Research finds potential cause of chronic inflammation in diabetic patients

Inflammation is one of the main reasons why people with diabetes experience heart attacks, strokes, kidney problems and other, related complications. Now, in a surprise finding, researchers at Washington University School of Medicine in St. Louis have identified a possible trigger of chronic inflammation. The study is available Nov. 2 as an advance online publication from the journal Nature.

Immune cells (shown in green) produce fatty acids that contribute
to diabetes-related inflammation. Credit: Semenkovich lab
Washington University School of Medicine

Semenkovich’s team made genetically altered mice that could not make the enzyme for fatty acid synthase (FAS) in immune cells called macrophages. Without the enzyme, it was impossible for the mice to synthesize fatty acids, a normal part of cell metabolism.

“We were surprised to find that the mice were protected from diet-induced diabetes,” said first author Xiaochao Wei, an instructor of medicine. “They did not develop the insulin resistance and diabetes that normally would have been induced by a high-fat diet.”

Through a series of experiments in the animals and in cell cultures, the researchers, including Douglas F. Covey, a professor of developmental biology and biochemistry, and Daniel S. Ory, MD, a professor of medicine and of cell biology and physiology, found that if macrophages could not synthesize fat from within, the external membranes of those cells could not respond to fat from outside the cells. That prevented the cells from contributing to inflammation.

But eliminating inflammation altogether is not the answer to preventing diabetic complications because inflammation is also vital for clearing infectious pathogens from the body and helps wounds heal. Still, Semenkovich said the new findings may have profound clinical implications.

“An inhibitor of fatty acid synthase actually is now in clinical trials as a potential cancer treatment,” he explained. “And other drugs have been developed to inhibit fatty acid synthase in diabetes, too. One possibility that our work suggests is that altering the lipid content in the cell membrane may help block cancer metastases and complications of diabetes.”

Drugs currently in use to block fatty acid synthase, as well as other developing strategies, potentially could allow for chronic inflammation to be blocked, without co
mpletely eliminating the ability of macrophages to fight infection. The researchers also plan to take a look at existing drug compounds that change the lipid composition in cells.

Citation:Wei X, Song H, Rizzo MG, Sidhu R, Covey DF, Ory DS, Semenkovich CF. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature. Nov. 2, 2016.
DOI: http://dx.doi.org/10.1038/nature20117
Adapted from press release by Washington University School of Medicine