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

ABSTRACT: 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

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Martin R. Larsen  

LAB HEAD: Shaun Alan Egolf

PROVIDER: PXD057744 | Pride | 2025-03-28

REPOSITORIES: Pride