The Oikawa-Nagao Mouse: A Polygenic Animal Model for Unraveling the Pathophysiology of Type 2 Diabetes and Obesity

The Oikawa-Nagao (ON) mouse is a polygenic animal model of type 2 diabetes and obesity developed by selective breeding of mice with inferior glucose tolerance [diabetes-prone (ON mouse DP^®; ON-DP) strain] and superior glucose tolerance [diabetes-resistant (ON mouse DR^®; ON-DR) strain]. Hybrid mice of three different inbred strains (C57BL/6, AKR, and AKR) were fed a high-fat diet and then selectively bred for higher and lower post-challenge blood glucose levels in oral glucose tolerance tests over 20 generations. Compared to ON-DR mice, ON-DP mice were found to be predisposed to develop obesity and diabetes after being fed a high-fat diet. Our recent studies suggest that the emergence of these phenotypes is associated with novel pathophysiology of type 2 diabetes and obesity, such as low insulin secretion capacity associated with high CD36 expression in pancreatic β-cells and hypoleptinemia preceding obesity due to low leptin secretion capacity in adipocytes. In addition, it has been suggested that ON-DP mice fed an atherogenic diet are a suitable model to reproduce atherosclerotic lesion formation due to fluctuations in blood glucose levels. This may facilitate the elucidation of mechanisms underlying diabetic macrovascular complications. This review will present the development strategy of the ON mouse strain, representative metabolic phenotypes and their underlying mechanisms. Furthermore, their relevance to the pathophysiology of type 2 diabetes and obesity in humans will be discussed.