Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes
Objective - The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions. - Methods - We investigated glucagon's...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
December 2024
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| In: |
Molecular metabolism
Year: 2024, Volume: 90, Pages: 1-17 |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2024.102064 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.molmet.2024.102064 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2212877824001959 
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| Author Notes: | Yuqin Wu, Andrea Y. Chan, Jana Hauke, Okka Htin Aung, Ashish Foollee, Maria Almira S. Cleofe, Helen Stölting, Mei-Ling Han, Katherine J. Jeppe, Christopher K. Barlow, Jürgen G. Okun, Patricia M. Rusu, Adam J. Rose |
| Summary: | Objective - The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions. - Methods - We investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed. - Results - Western diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice. - Conclusions - The study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions. |
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| Item Description: | Online verfügbar 12 November 2024, Version des Artikels 20 November 2024 Gesehen am 30.06.2025 |
| Physical Description: | Online Resource |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2024.102064 |