on glucose excursion during IPGTT was clearly present in both WT and KO mice (Fig 3E and 3F). This finding demonstrates the existence of a novel GPR142-independent pathway that underlies in vivo effect of L-Phe on glucose disposal and warrants additional investigation.

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