Mitochondrial Uncoupling Coordinated With PDH Activation Safely Ameliorates Hyperglycemia via Promoting Glucose Oxidation
- 30 August 2019
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 68 (12), 2197-2209
- https://doi.org/10.2337/db19-0589
Abstract
Uncoupling of mitochondrial respiration by chemical uncouplers has proven effective in ameliorating obesity, insulin resistance, and hyperglycemia. However, development of uncoupler-based therapy remains challenging due to its potentially lethal adverse effects. Here, we identify pyruvate dehydrogenase (PDH) as a key modifier of the toxicity profile of 2, 4-dinitrophenol (DNP), a prototypical mitochondrial uncoupler. PDH activation by dichloroacetic acid (DCA) protects mice from DNP-induced hyperlactacidemia, hyperthermia, and death while preserving the ability of DNP to promote fuel oxidation and improve insulin sensitivity in mice. Mechanistically, PDH activation switches on mitochondrial glucose oxidation to accommodate increased glycolytic flux, leading to reduced lactate secretion during uncoupler treatments. We devised a chemical screening strategy and discovered compound 6j as a dual-action compound that simultaneously activates PDH and uncouples mitochondrial respiration. Compound 6j exhibits an excellent efficacy and safety profile in restoring glucose homeostasis in diabetic mice. This work establishes a new principle to safely harness the power of chemical uncouplers for the treatment of metabolic disease.Keywords
Funding Information
- National Natural Science Foundation of China (81125023 and 81673493)
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