Is Type 2 Diabetes an Autoimmune Disease?

Sunday, July 17, 2016
Xavier Revelo in lab
Postdoctoral fellow Xavier Revelo in the lab

Researchers in the Department of Laboratory Medicine and Pathobiology recently discovered an immune mechanism that links obesity with insulin resistance, a condition that raises the risk of heart disease and often leads to type 2 diabetes.

The results, published last month by the journal Cell Reports, add to growing evidence that type 2 diabetes has an autoimmune component (in which the immune system attacks parts of healthy cells).

The lead author on the study was Xavier Revelo, a postdoctoral fellow based at University Health Network in the lab of Professor Daniel Winer. Revelo spoke with Faculty of Medicine writer Jim Oldfield about his research and what it means for the understanding and treatment of insulin resistance and diabetes.

What did you find in this study?

We investigated the role of a mechanism that releases extracellular traps, which are structures composed of nucleic acids that immune cells use to prevent infection. We found that in obese mice, an excess release of nucleic-acid material promotes inflammation in visceral adipose tissue and the liver. That leads to insulin resistance and the buildup of glucose in the blood, which precedes the development of type 2 diabetes. We describe the different players that take part in nucleic acid-targeting pathways and show that blocking those pathways can prevent metabolic disease in our mouse model of obesity.

Is type 2 diabetes an autoimmune disease?

Well, right now there isn't enough evidence to include or dismiss type 2 diabetes as a classic autoimmune disease. However, this study and others have shown that obesity-related insulin resistance has several hallmarks that are typical of autoimmune diseases. For example, we found that diet-induced obesity led to an increased adaptive immune response against nucleic acid-related antigens locally in the adipose tissue. It also resulted in the appearance of autoantibodies (immune proteins that target healthy tissue) in the circulation. Interestingly, the immune mechanism that involves the release of extracellular traps was discovered in 2004, and it has since been implicated in traditional autoimmune diseases such as systemic lupus, type 1 diabetes and psoriasis. Ours is the first report of the same mechanism playing a role in obesity-related insulin resistance.

How were you able to use these discoveries to prevent the development of insulin resistance?

We used commonly available compounds to inhibit or block some of the nucleic-acid targeting pathways in mice. For example, we treated mice with a chemical compound that prevents the formation of extracellular traps, and we found this treatment reduced inflammation and improved blood sugar levels in obese mice. Likewise, we treated mice with chemicals that prevent proteins called toll-like receptors from recognizing nucleic acids, which also improved inflammation and metabolic health. Although this is only proof-of-principle data and we need more research on these interventions in obesity-related insulin resistance, the results provide exciting new targets for the treatment and prevention of disease.

What was the most challenging part of this work?

We faced some difficulties with the microscopy analysis to quantify the extracellular traps, especially in immune cells purified from adipose tissue. These structures are very fragile, so it was challenging to isolate and extract the cells while keeping the traps intact for analysis under the microscope. But we used a protocol that requires minimal interference while the cells are releasing these fragile structures, and ultimately we were successful with the technique.

Should we be more focused on lifestyle than drugs to combat obesity?

It's absolutely important to maintain a healthy lifestyle, including increased physical activity and decreased caloric intake, to combat obesity and its related complications. However, therapeutic interventions are options for patients if lifestyle changes are not sufficient. The reality is that obesity is a serious problem worldwide. For example, about half of Canadian adults are overweight or obese. More alarmingly, the figure is higher in the U.S. and in many other countries the incidence of obesity rising. It's very concerning, especially because our efforts to fight this epidemic using conventional approaches don't seem to be working. So together with lifestyle changes, I think we need novel therapies and medicines if we really want to win this fight.