The challenges of treating diabetes are complicated; however, it is well understood that the newest strategies include focusing on reducing insulin resistance and improving the effectiveness of insulin overall. Background information in this article highlights the challenges associated with connecting the dots between obesity, which is known to be associated with hepatic insulin resistance, and the complex role of the liver in this resistance.

Corresponding author and Chief of the Department of Metabolism and Endocrinology at the University of Tsukuba Hospital, Hitoshi Shimano, MD, PhD, and colleagues have built upon their previous work in which they reported the discovery that a gene deletion yielded a protective effect on mice that were exposed to high-fat and high-sugar diets. The deletion of the single gene (Elovl6), which is responsible for coding an enzyme that produces lipids, prevented the mice from developing insulin resistance. 

“Our prior work showed that deleting the Elovl6 gene protects mice from several hallmark signs of diabetes, including insulin resistance,” said Dr. Shimano. “However, this was done by removing the gene from every cell in the mouse body. We’re now interested in understanding the role of Elovl6 in a more targeted setting, by deleting the gene specifically in liver and seeing its effect on insulin resistance in hepatic cells. This will give us a better picture of what’s happening in the liver, which will aid downstream efforts to develop targeted therapies.” 

Lead author and Professor of Medicine at the University of Tsukuba Takashi Matsuzaka, PhD, said  “We assumed that mice with a liver-targeted deletion of Elovl6 would be protected from hepatic insulin resistance.” He added, “We instead found a more nuanced effect, in that only mice that were fed a high-sugar diet were protected. The deletion had no effect on mice that were given a high-fat diet.” 

The research team concluded that the gene deletion altered the balance of lipids in the liver, specifically a group classified as ceramides that is associated with molecular signaling that establishes protective effects in the midst of high blood glucose otherwise associated with a high-sugar diet. They concluded that targeting Elovl6 could be an effective method of protecting against insulin resistance, and that additional research is necessary to delineate the underlying molecular pathways of Elov6 to aid in the development of treatments for diabetes. 

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