Molecule Associated with Obesity may Increase Diabetes Risk

A recent study shows what may be a major risk factor for those suffering from diabetes.

According to researchers from Beth Israel Deaconess Medical Center (BIDMC), a molecule called retinol binding protein 4 (RBP4) plays a key role in the development of the disease throughout the body. Lead study author Barbara Kahn, MD, developed a large body of research which suggests that this molecule is known for the development of insulin resistance in animals. Other findings also showed parallel results in human blood samples, according to a press release: 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.

"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," said Kahn, Vice Chair of the Department of Medicine at BIDMC and George Richards Minot Professor of Medicine at Harvard Medical School, via a press release. "It seems that in the case of obesity, RBP4 is acting like a foreign pathogen and provoking the immune system."

Researchers explain that as a result, the immune cells found in fat tissue become activated and produce inflammatory signals throughout the body that are usually reserved to repair damaged or infected tissues. This chronic inflammation often leads to insulin resistance.

"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 in autoimmune diseases that result from self-antigens," explains Moraes-Vieira. 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 to turn up the immune response if pathogens evade or overcome innate immune defenses.

"The magnitude of the body's immune response is determined by the number and availability of specific receptors which are present on two types of antigen presenting cells - macrophages and dendritic cells," explains Moraes-Vieira. "These belong to the innate immune system. But when either of these antigen presenting cells is exposed to foreign invaders, they, in turn, become activated and go on to trigger the CD4 T cells of the adaptive immune system."

A series of animal experiments showed that high levels of RBP4 are similar to what might be found in obese or insulin-resistance humans as "foreign invaders" that provide the trigger for activation of antigen-presenting cells, also known as CD4T cells that 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," says Kahn.

"The idea that the effect of this particular circulating molecule on immune cells can lead to metabolic syndrome [insulin resistance with associated cardiovascular risk factors, such as hypertension and elevated levels of LDL cholesterol] suggests that we could develop drugs that would result in decreased RBP4-induced inflammation, improved insulin sensitivity and reduced risk of metabolic disease," she adds. "This is an important discovery as the prevalence of obesity and diabetes continues to dramatically increase worldwide, and actually threatens to shorten our lifespans."

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More information regarding the study can be found via the journal Cell Metabolism.