In conclusion, our results show that the combination of pioglitazone with glimepiride is more effective in amelioration of DN than rosiglitazone with glimepiride drug therapy due to glycemic control, suppressing albumin excretion rate, total protein excretion rate and augmenting TNF-α signaling during the development of STZ induced type 2 diabetic nephropathy. Here, TNF is linked to type 2 diabetes nephropathy.