GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice

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 and Christopher J. Rhodes ()
Additional contact information
Rhianna C. Laker: AstraZeneca
Shaun Egolf: AstraZeneca
Sarah Will: AstraZeneca
Louise Lantier: Vanderbilt University Mouse Metabolic Phenotyping Center
Owen P. McGuinness: Vanderbilt University Mouse Metabolic Phenotyping Center
Charles Brown: AstraZeneca
Nicholas Bhagroo: AstraZeneca
Stephanie Oldham: AstraZeneca
Kyle Kuszpit: AstraZeneca
Alex Alfaro: AstraZeneca
Xidan Li: AstraZeneca
Taewook Kang: University of Southern Denmark
Giovanni Pellegrini: AstraZeneca
Anne-Christine Andréasson: AstraZeneca
Sarina Kajani: AstraZeneca
Sadichha Sitaula: AstraZeneca
Martin R. Larsen: University of Southern Denmark
Christopher J. Rhodes: AstraZeneca

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59773-4

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