Unraveling the pathophysiology of type 2 diabetes with a new selectively bred animal model, the Oikawa-Nagao mouse.

Type 2 diabetes (T2D) is a polygenic disease, and the development of animal models by selective breeding is crucial for understanding its etiology, pathophysiology, complications, and treatments. We recently developed a new T2D model, the Oikawa-Nagao (ON) mouse, by selectively breeding 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] on a high-fat diet. ON-DP mice are predisposed to develop diabetes and obesity after being fed a high-fat diet, compared to ON-DR mice. These phenotypes provide valuable insights into the genetic and environmental interactions for the etiology of T2D. Our studies revealed that the emergence of these phenotypes is associated with novel pathophysiological mechanisms, 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, ON-DP mice fed an atherogenic diet exhibit accelerated atherosclerosis, likely related to blood glucose fluctuations. These findings provide new perspectives on the pathogenesis of T2D and suggest potential prevention and treatment strategies. This review will present the development strategy of the ON mouse strain, representative metabolic phenotypes, and discuss the mechanisms driving these traits, and explore their relevance to human T2D and obesity.