TNFα-CXCR1/2 partners in crime in insulin resistance conditions

Type 2 diabetes mellitus (T2D) is defined by chronic hyperglycemia due to insufficient insulin secretion or activity and decreased insulin sensitivity, known as insulin resistance (IR). This condition leads to oxidative stress and inflammation, increasing the risk of systemic inflammatory diseases. Obesity and a sedentary lifestyle are major risk factors for IR and T2D. Various metabolites act as mediators of IR by disrupting communication between organs. Lipids, including free fatty acids and short-chain fatty acids, along with intracellular lipotoxins, impair insulin function and mitochondrial activity, contributing to IR through direct and indirect mechanisms such as oxidative stress and inflammation. Our research explores the role of TNFα and CXCR1/2 in IR conditions, emphasizing their interactions and potential as therapeutic targets. In this study we selected two models of IR, adipocytes and hepatocytes, since are key players in glucose and lipid metabolism. To develop IR model, TNFα was used as challenge and we focused on investigating the role of CXCR1/2 inhibition. We assessed glucose uptake, insulin signaling pathways, and gene expression related to IR. Cells treated with TNFα showed reduced p-Akt and increased p-JNK levels, indicative of IR. In contrast, CXCR1/2 inhibition restored p-Akt levels and reduced p-JNK levels, suggesting improvements in insulin signaling and glucose uptake. Furthermore, CXCR1/2 inhibition counteracted the TNFα-induced decrease in IGF expression and restored GLUT2 expression, indicating enhanced insulin sensitivity. These results underscore the pivotal role of CXCR1/2 in modulating the inflammatory response and insulin signaling in IR conditions in both IR models. CXCR1/2 inhibition can mitigate IR and improve glucose metabolism. Thus, targeting the TNFα-CXCR1/2 pathway presents a promising therapeutic approach for managing IR and T2D. Further investigation is necessary to understand the clinical implications of these findings and develop effective treatments for patients with IR and T2D.