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Insulin Resistance in Dietary-induced Obese Animals

Insulin Resistance in Dietary-induced Obese Animals

 

Genetic animal models of insulin resistance and type 2 diabetes provide useful insights into the efficacy of new drugs to improve glycaemic control. However, genetically-predisposed animals display marked hyperinsulinaemia which does not occur in patients with type 2 diabetes. Furthermore, as these animals are inbred and generally inherited the condition as a single gene mutation, the underlying genotype is not relevant to the aetiology of type 2 diabetes in man, which is thought to result from interactions between multiple gene defects and environmental factors.

Alternative polygenic models of insulin resistance are based on the syndrome that accompanies dietary-induced obesity in normal, lean non-diabetic mice fed a high fat diet (supplying 45% or 60% calories as fat) or normal rats made obese by exposure to a simplified cafeteria diet. This is much 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 but do not typically develop diabetes (hyperglycaemia). Both plasma glucose and insulin levels are increased following a glucose challenge ie the obesity is associated with impaired glucose tolerance and insulin resistance.

 Insulin Resistance in Dietary-induced Obese Animals

 

DIO mice and rats can therefore be used to evaluate the effects of novel drugs on glycaemic control.

Liraglutide Improves Glucose Tolerance and Insulin Sensitivity in DIO Mice

 

DIO mice and rats can also be used to investigate the effects of novel antidiabetic agents on 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 antidiabetic drugs 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.

Please contact us for further information on dietary-induced obese, insulin resistant rats and mice.

 

Posters

 

Burkey et al. 2017. The MetAP2 inhibitor ZGN-1061 improves glycaemia in high-fat diet-induced obese mice. Program No. 845. 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD), Lisbon, Portugal, 11th to 15th September, 2017. 

 

Cheetham et al. 2008. Effect of the MCH1 antagonist, GW803430, on body weight, food and water intake, glucose tolerance, fat pad weight, ex vivo binding and various plasma parameters in dietary-induced obese C57BL/6J mice. Program No. 584.24. Society for Neuroscience Meeting, Washington, DC, 15th-19th November 2008.

 

Grempler et al. 2011. The novel SGLT-2 inhibitor BI 10773 (empagliflozin) prevents pioglitazone-induced weight gain and further improves glycemic control in dietary-induced obese rats. Abstract No. 1851-P. American Diabetes Association 71st Scientific Sessions, San Diego, California, 24th-28th June 2011.

 

Surman et al. 2011. ALB-127158(a): An MCH1 receptor antagonist that exhibits weight loss and improvements in insulin sensitivity in diet-induced obese mice. Abstract No. 0108-LB. American Diabetes Association 71st Scientific Sessions, San Diego, California, 24th-28th June 2011.

 

Manuscripts

 

Vickers et al. 2014. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body weight reduction and glucose homeostasis of obese rats fed a cafeteria diet. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 7: 265-275. [PubMed]