An insulin-resistant hypertriglyceridaemic normotensive obese dog model: assessment of insulin resistance by the euglycaemic hyperinsulinaemic clamp in combination with the stable isotope technique

Many studies have shown that in humans insulin resistance (IR) is associated with obesity and hypertriglyceridaemia. The aim of our study was to develop slowly dietary-induced obesity in dogs through long-term overfeeding of a high-fat diet, and to characterize this IR, hypertriglyceridaemic and normotensive model. Insulin resistance was assessed by the euglycaemic hyperinsulinaemic clamp technique. The contribution of hepatic glucose production during the clamp was evaluated using a constant stable-isotope-labelled glucose infusion. Overfeeding a high-fat diet for 7 months was associated with a 43 +/- 5% body weight increase. Insulin resistance was characterized by hyperinsulinaemia in the unfed state (10 +/- 1 vs. 24 +/- 1 muU/ml, in healthy and obese dogs, respectively, p < 0.02) and by a reduction of the insulin-mediated glucose uptake (28 +/- 3 vs. 16 +/- 1 mg/kg/min, p < 0.02). Hepatic glucose production suppression under insulin infusion allowed to conclude that this reduced glucose uptake resulted from a decrease of insulin sensitivity in obese dogs. Furthermore, animals remained normotensive and exhibited a marked hypertriglyceridaemia (0.26 +/- 0.04 vs. 0.76 +/- 0.15 mmol/l, in healthy and obese dogs, respectively, p < 0.02). Because hypertriglyceridaemia is the most common lipid abnormality in insulin-resistant humans, this dog with slowly induced obesity may constitute a good model to study the consequences of IR in lipid metabolism independently of vascular changes.