Do obesity and physical inactivity underlie the insulin resistance of aging?

Insulin resistance (IR) is the hallmark of type 2 diabetes (T2DM) and can precede its onset for many years. Since the prevalence of T2DM is higher among older adults, it has been suggested that aging is associated with IR. While some studies support the concept of age-related IR, others support the hypothesis that IR may not be associated with aging but rather with lifestyle patterns linked with aging, such as physical inactivity and obesity. To determine the effects of older age on IR independently of physical inactivity and obesity, we compared 7 older and 7 younger normal weight sedentary volunteers matched by gender, body mass index (BMI) and physical inactivity. In normal weight sedentary subjects, i.e., after accounting for both obesity and level of chronic physical activity, aging per se was not associated with IR. To determine the effects of obesity on IR independently of age and physical inactivity, we compared 7 older normal weight sedentary subjects to 14 obese sedentary subjects matched by age, gender and physical inactivity. After accounting for both age and physical inactivity, obesity was associated with both peripheral and hepatic IR. To determine the effects of chronic exercise on IR independently of age and obesity, we compared 14 older endurance trained athletes to 7 normal weight sedentary subjects matched by age and BMI. Within subjects of similar age and body weight, and after adjusting for body fat, higher physical activity was associated with greater peripheral insulin sensitivity, but not with greater hepatic insulin sensitivity. Intramyocellular lipids (IMCL) and fatty acid metabolites such as diacylglycerols (DAG) and ceramides (Cer) may play an important role in the pathophysiology of IR. We demonstrated that intramyocellular triglycerides (IMTG) were higher but ceramide content was lower in athletes. Moreover, the distribution of DAG and ceramide species was different in athletes compared to obese sedentary subjects. In conclusion, these data indicate that IR is not associated with age per se but rather is determined by obesity and physical activity. This study further elucidates the association among intramyocellular lipid content, aging obesity, physical activity and IR