Dysregulation of Glucose Homeostasis in Aging

DESCRIPTION (provided by applicant): Aging is associated with an increase in the ratio of fat mass to lean body mass, changes in fat distribution, and resistance to the action of insulin. These characteristics of the metabolic syndrome of aging (MS) are associated with increased incidence of age-related diseases such as diabetes, cardio-vascular diseases, cancer, and Alzheimer's disease. In the last few years we have studied the biological and physiological dysregulation associated with changes in fat distribution and insulin action. We have proved a cause-effect relationship between visceral fat (VF) and insulin resistance, and implicated the age-dependent resistance to the fat-derived peptide leptin in these metabolic derangements of aging. In parallel to the development of 'leptin resistance', aging is also characterized by decrease in growth hormone (GH) secretion and influencing the levels of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (BP-3), and is the subject for this competitive renewal. We hypothesize that IGF-1 and BP3 have 2 direct but opposing effects on 1) body fat distribution, and 2) on insulin action. Furthermore, we hypothesize that these effects are mediated through pathways in the central nervous system (CNS). We will study young and old rats, by chronic and acute administration of IGF-1 peripherally and in to the third ventricle (ICV). We will bock IGF-1 and insulin receptors and block some of the IGF-1/insulin signaling pathways in order to identify the down stream pathway for IGF-1 action in the CNS. Similarly, we will administer acutely and chronically BP3 peripherally and ICV, as well as a BP3 mutant that lacks the active site of BP3. From the studies with chronic administration IGF-1 (SA1) and BP3 (SA2) we will learn their opposing effects on body fat distribution, muscle mass, energy expenditure, and the biological characteristics of fat depots (by gene array technology and RT-PCR). From the acute study, we will determine the opposing effects of IGF-1 (SA3) and BP3 (SA4) on peripheral and hepatic insulin action (by clamp technology). Because GH administration has unwarranted side effects in aging subjects, a better understanding of the age-dependent changes due to decline in the GH/IGF-1/BP3 axis is likely to lead to better strategies to prevent and/or reverse this constellation of metabolic defects early during the aging process.