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    Newswise  Obesity causes inflammation, which can in turn lead    to type 2 diabetes. What isnt well established is how    inflammation causes diabetes  or what we can do to stop it.    Researchers at University of California, San Diego School of    Medicine have discovered that the inflammatory molecule LTB4    promotes insulin resistance, a first step in developing type 2    diabetes. Whats more, the team found that genetically removing    the cell receptor that responds to LTB4, or blocking it with a    drug, improves insulin sensitivity in obese mice. The study is    published Feb. 23 by Nature Medicine.  
    This study is important because it reveals a root cause of    type 2 diabetes, said Jerrold M. Olefsky, MD, professor of    medicine, associate dean for scientific affairs and senior    author of the study. And now that we understand that LTB4 is    the inflammatory factor causing insulin resistance, we can    inhibit it to break the link between obesity and diabetes.  
    Heres whats happening in obesity, according to Olefskys    study. Extra fat, particularly in the liver, activates resident    macrophages, the immune cells living there. These macrophages    then do what theyre supposed to do when activated  release    LTB4 and other immune signaling molecules to call up an influx    of new macrophages. Then, in a positive feedback loop, the    newly arriving macrophages also get activated and release even    more LTB4 in the liver.  
    This inflammatory response would be a good thing if the body    was fighting off an infection. But when inflammation is    chronic, as is the case in obesity, all of this extra LTB4    starts activating other cells, too. Like macrophages, nearby    liver, fat and muscle cells also have LTB4 receptors on their    cell surfaces and are activated when LTB4 binds them. Now, in    obesity, those cells become inflamed as well, rendering them    resistant to insulin.  
    Once Olefsky and his team had established this mechanism in    their obese mouse models, they looked for ways to inhibit it.    First, they genetically engineered mice that lack the LBT4    receptor. When that approach dramatically improved the    metabolic health of obese mice, they also tried blocking the    receptor with a small molecule inhibitor. This particular    compound was at one time being tested in clinical trials, but    was dropped when it didnt prove all that effective in treating    its intended ailment. Olefskys team fed the prototype drug to    their mice and found that it worked just as well as genetic    deletion at preventing  and reversing  insulin resistance.  
    When we disrupted the LTB4-induced inflammation cycle either    through genetics or a drug, it had a beautiful effect  we saw    improved metabolism and insulin sensitivity in our mice,    Olefsky said. Even though they were still obese, they were in    much better shape.  
    Co-authors of this study include Pingping Li, Da Young Oh,    Gautam Bandyopadhyay, William S. Lagakos, Saswata Talukdar,    Olivia Osborn, Andrew Johnson, Heekyung Chung, Rafael Mayoral,    Michael Maris, Jachelle M Ofrecio, Sayaka Taguchi, Min Lu, all    at UC San Diego.  
    This research was funded, in part, by the National Institute of    Diabetes and Digestive and Kidney Diseases (DK033651, DK074868,    DK063491, DK09062), the Eunice Kennedy Shriver National    Institute of Child Health and Human Development, and Merck,    Inc.  
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Molecular Link between Obesity and Type 2 Diabetes Reveals Potential Therapy