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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have rapidly evolved from glucose-lowering agents into pleiotropic cardiometabolic therapeutics with established benefits in obesity, type 2 diabetes, cardiovascular disease, and chronic kidney disease. Although their classical actions are well defined, emerging evidence suggests that mitochondrial remodeling may represent a central mechanistic layer through which GLP-1RAs exert tissue-protective effects. Across pancreatic beta cells, myocardium, liver, adipose tissue, skeletal muscle, kidney, vasculature, and neural tissues, GLP-1 signaling is repeatedly associated with improved mitochondrial quality control, lower oxidative stress, improved respiratory efficiency, and reduced apoptosis. However, the literature is mechanistically heterogeneous. Some mitochondrial effects appear to be direct and receptor-mediated, whereas others are likely secondary to weight loss, reduced glucotoxicity, improved insulin sensitivity, or lower inflammatory burden. This review argues that mitochondria are not merely downstream beneficiaries of improved metabolism during GLP-1 therapy. Rather, mitochondrial rescue likely represents a recurrent intracellular effector system through which GLP-1RAs translate receptor activation into durable organ protection. Framing GLP-1 pharmacology through a mitochondrial lens helps unify otherwise disparate observations across metabolic tissues and provides a clinically meaningful framework for future translational research‎.

Keywords: GLP-1 receptor agonists, Mitochondria, Obesity, Type 2 diabetes, Insulin resistance, Metabolic disease

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