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Amino acids are sensitive glucagon receptor‐specific biomarkers for glucagon‐like peptide‐1 receptor/glucagon receptor dual agonists
Author(s) -
Li Wenyu,
Kirchner Thomas,
Ho George,
Bonilla Fany,
D'Aquino Katharine,
Littrell James,
Zhang Rui,
Jian Wenying,
Qiu Xi,
Zheng Songmao,
Gao Bin,
Wong Peggy,
Leonard James N.,
Camacho Raul C.
Publication year - 2020
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.14173
Subject(s) - glucagon receptor , glucagon , amino acid , agonist , medicine , glucagon like peptide 1 receptor , endocrinology , receptor , dulaglutide , chemistry , biology , insulin , biochemistry , exenatide , type 2 diabetes , diabetes mellitus
Aim The aim of this study was to evaluate amino acids as glucagon receptor (GCGR)‐specific biomarkers in rodents and cynomolgus monkeys in the presence of agonism of both glucagon‐like peptide‐1 receptor (GLP1R) and GCGR with a variety of dual agonist compounds. Materials and methods Primary hepatocytes, rodents (normal, diet‐induced obese and GLP1R knockout) and cynomolgus monkeys were treated with insulin (hepatocytes only), glucagon (hepatocytes and cynomolgus monkeys), the GLP1R agonist, dulaglutide, or a variety of dual agonists with varying GCGR potencies. Results A long‐acting dual agonist, Compound 2, significantly decreased amino acids in both wild‐type and GLP1R knockout mice in the absence of changes in food intake, body weight, glucose or insulin, and increased expression of hepatic amino acid transporters. Dulaglutide, or a variant of Compound 2 lacking GCGR agonism, had no effect on amino acids. A third variant with ~31‐fold less GCGR potency than Compound 2 significantly decreased amino acids, albeit to a significantly lesser extent than Compound 2. Dulaglutide (with saline infusion) had no effect on amino acids, but an infusion of glucagon dose‐dependently decreased amino acids on the background of GLP1R engagement (dulaglutide) in cynomolgus monkeys, as did Compound 2. Conclusions These results show that amino acids are sensitive and translatable GCGR‐specific biomarkers.