DYSREGULATION OF GLUCOSE HOMEOSTATIS IN AGING

DESCRIPTION (Adapted from the Applicant's Abstract): Impaired glucose metabolism and increased visceral/abdominal fat are common phenomena in aging. Impaired glucose metabolism is characterized mainly by increased glucose and insulin levels, and a higher prevalence of diabetes mellitus. Such dysregulation may be associated with impairments in insulin action on the muscle and liver, and a decreased ability to secrete insulin by the beta-cells of the pancreas. An increase in visceral/abdominal fat, more so than a general increase in fat mass, is a specific risk factor for a variety of conditions such as hyperlipidemia and diabetes, resulting in increased cardio-vascular mortality with aging. The investigators have previously characterized aging animal models that exhibit some of the metabolic features of human aging, and demonstrated the major role that age-related changes in body composition have on the impairment in hepatic and peripheral insulin action. Interestingly, longevity is increased in caloric restricted animal models, supporting the notion that fat mass has deleterious effects leading to mortality. They hypothesize that the typical increase in visceral/abdominal fat determines the impairment in glucose metabolism seen in aging. They will test this hypothesis by preventing the increase in visceral/abdominal fat in rodents, and studying whether the age-related impairments in peripheral and hepatic insulin action, and in insulin secretion are thereby averted. Furthermore, they will determine the molecular physiology by which visceral/abdominal fat exerts its effects on glucose metabolism in aging. In these studies animals will be either ad libidum fed or subjected to chronic interventions by caloric restriction and by beta3-adrenoreceptor agonists, resulting in a spectrum of visceral/abdominal fat weights. The effect of the changes induced in body composition on peripheral and hepatic glucose metabolism, and insulin secretion will be determined in vivo. Muscle, liver and pancreatic tissue will be analyzed to determine the relevant substrates, enzyme activities, and gene expressions after acute manipulations in aging rats.