Impaired lipid metabolism and inflammatory pathways have individually been implicated in the development of insulin resistance in skeletal muscle; however, little evidence is available to date linking the two in this context. In this study, we explored a potential molecular mechanism underlying insulin resistance in myoblasts mediated by the crosstalk between lipid accumulation and inflammatory pathways. We examined the influence of perilipin 2 (PLIN2), one of the most highly expressed lipid droplet-associated proteins in skeletal muscle, on glucose uptake and on the nucleotide‑binding domain, leucine‑rich repeat containing protein 3 (NLRP3) inflammasome in vitro. PLIN2 overexpression in C2C12 cells led to an increased expression of NLRP3, caspase‑1 and interleukin (IL)‑1β, along with an impaired insulin‑induced glucose uptake. This defect was remedied by the RNAi‑mediated knockdown of NLRP3 expression. We also found that insulin receptor substrate‑1 (IRS‑1), a component of insulin signaling, was negatively regulated by NLRP3 and IL‑1β, and that IL‑1β inhibited insulin‑induced glucose uptake in myoblasts. These results suggest that PLIN2 inhibits insulin‑induced glucose uptake by activating NLRP3, caspase‑1 and IL‑1β, leading to a decreased IRS‑1 expression. This study provides in vitro evidence supporting an association between lipid metabolism and inflammatory pathways in the pathogenesis of insulin resistance in skeletal muscle, and suggests potential therapeutic targets that warrant further investigation.