32-OR: Coordination of Mitochondrial Uncoupling with Pyruvate Dehydrogenase Activation Safely Ameliorates Hyperglycemia through Preferential Glucose Oxidation

Abstract

Type 2 diabetes (T2D), which is characterized by hyperglycemia and insulin resistance, has become global epidemic. Uncoupling of mitochondria by chemical uncoupler, 2,4-dinitrophenol (DNP), is an efficient way to ameliorate hyperglycemia and insulin resistance. However, DNP use ceased in 1930s due to the systemic toxicities including hyperlactacidemia, hyperthermia and even death, which were mainly resulted from uncoupling actions induced excessive fat combustion and anaerobic glycolysis. To relieve the adverse effects derived from uncoupling activity, here we identified an effect-enhancing and toxicity-reducing way linking activation of pyruvate dehydrogenase (PDH) with DNP to T2D therapy. Activation of PDH by its classical activator, dichloroacetic acid (DCA), protected mice from DNP-derived hyperlactacidemia, hyperthermia and even death. Meanwhile, DCA combined with DNP further promoted glucose disposal in streptozotocin-induced hyperglycemic mice and enhanced insulin signaling in high-fat diet mice. Mechanistically, PDH activation corrected the excessive fatty acid oxidation and anaerobic glycolysis by DNP that was strongly associated with the adverse effects, and preferentially promoted glucose oxidation to improve hyperglycemia. Based on the beneficial effects of DNP combined with DCA, a novel compound possessing both mitochondrial uncoupling and PDH activation effects, named 6j, was identified and confirmed to promote glucose oxidation preferentially in vitro and in vivo. Therefore, our study suggested that combination of mitochondrial uncoupling and PDH activation might be a novel effective pharmacological approach for safely treating T2D. Disclosure J. Li: None. J. Li: None. Funding National Natural Science Foundation of China; Chinese Academy of Sciences; Shanghai Science and Technology Commission; K.C. Wong Education Foundation