GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.
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 null 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.
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Hua V
http://orcid.org/0000-0001-5001-5567
HV
Lin
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly & Company, Indianapolis, Indiana, United States of America.
Alexander M
AM
Efanov
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Xiankang
X
Fang
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly & Company, Indianapolis, Indiana, United States of America.
Lisa S
LS
Beavers
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Xuesong
X
Wang
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Jingru
J
Wang
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly & Company, Indianapolis, Indiana, United States of America.
Isabel C
IC
Gonzalez Valcarcel
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Tianwei
T
Ma
D000818:Animals; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010649:Phenylalanine / Q000008:administration & dosage / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000187:drug effects / Q000235:genetics*; D014364:Tryptophan / Q000008:administration & dosage / Q000378:metabolism*
D001786:Blood Glucose; C511538:GPR142 protein, mouse; D054795:Incretins; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D010649:Phenylalanine; D014364:Tryptophan; D005947:Glucose