Palmitate-induced hepatic insulin resistance as an in vitro model for natural and synthetic drug screening: A scoping review of therapeutic candidates and mechanisms

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance (IR) and β-cell dysfunction, often exacerbated by excessive intake of saturated fatty acids, particularly palmitic acid (PA). As the most abundant saturated fatty acid in Western diets, PA contributes to metabolic dysregulation by inducing mitochondrial dysfunction, enhancing reactive oxygen species (ROS) generation, activating inflammatory pathways, and impairing insulin signaling in hepatocytes. Consequently, PA-induced hepatic IR has become a widely accepted in vitro model for investigating therapeutic strategies to restore insulin sensitivity. This scoping review aims to identify and summarize natural and synthetic compounds evaluated in this model, emphasizing mechanisms of action and highlighting research gaps. A total of 78 eligible studies were selected through a systematic search of PubMed, Scopus, and Web of Science. Most studies employed HepG2 cells and adopted co-incubation or post-treatment protocols to simulate preventive or therapeutic contexts. Natural compounds predominate, particularly polyphenols, flavonoids, alkaloids, and plant extracts. Reported mechanisms involved activation of insulin signaling pathways (phosphoinositide 3-kinase/protein kinase B [PI3K/Akt], adenosine monophosphate-activated protein kinase [AMPK]), attenuation of oxidative stress (reduced ROS and malondialdehyde [MDA], increased superoxide dismutase [SOD] and catalase [CAT]), inhibition of inflammatory mediators (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], nuclear factor kappa B [NF-κB]), and regulation of apoptosis (caspase-3, Bcl-2-associated X protein/B-cell lymphoma 2 [BAX/Bcl-2]). Overall, this model provides a robust and translationally relevant platform for screening bioactive compounds targeting multiple pathological features of T2DM.