Excess energy intake, especially increased fat intake, is one of the major causes of diabetes and obesity. However, physiological free fatty acid concentrations are essential for insulin secretion, which would increase, in the short term, the secretion of glucose-responsive insulin. On the other hand, prolonged excess fat intake results in triglyceride accumulation in pancreatic beta cells, leading to decreased insulin secretion. It has been reported that fat intake contributes to obesity more than carbohydrate and protein intakes. Individuals with higher fat intakes are, therefore, more prone to obesity than those with lower fat intakes, even if total energy intakes are the same. In this project, we examine the impacts of diets with different nutrient compositions on insulin secretion, glucose tolerance, insulin resistance, and obesity in genetically modified diabetes-, insulin resistant- and obesity-model animals. In this way, our project aims to identify novel clinical applications by developing the optimal nutritional therapy, in terms of nutrient-to-energy ratio, for preventing lifestyle-related diseases.