The University of California San Diego School of Medicine has clarified the inflammation pathway leading up to type 2 diabetes, thus uncovering the root cause. Inflammation is triggered by obesity which activates an inflammatory molecule called LTB4. The molecule promotes insulin resistance.
The scientists used a mouse model to investigate the inflammation pathway. Genetically removing the cell receptor that responds to LTB4 or blocking it with a drug improved and reversed insulin sensitivity in obese mice. Obesity causes extra fat deposits in the liver, which mobilizes immune cells called macrophages. Macrophages act by releasing LBT4 and other immune signaling molecules which again activate more macrophages who in turn release more LBT4 molecules creating a circular inflammatory chain reaction.
Chronic inflammation caused by obesity has a negative health impact on the body as the presence of extra LBT4 activates other cells who also have LBT4 receptors. These cells then become inflamed to rendering them resistant to insulin.
“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.”
“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.”
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, Jerrold M Olefsky. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nature Medicine, 2015; DOI: 10.1038/nm.3800