Type 2 diabetes is a progressive disorder with a consistent and steady increase in HbA1c over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. Administration of Streptozotocin (65 mg/kg, i.p) and Nicotinamide (110 mg/kg, i.p) produced symptoms such as hyperglycemia, loss of body weight. Also impaired glucose metabolism and altered hepatic function. The treatment with Metformin (50 mg/kg, p.o) reduced elevated levels of serum AST, ALT, ALP, GammaGTP and CPK levels which show the protective effect of Metformin (50 mg/kg/day, p.o). This study concluded that Glimepiride (0.5 mg/kg, p.o) alone and combination with Pioglitazone (10 mg/kg, p.o) and Metformin (50 mg/kg, p.o) may show some toxicity in STZ-NIC induced diabetic rats whereas with doses. Treatment with Pioglitazone (10 mg/kg, p.o), or combination thereof Metformin (50 mg/kg, p.o) and Glimepiride (0.5 mg/kg, p.o) showed a significant decrease in diabetic as compared to control nondiabetic rats and diabetic control rats indicate the toxicity in diabetic animal.