Dietary Induced Insulin Resistance in Obese Animals
Genetically-predisposed animals are widely used to screen for antidiabetic action, however, the animals display marked hyperinsulinaemia which does not occur in patients with type 2 diabetes. Furthermore, the underlying genotype is not relevant to the aetiology of type 2 diabetes in man. Alternative polygenic models are based on the insulin resistance that accompanies dietary-induced obesity in mice fed a high fat diet (supplying 45% or 60% calories as fat) or rats made obese by exposure to a simplified cafeteria diet. This is closer to the clinical situation as dietary-induced obesity is a major predisposing risk factor for type 2 diabetes in man.
Dietary-induced obese (DIO) animals have moderate elevations in plasma insulin levels compared to control animals fed normal rodent chow whereas plasma glucose levels may or may not be increased. These animal models can be used to evaluate the effects of novel drugs on both insulin resistance and body weight. This is important as patients with type 2 diabetes are often obese and further weight gain is undesirable.
New drugs to treat diabetes should be weight-neutral or ideally produce weight-loss. The use of DIO rats and mice to predict the effects of novel drugs with antidiabetic potential on body weight has been validated using thiazolidinediones such as pioglitazone. These drugs increase body weight in obese animals in a similar manner to the weight gain observed in diabetic patients. Furthermore, other drugs such as the DPP-IV inhibitor, sitagliptin, improve glucose tolerance in DIO rats and are weight-neutral, again reflecting the clinical situation.
