Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes

Abstract

The Zucker diabetic fatty (ZDF) rat is a commonly used animal model of type 2 diabetes yet complete descriptions of insulin resistance in this model are limited. We present a full characterisation of in vivo insulin resistance in obese (fa/fa) animals compared to lean (+/?) littermates. Anaesthetised, ten-week old, obese ZDF rats and their lean littermates underwent a hyperinsulinaemic euglycaemic glucose clamp. Compared with lean littermates, obese ZDF rats required an 89% lower glucose infusion rate to maintain euglycaemia and showed a 35% decrease in peripheral glucose disposal. Insulin-stimulated glucose uptake (R_g') in obese animals was also significantly less in all skeletal muscles studied. R_g' in cardiac and white adipose tissue was not different between the two groups. Total glycogen content in skeletal and cardiac muscle was significantly less in obese animals, while total glycogen content in the liver was significantly greater than in lean littermates. Glycogen synthesis was also decreased in skeletal muscle of obese animals. Compared with lean animals, total triglyceride content was significantly greater in skeletal muscle, heart and liver of obese ZDF rats. Obese animals also showed significantly increased glucose incorporation into lipid in all of these tissues, indicating an increase in lipogenesis. Collectively, these results provide an integrated characterisation of in vivo insulin resistance in obese ZDF rats and a direct comparison with lean littermates.