DYSREGULATION OF GLUCOSE HOMEOSTASIS IN AGING

In this project, we propose to continue our investigation of the biochemical and molecular mechanism(s) by which the regulation of glucose metabolism fails with aging. Such dysregulation is 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, hypertension and diabetes, resulting in increased cardio-vascular mortality with aging. We have previously characterized aging animal models that exhibit some of the metabolic features of human aging, and demonstrated a major cause/effect relationship between age-related changes in body composition and 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. Recently we discovered that the fat-derived peptide leptin regulates body fat distribution, in addition to its effect to increasing insulin action. We hypothesize that the typical increase in visceral/abdominal fat determines the impairment in glucose metabolism seen in aging. Furthermore, we suggest that aging is an "leptin resistance" state, in which leptin fails to regulate body fat distribution and to maintain insulin action. We will test this hypothesis by preventing the increase in visceral/abdominal fat in rodents by caloric restriction or surgical removal of the visceral fat. We will study whether the age-related impairments in the molecular physiology of peripheral and hepatic insulin action, and in insulin secretion are thereby averted. Furthermore, we will determine if chronic leptin administration to aging rats will fail to regulate body fat distribution and insulin action. The effect of the changes induced in body composition on glucose metabolism, will be determined in vivo, and muscle, liver and pancreatic tissue will be analyzed to determine the relevant substrates, enzyme activities, and gene expressions after acute manipulations. This proposal is significant for determining the causal role that visceral fat has on the impaired glucose metabolism in aging, and the potential cause for this phenomenon. Once mechanisms for dysregulation of glucose metabolism are identified in animal models, interventions specifically designed to alter body composition in human aging may be proposed.