RenaSci

Genetic Models of Insulin Resistance and Type 2 Diabetesdb/db Mouse

 

Potential antidiabetic drugs can be evaluated in any commercially available genetic animal model of insulin resistance or type 2 diabetes. Animals genetically predisposed to developing syndromes with similar characteristics to insulin resistance or type 2 diabetes in man include :-

     •   ob/ob mice
     •   db/db mice
     •   Zucker fatty fa/fa rats
     •   Zucker diabetic fatty fa/fa (ZDF) rats

These inbred animal models develop spontaneous insulin resistance or overt diabetes because of a mutation in a single gene. All four models display hyperinsulinaemia and are insulin-resistant but differ in the degree of hyperglycaemia. For example, Zucker fatty fa/fa rats are not hyperglycaemic, ob/ob mice exhibit mild to moderate increases in plasma glucose levels whereas db/db mice and ZDF rats are overtly diabetic and display pronounced hyperglycaemia. The ob/ob mice, db/db mice, Zucker fatty fa/fa rats and ZDF rats are also obese.

Genetic models of insulin resistance or type 2 diabetes have been extensively used to screen compounds with antidiabetic potential and will detect drugs with various modes of action.

 

Effect of Sitagliptin on Glucose Tolerance in ob/ob Mice

 

Typical measurements in studies in genetic models of insulin resistance and type 2 diabetes include glucose tolerance tests, blood HbA1c, plasma fructosamine, plasma lipid profiles including HDL-C and LDL-C levels and urinary glucose excretion. At the end of studies, pancreatic insulin levels may be determined. In addition, pancreatic slices can be taken for insulin immunohistochemistry or prepared for determination of β-cell mass (out-of-house).

 

Liraglutide Prevents the Progression of Diabetes in db/db Mice

 

 

ZDF Rat Model of Type 2 Diabetes


We have recently characterised the diabetic profile of ZDF rats and confirmed that rats with the genotype fa/fa (ZDF) develop severe diabetes and display changes in terminal plasma parameters consistent with the metabolic syndrome compared to +/+ or +/fa control animals.  

Plasma Glucose Levels in the ZDF Rat Model of Type 2 Diabetes

 

OGTT in ZDF Rats Shows Increased Plasma Glucose and Insulin at Baseline and Post-Glucose

 

Plasma Fructosamine and Blood HbA1c in ZDF Rats

 

Increased Urinary Glucose Excretion in the ZDF Rat Model of Type 2 Diabetes

 

Terminal Plasma Parameters in ZDF Rats

 

For further information about our genetic models of insulin resistance and type 2 diabetes please get in touch. 

 

Posters

 

Headland et al. 2013. The effect of combination linagliptin and voglibose on glucose control and body weight. Abstract No. 1091-P. American Diabetes Association 73rd Scientific Sessions, Chicago, Illinois, USA, 21st-25th June 2013.

 

Vickers et al. 2008. Effect of rimonabant on body weight, glucose tolerance, body composition and lipolysis in fa/fa Zucker rats: A comparison with pair-fed controls. Program No. 584.18. Society for Neuroscience Meeting, Washington, DC, 15th-19th November 2008. 

 

Manuscripts

 

Jones et al. 2014. Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats. Eur J Pharmacol 729: 59-66. [PubMed]

 

Moser et al. 2014. Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice. Phytomedicine  21: 1382-1389. [PubMed]