PXD057744

PXD057744 is an original dataset announced via ProteomeXchange.

Title	GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese mice
Description	Early 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
HostingRepository	PRIDE
AnnounceDate	2025-03-28
AnnouncementXML	Submission_2025-03-28_08:32:10.410.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martin R. Larsen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-11 05:55:23	ID requested
⏵ 1	2025-03-28 08:32:10	announced

Dataset with its publication pending

submitter keyword: hepatic steatosis, mass spectrometry,T2D, insulin signaling, phosphorylation, Liver

Shaun Alan Egolf
contact affiliation	Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
contact email	shaun.egolf@astrazeneca.com
lab head
Martin R. Larsen
contact affiliation	University of Southern Denmark
contact email	mrl@bmb.sdu.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057744
     1. Label: PRIDE project
     2. Name: GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese mice