Background: Diabetes complications are the primary causes of DM morbidity and mortality. Objectives: comparing the anti-diabetic, lipidemic, and pro-inflammatory effects of metformin and glibenclamide in treating T2DM-obese patients, suggesting a probable novel mode of action and providing a more comprehensive understanding of T2DM pathophysiology for future therapeutic application. The effect of the adipocytokines and pro-inflammatory cytokines in T2DM was also investigated. Patients and methods: 150 subjects were allocated into five equal groups (n=30): the normal, the obese control, the obese diabetic control, the obese diabetic treated with 500 mg metformin twice daily, and the obese diabetic glibenclamide-treated, receiving 5 mg glibenclamide once daily. The blood samples were collected after six months of treatment. Results and conclusion: Metformin improved BMI, FSG, glycosylated hemoglobin, total cholesterol, and triglycerides, but it raised low-density lipoproteins and lowered high-density lipoproteins. The glibenclamide treatment significantly improved fasting insulin and C-peptide serum levels with subsequent better homeostatic model assessment for insulin resistance, but it increased BMI, TC, and TG. Visfatin and Retinol binding protein-4 showed less improvement in the glibenclamide than in the metformin-treated obese diabetic patients. In contrast, resistin decreased with glibenclamide treatment compared to metformin. The IL-1β expression was higher in the obese diabetic control and declined in the glibenclamide-treated obese diabetic patients while, IL-6, TNF-α, and IFN-γ expression decreased in metformin-treated obese diabetic patients than in glibenclamide ones. Our results also demonstrated a high positive correlation between the adipocytokines, visfatin, resistin, and RBP4 and the pro-inflammatory, cytokines IL-1β, IL-6, TNF-α and IFN-γ. From those results, treatment with metformin is recommended in the cases of obesity, inflammation, hypercholesterolemia, and hypertriglyceridemia. In addition, treatment with glibenclamide is recommended in the cases of insulin resistance and dyslipidemia.