Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Hepatic glucagon function in obesity and type 2 diabetes insights from mouse models (#192)

Yuqin Wu 1 , Andrea Chan 1 , Okka Aung 1 , Ashish Foollee 1 , Jana Hauke 2 , Meiling Han 3 , Patricia Rusu 1 , Christopher Barlow 4 , Juergen Guenther 2 , Adam Rose 1
  1. Nutrient Signalling and Metabolism Laboratory, Department of Biochemistry and Molecular Biology & Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne
  2. Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany
  3. Infection and Immunity Program, Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Melbourne
  4. Biomedical Proteomics and Metabolomics Facility and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne

Recent studies suggest hepatic glucagon resistance may drive metabolic dysfunction in obesity and hepatic steatosis. We investigated glucagon's effects in male mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including BKS-db/db, high-fat diet-fed, and Western diet-fed C57Bl/6 mice. Glucagon tolerance tests, blood glucose levels, liver glycogen content, liver protein expression related to glucagon signalling, and liver metabolomics were assessed using liquid chromatography-mass spectrometry. Western diet-fed mice showed impaired blood glucose response to glucagon, while high-fat diet-fed and db/db mice exhibited normal glucagon sensitivity, with significant increases in blood glucose, reductions in liver glycogen, and changes in phospho-PKA motif protein levels. Despite normal glucagon sensitivity in glucose metabolism and PKA signalling, db/db mice had a distinct metabolomic response, with glucagon significantly altering 225 metabolites in db/+ mice but only 81 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice. On the other hand, certain liver metabolites were even higher on glucagon treatment of db/db mice. Liver amino acid profiles revealed varied responses, with glucagon reducing liver glutamine levels in chow, high-fat, and Western diet-fed mice, as well as in db/+ mice, but not in db/db mice. Glucagon treatment also lowered liver alanine and histidine levels in chow and high-fat diet-fed mice, but not in Western diet-fed mice. Additionally, some amino acids, such as methionine and homocitrulline, were increased by glucagon only in chow diet control mice. These findings indicate hepatic glucagon insensitivity in obese and T2D mice is not uniform, suggesting that glucagon resistance in obesity and T2D is complex and warrants a nuanced view of hepatic glucagon action in obesity, fatty liver, and T2D.