胰高血糖素受体
胰高血糖素
氨基酸
兴奋剂
内科学
胰高血糖素样肽1受体
内分泌学
受体
杜拉鲁肽
化学
生物
胰岛素
生物化学
艾塞那肽
2型糖尿病
糖尿病
医学
作者
Wenyu Li,Thomas Kirchner,George Ho,Fany Bonilla,Katharine D’Aquino,James Littrell,Rui Zhang,Wenying Jian,Xi Qiu,Songmao Zheng,Bin Gao,Peggy Wong,Janet L. Leonard,Raul C. Camacho
摘要
Abstract 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.
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