Sedentary death syndrome (SeDS) is a major public health burden due to its causing multiple chronic diseases and millions of premature deaths each year. Despite the impact of physical inactivity, very little is known about the actual causes of physical inactivity-induced chronic diseases. It is important to study the mechanisms underlying molecular changes related to physical inactivity in order to better understand the scientific basis of individualized exercise prescription and therapies for chronic diseases, and to support improved public health efforts by providing molecular proof that physical inactivity is an actual cause of chronic diseases. Physical activity has a genetic basis. A subpopulation of genes, which have functioned to support physical activity for survival through most of humankind's existence, require daily exercise to maintain long-term health and vitality. Type 2 diabetes (T2D) is an example of a SeDS condition, as it is almost entirely preventable with physical activity. To determine the true role of physical inactivity in the development and progression of T2D, information is presented which indicates that comparisons should be made to physically active controls, rather than sedentary controls, as this population is the healthiest. Use of sedentary subjects as the control group has led to potentially misleading interpretations. If physically active individuals were designated as the control group, a different interpretation would have been drawn. It is thought that there is no difference in GLUT4 concentration between T2D and sedentary groups. However, GLUT4 expression is higher in active controls than in sedentary and T2D groups. Therefore, to obtain causal mechanisms for SeDS in order to allow for scientifically based prevention and therapy strategies, physically active subjects must serve as the control group.