Researchers Identify Critical Link Between Obesity and Diabetes

Researchers have found a critical link between extra body fat, insulin resistance, and elevated blood glucose, the hallmark of diabetes. The connection is a molecule called Retinol Binding Protein 4 (RBP4) which plays a key role in the development of insulin resistance.

Additional work, published in Cell Metabolism revealed that obese, insulin-resistant individuals had high RBP4 levels and lean, insulin-sensitive people had low RBP4 levels. Additionally, people with genetic changes in RBP4 that resulted in high blood levels of RBP4 had a higher risk of developing diabetes.

RBP4 creates a complex interplay between two branches of the body's immune system, leading to chronic fat tissue inflammation and, ultimately, insulin resistance.

In the case of obesity, RBP4 acts like a foreign pathogen and provokes the inflammatory response in the autoimmune system. In turn, the immune cells in the fat tissue become activated and produce inflammatory signals that the body usually reserves to repair tissue that is damaged or infected. This inflammation then creates an environment that leads to insulin resistance, a state in which the body is unable to properly respond to insulin, the hormone that transports sugar from the blood into cells to be used for energy production and fuel storage.

Sequentially, certain immune cells called CD4 T cells play a key role in the body's adaptive immune system, which regulates the immune response against foreign invaders following infection or injury, as well as autoimmune diseases. Unlike the innate immune system, which is made up of cells and proteins that are always present and ready to respond against attacking microbes, the adaptive system is normally silent and is only called to action if pathogens evade the innate immune system. When RBP4 exposes itself as a foreign invader, the innate immune system becomes activated and goes on to trigger the CD4 T cells of the adaptive immune system.

Through a series of animal experiments, the researchers discovered that high levels of RBP4 - similar to what would be found in obese or insulin-resistant humans -was the "foreign invader" that was providing the trigger for activation of the antigen-presenting cells, which then caused CD4 T cells to spring into action.

"When we took normal immune cells from normal animals, treated them with RBP4 outside the body, and then put those cells back into the normal animals, the mice became insulin resistant with widespread inflammation in fat tissue," said, Beth Israel Deaconess Medical Center (BIDMC) endocrinologist, Barbara Kahn.

High RBP4 leads to insulin resistance, as well as cardiovascular risk factors such as hypertension and elevated levels of LDL cholesterol. The results of the study suggest that scientists could develop drugs to decrease RBP4 -induced inflammation in order to improve insulin sensitivity and reduce the risk of metabolic diseases.