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-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 up

SUBMITTER: Laker RC 

PROVIDER: S-EPMC12095689 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature