Insulin resistance and impaired glucose handling are becoming more prevalent as chronic conditions associated with aging. Sirtl a protein deacetylase and member of the sirtuin family of proteins has emerged as a novel target in the regulation of insulin action. Our laboratory has previously shown that the hypothalamus plays a major role in regulating glucose homeostasis. In our preliminary studies we have demonstrated that in young rodents, acute intrahypothalamic or systemic infusion of resveratrol, a Sirtl activator reduces hepatic glucose production and increases insulin sensitivity. We have also shown that central inhibition of Sirtl significantly abrogates the effect of resveratrol. These results are significant in that they are the first to show that central Sirtl has an integral role in regulating glucose homeostasis. In this proposal we hypothesize that a decline in Sirtl function with aging contributes to impaired regulation of glucose metabolism and insulin action. For the proposed studies we will first infuse resveratrol centrally into the hypothalamus or systemically in young and old F1 hybrid F-344/BN rats to determine if there is a differential effect on hepatic insulin action. Second, we will inhibit Sirtl centrally while infusing resveratrol centrally or systemically to elucidate the significance of hypothalamic Sirtl on insulin action. Third by using adeno-associated viral constructs to either overexpress or underexpress Sirtl we will evaluate how chronic alteration of the protein affects glucose homeostasis. Finally, we will also administer resveratrol orally over several weeks to determine its effects on body composition, insulin sensitivity, metabolic markers and inflammation in adipose tissue and adispose tissue macrophages in aging rats. After each treatment, the animals will undergo hyperinsulinemic-euglycemic clamp studies to assess several factors such as plasma insulin and glucose levels, hepatic glucose production, hepatic glucose fluxes and peripheral glucose uptake. Subsequently, we will carry out further analyses utilizing common techniques such as RT-PCR and western blot analysis to ascertain which transcription factors are affected by Sirtl activation. It is my goal that this study will shed new light on the role of Sirtl in aging and age-related conditions associated with insulin resistance such as type-2 DM. These studies will be instrumental in advancing my development and increasing my exposure as a researcher in aging. The NIH funded program in Aging Research at the Albert Einstein College of Medicine in which I am already a participant is well equipped to assist me in attaining mv research and career goals.
This research will be helpful in elucidating the role of Sirtl in the regulation of glucose homeostasis and insulin action in aging and the potential mechanism(s) involved. The results attained from this study will be directly applicable to the search for new therapeutic models for the management of chronic disorders such as diabetes mellitus and the metabolic syndrome. Most significantly this study will assess how Sirtl function is altered in aging and its relationship to metabolic processes.
|Knight, Colette M; Gutierrez-Juarez, Roger; Lam, Tony K T et al. (2011) Mediobasal hypothalamic SIRT1 is essential for resveratrol's effects on insulin action in rats. Diabetes 60:2691-700|