Abstract #4307

Pyruvate dehydrogenase kinase knockout restores hepatic pyruvate oxidation in STZ-induced diabetic mice as revealed by hyperpolarized 13C-MRI

Gaurav Sharma¹, Alexander Funk¹, Cheng-Yang Wu¹, Xiaodong Wen¹, Nesmine Maptune¹, R. Max Wynn^2,3, Craig R. Malloy^1,3,4, A. Dean Sherry^1,4,5, David T. Chaung^2,3, and Chalermchai Khemtong^1,4

¹Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States, ²Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States, ³Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States, ⁴Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, United States, ⁵Department of Chemistry, University of Texas at Dallas, Richardson, TX, United States

Pyruvate dehydrogenase (PDH) kinase (PDK) modulates mitochondrial oxidative metabolism of carbohydrate by phosphorylating and inhibiting PDH. PDK is, therefore, an important therapeutic target for treating and managing metabolic diseases. This study evaluated real-time in-vivo metabolism of hyperpolarized ¹³C-pyruvate in PDK double knockout (DKO) and consequence of PDK knockout on STZ induced diabetes. Our results showed that STZ-induced type 1 diabetes leads to decreased oxidative pyruvate metabolism in the liver and DKO partially restores hepatic oxidation of pyruvate. The results demonstrate that hyperpolarized ¹³C-MRI could be used to evaluate efficacy and therapeutic responses of metabolic drugs targeting PDK inhibition.

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