Insulin resistance and subsequent insulin secretory defect are two main features of type 2 diabetes and associated metabolic disorders. The animal models of type 2 diabetes are very complex and are as heterogeneous as the disease. We have evaluated the effect of various antidiabetic and lipid lowering agents (fenofibrate, rosiglitazone, glimepiride, metformin and simvastatin) on the metabolic abnormalities induced by combining a high-fat diet and multiple low-dose streptozocin (MLDS) in mice. Male Swiss albino mice were orally treated with the above agents and fed with a diet containing high fat for 28 days. On day 15 the animals were injected intraperitoneally with low-dose streptozocin (40 mg kg(-1)), which was administered for five consecutive days. At the end of the 28-day treatment plasma metabolic parameters (glucose, triglyceride and immunoreactive insulin) were estimated. The antidiabetic and hypolipidaemic agents exhibited differential effects on these metabolic parameters. With the exception of fenofibrate all these agents reduced the plasma glucose levels, and the effects of metformin and rosiglitazone on glucose were found to be statistically significant. Although the effect of the test drugs on cholesterol was modest, a significant decrease in triglyceride levels was observed with sub-chronic treatment with these agents. Interestingly, glimepiride mildly elevated the insulin levels while the other antidiabetics and hypolipidaemics reduced the insulin levels, with metformin and rosiglitazone exhibiting statistically significant effects on insulin. To our knowledge this is the first report on the effect of various peroxisome proliferator-activated receptor modulators and newer antidiabetics on the metabolic effects induced by the combined high-fat diet and MLDS model of type 2 diabetes in Swiss albino mice. The results suggested the complexity of the hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia induced by the high-fat diet and MLDS mouse model, and their correction by various antidiabetics and antihyperlipidaemics may have involved diverse mechanisms.