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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.
Laker et al. (Wed,) studied this question.