Background <p>Spexin is an adipokine secreted by various tissues, including white adipocytes and the brain. Its release is inversely associated with the state of energy storage. Curcumin (CUR), a polyphenolic substance extracted from turmeric, has been widely investigated for its beneficial effects, including the inhibition of oxidative stress and inflammation. Nano-curcumin (nCUR) is a novel preparation developed to enhance curcumin's absorption and therapeutic potency. This present study aimed to examine the comparative impacts of CUR and nCUR on plasma levels of Spexin, its gene expression in liver tissue, insulin resistance, lipid profiles, and fasting blood glucose (FBG) in type 2 diabetes mellitus (T2DM) rats. </p> Methods <p>Twenty-four male Wistar rats were divided into four groups: A T2DM group receiving 200 mg/kg nCUR, a T2DM group receiving 200 mg/kg CUR, a T2DM group, and a control group. The rats in the T2DM groups developed diabetes through a high-fat and high-glucose diet, along with streptozotocin injection. Plasma levels of Spexin, FBG, insulin resistance, and lipid profile were assessed. Additionally, the Spexin gene expression in liver samples was evaluated using quantitative real-time PCR (qRT-PCR).</p> Results <p>Both nCUR and CUR significantly improved insulin resistance, reduced FBG, and improved lipid levels in T2DM rats compared to the diabetic control rats (p &lt; 0.05). Notably, nCUR demonstrated a more pronounced elevation in plasma Spexin levels and its gene expression in liver tissue than CUR.</p> Conclusion <p>nCUR offers superior therapeutic benefits over CUR in managing T2DM, particularly in improving lipid metabolism, and Spexin regulation.</p>