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. 2020 Dec;22(12):2437-2450.
doi: 10.1111/dom.14173. Epub 2020 Sep 23.

Amino acids are sensitive glucagon receptor-specific biomarkers for glucagon-like peptide-1 receptor/glucagon receptor dual agonists

Wenyu Li  1 , Thomas Kirchner  1 , George Ho  1 , Fany Bonilla  1 , Katharine D'Aquino  1 , James Littrell  1 , Rui Zhang  1 , Wenying Jian  2 , Xi Qiu  2 , Songmao Zheng  3 , Bin Gao  4 , Peggy Wong  5 , James N Leonard  1 , Raul C Camacho  1
Affiliations

Amino acids are sensitive glucagon receptor-specific biomarkers for glucagon-like peptide-1 receptor/glucagon receptor dual agonists

Wenyu Li et al. Diabetes Obes Metab. 2020 Dec.

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.

Keywords: amino acids, glucagon receptor, glucagon‐like peptide‐1 receptor, oxyntomodulin, pharmacology.

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References

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