Determination of the mechanistic targets of metformin

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PROJECT SUMMARY Diabetes affects over 30 million Americans, which represents a staggering 9.4% of the population. Diabetes causes an elevated blood glucose level. Over time, the presence of high glucose in the body results in damage to various tissues. Metformin is an FDA drug commonly used as a first line therapy for the treatment of Type 2 Diabetes. It mainly acts to make tissues more sensitive to insulin, thereby enhancing the effects of insulin produced by the pancreas to homeostatically lower blood glucose levels. Importantly, however, Metformin also prolongs lifespan and delays the onset of aging from yeast to mammals. In higher organisms, it additionally reduces the risk of cardiovascular disease and inhibits tumor growth. Astoundingly, given its clinical use in humans since 1958, the exact molecular mechanisms underlying its wide-ranging health benefits are unknown. This Catalyst project is directed towards elucidating the direct cellular protein targets of Metformin for the first time. Our encouraging preliminary data shows that we can apply cutting-edge proteomics approaches to such binding events in an unbiased way. In this project, we wish to extend this extremely promising approach to a diverse range of organisms. By identifying molecular targets of Metformin in a variety of phylogenetically different model organisms (yeast, worms, flies, mouse, and humans), we will be able to home in on proteins of crucial importance, while simultaneously screening out non-specific binders. We will mechanistically test discovered targets by loss- and gain-of-function experiments using various assays, which will be adapted as the project advances. After validation of a small number of strong candidate Metformin binding proteins, we will test these promising candidates in mammals by making transgenic mice harboring deletions in the relevant genes coding for these proteins. We anticipate that the identification of specific mechanistic Metformin targets will facilitate the development of novel therapeutics to treat diabetes and promote healthy aging. Both of these goals are closely aligned with the core missions of NIDDK, and the wider NIH.