Type 2 Diabetes (T2D) has reached epidemic proportions in the United States. There are currently 18 million patients in North America and the National Institute of Diabetes and Digestive Kidney Disease (NIDDK) estimates that approximately 800,000 new cases of diabetes are diagnosed each year in the U.S. alone. In 2002 the direct costs of T2D were estimated to be $92 billion (up from $44 billion in 1997), constituting roughly 19% of the total health care expenditure of the U.S. The purpose of this study is to develop caloric-restriction mimetics for the treatment of type 2 diabetes. OBJECTIVES: Based on the high prevalence and extraordinary growth of T2D and obesity in the U.S., interventions which can treat both of these conditions would be a tremendous asset to the nation. An understanding that these conditions are inter-related facets of Metabolic Syndrome, coupled with recent data suggesting that activation of SIRT1 can benefit these disorders in a manner similar to CR, makes such an intervention appear within reach. This Phase I study is comprised of two Aims which together will examine the scientific and technical feasibility of using plant polyphenol, SIRT1 activators (and related analogs) as therapeutics for T2D and obesity. Although SIRT1 activators show efficacy against insulin resistance and obesity in cell culture models, it is essential to examine these parameters in whole animal models. As stated above T2D and obesity are favorable conditions to examine in animals, as proof of principal may be readily shown in a short time period, using relatively few animals. This Phase I study will therefore attempt to identify molecules with improved drug-like characteristics, and test them against a number of parameters, in a small group of rats. Phase II studies will (i) use the knowledge generated from substructure/similarity searches and basic SAR analyses in Aim I to perform medicinal chemistry and high-throughput screening of focused libraries for novel activators, (ii) initiate in vivo ADME studies on all candidates of interest and (iii) use the results of the pilot animal study in Aim 2 to design comprehensive pre-clinical animal studies to test the ability of the most promising lead compounds against T2D and obesity. If successful, these studies will lead to development of a compound that can enter the clinic as a first-in-class drug candidate for the treatment of metabolic diseases including, but perhaps not limited to, T2D and obesity. Based on current and projected data from the CDC and elsewhere concerning these conditions, as well as on the emerging data from CR primates, the health-related and economic benefits of such a drug would be tremendous. In addition, this work will; (i) provide important new information concerning the effects of several classes of small dietary molecules and foods on key cellular processes, (ii) expand our understanding of the effects and benefits of low caloric diets and (iii) expand our understanding of how the various aspects of Metabolic Syndrome are inter-related at the cellular and molecular levels. While the cost incurred developing any drug candidate is high, it becomes relatively minor in light of the direct and indirect costs associated with T2D alone ($132 billion in U.S. in 2002). APPROACH: The overall goal of the experiments described in this proposal is to examine the technical feasibility of, and lay the groundwork for the development of CR-mimetic therapeutics to treat T2D and obesity. The goal of Aim 1 is to identify SIRT1-activators with the most favorable drug-like properties. The benefit of this will be two-fold. First, this will allow us to use the most appropriate molecules for the proof of concept (POC) animal studies in Aim 2. Second, these studies will allow preliminary structure activity relationship (SAR) analyses that will be utilized and expounded upon by medicinal chemistry and focused screening in Phase II. Aim 2 of this proposal will determine whether small molecule SIRT1 activators can positively influence the underlying causes of Metabolic Syndrome in animals. If successful endpoints are achieved, these experiments will form the basis for more comprehensive animal studies, using novel activators generated in Phase II, and testing a broader array of physiologic effects. In sum, this Phase I study will answer the questions: Can we identify polyphenols or novel analogs with improved pharmacokinetic properties? Can these molecules recapitulate the beneficial effects observed by SIRT1 activation in cells? Do SIRT activators have the potential to serve as a novel class of therapeutic for treating various aspects of Metabolic Syndrome?
