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Insulin sensitizers treat a root cause of type 2 diabetes and have not only the potential to durably treat, but to actually prevent diabetes.Unfortunately, only three insulin sensitizers have been approved for clinical use and two have been removed from the market because of different side effects.The remaining compound, pioglitazone, has positive effects with respect to treatment of diabetes, improved cardiovascular outcomes, and reduction of cancer deaths.However, its use is limited by increases in adiposity and volume expansion, and concerns over possible connection with bladder cancer, all secondary to activation of PPAR receptors.Although the mechanism of action of these compounds, which were discovered empirically, has never been completely elucidated, it generally assumed that direct activation of the nuclear receptor PPAR is required.This hypothesis was based on studies with potent PPAR activators, such as rosiglitazone, which has been removed from the market, and from numerous research programs designed to find potent activators of this receptor.Unfortunately, these approaches have not led to a product.Our research suggests that the actual target of these compounds has been unappreciated.Using drug analog photoaffinity crosslinking, we identified a phylogenetically conserved mitochondrial protein that pinpoints the site of action to the regulation of metabolism, which can explain the insulin sensitizing pharmacology of these compounds and their ability to influence other important cell functions, including differentiation and preservation of cellular phenotype.Given this understanding, we have taken two compounds, selected for maintaining this action, while reducing the ability to bind to PPAR, into phase 2 clinical trials.The results demonstrate that these compounds can lower glucose as effectively as pioglitazone with reduced side effects associated with activation of nuclear receptors.This new understanding of the mechanism of action of insulin sensitizers provides a path forward for the development of agents that may more effectively treat, and perhaps prevent, type 2 diabetes.