- 期刊
Molecular Pathogenesis of Type 2 Diabetes in Knockout Mice Models
並列摘要
Type 2 diabetes is a complex disease caused by interactions of multiple genes and environmental factors such as high-fat diet and sedentary life-style. Since type 2 diabetes is characterized by insulin resistance and relative insulin deficiency, we have tried to dissect molecular pathogenesis of type 2 diabetes by generating several knockout mice models with a lack of each key molecules of signaling pathways of either insulin action or insulin secretion such as insulin receptor substrate-l (IRS-l)(l), IRS-2(2), P13 kinase(3), PPARg(4), b-cell glucokinase(5), or the NADH shuttle system(6). Moreover, in order to study gene-gene and gene-environment interactions in the development of type 2 diabetes, we have crossed these animals(7) and/or exposed them to a certain environmental factors such as high-fat diet(4). DNA chip analysis has also been used to systematically identify crucial pathways for the development of type 2 diabetes in each tissue of these animals. These efforts have begun to reveal some key aspects of molecular pathogenesis of type 2 diabetes(8). We have found that insulin resistan6e can lead to type 2 diabetes only when b cell defects exist simultaneously such as decreased insulin response to glucose(7) or impaired b cell hyperplasia(2). We have also found that PPARg plays a crucial role in the development of highfat diet-induced obesity, insulin resistance and type 2 diabetes (4). Importantly, pathways identified to have a role in the development of type 2 diabetes in these analyses can be tested as candidate susceptibility loci of human type 2 diabetes. Conversely, functional impact of human type 2 diabetes susceptibility loci can be analyzed by generating corresponding mutant mice. Finally, we have begun to apply information obtained in these analyses to develop potential tailar-made medicine to provide fundamental prevention and therapeutic strategies for type 2 diabetes.