Editors' ChoiceDiabetes

Short-Circuiting Mitochondria Leads to Improvement in Mouse Models of Diabetes

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Science Translational Medicine  22 Oct 2014:
Vol. 6, Issue 259, pp. 259ec179
DOI: 10.1126/scitranslmed.aaa0866

Mitochondria are the center of energy production for virtually every cell in a eukaryotic organism. Thus, it would seem counterintuitive that poisoning the ability of mitochondria to make adenosine triphosphate (ATP) could potentially improve health in a complex organism such as a mouse. Yet in a recent paper, Tao et al. show just that in a mouse model of type 2 diabetes by treating the animals with a mitochondrial decoupling agent and measuring remarkable effects on diabetes-related symptoms.

Mouse models of type 2 diabetes that develop fatty liver, insulin resistance, severe hyperglycemia, obesity, and lipid accumulation were treated with a known mitochondrial decoupling agent, niclosamide ethanolamine salt (NEN). When the compound was administered to the mice, it distributed to the liver and, to a lesser degree, kidney. The mice demonstrated several signs of mitochondrial inefficiency, such as higher energy expenditure, but seemed to avoid the side effect of elevated temperature. More importantly, they also showed improved glycemic control, even after hyperglycemia and insulin resistance were established after 4 months of eating a high-fat diet. Other markers of type 2 diabetes improved as well, including diacyl glycerol concentrations. Even the concentration of hemoglobin A1c, a marker of glycemic control used in clinical care, was reduced in treated mice by more than 2%.

Given the mechanism of action, one might guess that translating the uncoupling of mitochondria from a mouse to human treatment would be a major safety challenge. However, NEN is already a U.S. Food and Drug Administration–approved drug used to treat tapeworms, and it has a very good safety profile. The drug has a short half-life (1.5 hours), and it is unclear whether a pill form of the drug will be as effective in humans as it was in mice, which consistently ate the compound in their chow. However, with these intriguing results NEN and other mitochondrial decouplers may soon receive renewed interest.

H. Tao et al., Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat. Med. 10.1038/nm.3699 (2014). [Abstract]

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