GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice
Abstract An early driver of Type 2 diabetes mellitus (T2D) is ectopic fat accumulation, especially in the liver, that impairs insulin sensitivity. In T2D, GLP-1R/GCGR dual-agonists reduce glycaemia, body weight and hepatic steatosis. Here, we utilize cotadutide, a well characterized GLP-1R/GCGR dual...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59773-4 |
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| author | Rhianna C. Laker Shaun Egolf Sarah Will Louise Lantier Owen P. McGuinness Charles Brown Nicholas Bhagroo Stephanie Oldham Kyle Kuszpit Alex Alfaro Xidan Li Taewook Kang Giovanni Pellegrini Anne-Christine Andréasson Sarina Kajani Sadichha Sitaula Martin R. Larsen Christopher J. Rhodes |
| author_facet | Rhianna C. Laker Shaun Egolf Sarah Will Louise Lantier Owen P. McGuinness Charles Brown Nicholas Bhagroo Stephanie Oldham Kyle Kuszpit Alex Alfaro Xidan Li Taewook Kang Giovanni Pellegrini Anne-Christine Andréasson Sarina Kajani Sadichha Sitaula Martin R. Larsen Christopher J. Rhodes |
| author_sort | Rhianna C. Laker |
| collection | DOAJ |
| description | Abstract An early driver of Type 2 diabetes mellitus (T2D) is ectopic fat accumulation, especially in the liver, that impairs insulin sensitivity. In T2D, GLP-1R/GCGR dual-agonists reduce glycaemia, body weight and hepatic steatosis. Here, we utilize cotadutide, a well characterized GLP-1R/GCGR dual-agonist, and demonstrate improvement of insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese (DIO) mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide-treated mice identifies previously unknown and known phosphorylation sites on key insulin signaling proteins associated with improved insulin sensitivity. Cotadutide or GCGR mono-agonist treatment also increases brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R mono-agonist shows a weak effect. BAT from cotadutide-treated mice have induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Finally, the cotadutide-induced improvement in insulin sensitivity is associated with reduction of insulin secretion from isolated pancreatic islets indicating reduced insulin secretory demand. Here we show, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a potentially effective T2D treatment. |
| format | Article |
| id | doaj-art-2f420744a2da475aaeafc829f70f1949 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2f420744a2da475aaeafc829f70f19492025-08-20T02:34:14ZengNature PortfolioNature Communications2041-17232025-05-0116112110.1038/s41467-025-59773-4GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male miceRhianna C. Laker0Shaun Egolf1Sarah Will2Louise Lantier3Owen P. McGuinness4Charles Brown5Nicholas Bhagroo6Stephanie Oldham7Kyle Kuszpit8Alex Alfaro9Xidan Li10Taewook Kang11Giovanni Pellegrini12Anne-Christine Andréasson13Sarina Kajani14Sadichha Sitaula15Martin R. Larsen16Christopher J. Rhodes17Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaVanderbilt University Mouse Metabolic Phenotyping CenterVanderbilt University Mouse Metabolic Phenotyping CenterImaging and Data Analytics, Clinical Pharmacology and Safety Sciences, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaImaging and Data Analytics, Clinical Pharmacology and Safety Sciences, AstraZenecaImaging and Data Analytics, Clinical Pharmacology and Safety Sciences, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaDepartment of Biochemistry and Molecular Biology, PR group, University of Southern DenmarkResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaDepartment of Biochemistry and Molecular Biology, PR group, University of Southern DenmarkResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZenecaAbstract An early driver of Type 2 diabetes mellitus (T2D) is ectopic fat accumulation, especially in the liver, that impairs insulin sensitivity. In T2D, GLP-1R/GCGR dual-agonists reduce glycaemia, body weight and hepatic steatosis. Here, we utilize cotadutide, a well characterized GLP-1R/GCGR dual-agonist, and demonstrate improvement of insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese (DIO) mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide-treated mice identifies previously unknown and known phosphorylation sites on key insulin signaling proteins associated with improved insulin sensitivity. Cotadutide or GCGR mono-agonist treatment also increases brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R mono-agonist shows a weak effect. BAT from cotadutide-treated mice have induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Finally, the cotadutide-induced improvement in insulin sensitivity is associated with reduction of insulin secretion from isolated pancreatic islets indicating reduced insulin secretory demand. Here we show, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a potentially effective T2D treatment.https://doi.org/10.1038/s41467-025-59773-4 |
| spellingShingle | Rhianna C. Laker Shaun Egolf Sarah Will Louise Lantier Owen P. McGuinness Charles Brown Nicholas Bhagroo Stephanie Oldham Kyle Kuszpit Alex Alfaro Xidan Li Taewook Kang Giovanni Pellegrini Anne-Christine Andréasson Sarina Kajani Sadichha Sitaula Martin R. Larsen Christopher J. Rhodes GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice Nature Communications |
| title | GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice |
| title_full | GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice |
| title_fullStr | GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice |
| title_full_unstemmed | GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice |
| title_short | GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice |
| title_sort | glp 1r gcgr dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β cell function in obese male mice |
| url | https://doi.org/10.1038/s41467-025-59773-4 |
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