Neohesperidin attenuated fasting blood glucose and insulin resistance. The levels of total cholesterol, triglycerides, and leptins were significantly decreased, while the phosphorylation of AMP-activated protein kinase (AMPK) and its target genes was increased in the drug-treated mice. It also significantly decreased the size of epididymal adipocytes in the diabetic mice. This evidence concerns the gene LEP and Insulin resistance.