It's by now well established that obesity is a major risk factor for diabetes. But what exactly is it about extra body fat that leads to insulin resistance and blood glucose elevation, the hallmarks of diabetes? Over the past several years, Beth Israel Deaconess Medical Center (BIDMC) endocrinologist Barbara Kahn, M.D., has developed a large body of research suggesting that a molecule called retinol binding protein 4 (RBP4) (image) plays a key role in the process. Dr. Kahn's lab was the first to show that elevated levels of RBP4 – previously known only for its role as a transport protein for Vitamin A – led to the development of insulin resistance in animal models. Additional work revealed parallel results in human blood samples: obese, insulin-resistant individuals had high RBP4 levels and lean, insulin-sensitive people had low RBP4 levels. Furthermore, people with genetic changes in RBP4 that resulted in high blood levels of the protein had an elevated risk of developing diabetes. Now, Dr. Kahn and her colleagues explain the mechanism by which RBP4 contributes to increased risk of diabetes. In a study that appears online in the March 4, 2014 issue of the journal Cell Metabolism, the investigators describe how the protein sets in motion a complex interplay between two branches of the body's immune system, leading to chronic fat tissue inflammation and, ultimately, insulin resistance. "Although the inflammatory response is a key part of our immune system and an important means of protection and tissue repair in response to infection or injury, under certain conditions of metabolic dysfunction, this response is activated even in the absence of foreign pathogens," explains Dr.Login Or Register To Read Full Story