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PXD057744

PXD057744 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleGLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese mice
DescriptionEarly drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide treated diet-induced obese (DIO) mice identified novel phosphorylation sites on key insulin signalling pathway proteins associated with improved insulin sensitivity. Cotadutide or GCGR monoagonist treatment also resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had 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 was associated with reduced insulin secretion from isolated pancreatic islet β-cells indicating reduced insulin secretory demand. Thus, 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 novel and effective T2D treatment
HostingRepositoryPRIDE
AnnounceDate2025-03-28
AnnouncementXMLSubmission_2025-03-28_08:32:10.410.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMartin R. Larsen
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListphosphorylated residue
InstrumentOrbitrap Eclipse; Orbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-11-11 05:55:23ID requested
12025-03-28 08:32:10announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: hepatic steatosis, mass spectrometry,T2D, insulin signaling, phosphorylation, Liver
Contact List
Shaun Alan Egolf
contact affiliationResearch and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
contact emailshaun.egolf@astrazeneca.com
lab head
Martin R. Larsen
contact affiliationUniversity of Southern Denmark
contact emailmrl@bmb.sdu.dk
dataset submitter
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Dataset FTP location
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