Type-2 diabetes is characterized by the gradual development of insulin resistance, which affects the ability of the body to properly metabolize glucose. It’s associated with being overweight, but it can also have a genetic component. But despite the fact that millions of people have type-2 diabetes, the root cause of the insulin resistance is not known
Today, Stanford researchers reported that type-2 diabetes is looking more and more like an autoimmune disease, rather than a strictly metabolic disorder.
“The main point of this study is trying to shift the emphasis in thinking of type 2 diabetes as a purely metabolic disease, and instead emphasize the role of the immune system in type 2,” says the study’s co-first author Daniel Winer, MD.
Commenting on the findings, Dr. David Kendall, chief scientific and medical officer for the American Diabetes Association, said, “This doesn’t change our current approach to type 2 diabetes therapy, but it’s important to understand that type 2 has multiple contributors to its onset. For some people, it may be an immune component, and if it is, we should be able to develop some better therapies.”
“People with type 2 diabetes are often blamed for bringing the disease on, but it’s a combination of genetic and physiological factors exposed to a certain environment. And, this study points out what may be another important biologic factor,” he added.
Be that as it may, these findings ‒ published online April 17 in the journal Nature Medicine ‒ will change the way people think about obesity, and will likely impact medicine for years to come as physicians begin to switch their focus to immune-modulating treatments for type-2 diabetes.
Although the causes of type 2 haven’t been clear, it’s known that the disease runs in families, suggesting a genetic component. Also, while type 2 is strongly linked to increased weight, not everyone who is overweight gets type 2 diabetes. And, that’s what got the researchers searching for another factor.
In 2009, Daniel Winer (along with his twin brother Shawn) showed that T- cells of the immune system were involved in people developing insulin resistance. They have now discovered that another immune cell, called a B-cell, also plays an important role.
Winer explained that excess weight has been linked to inflammation, which can cause the immune system to react. As visceral fat (abdominal fat) expands, it eventually runs out of room. At that point, the fat cells may become stressed and inflamed, and eventually the cells die. When that happens, immune system cells known as macrophages come to sweep up the mess.
Other immune system cells, known as T-cells and B-cells, also respond to the stressed or dying cells. But, these cells are the ones that create specific antibodies to remember a threat to the body. For example, these are the cells responsible for creating immunity when you’re exposed to a certain flu virus.
In this case, however, instead of creating antibodies against a foreign substance, immune system cells ‒especially the B cells ‒ create antibodies against fat cells. Those antibodies then start attacking the fat cells, making them insulin resistant and hindering their ability to process fatty acids. In addition to type 2 diabetes, this onslaught against the fat cells is associated with fatty liver disease, high cholesterol and high blood pressure, according to the researchers.
The researchers found that mice genetically engineered to lack B cells were protected from developing insulin resistance even when they grew obese on the high-fat diet (60 percent fat). However, injecting these mice with B cells or purified antibodies from obese, insulin-resistant mice significantly impaired their ability to metabolize glucose and caused their fasting insulin levels to increase.
Interestingly, treating the mice with a compound called anti-CD20, which targets mature B cells for destruction, kept the animals from developing insulin resistance. The human version of anti-CD20, called rituximab, is already FDA-approved to treat some blood cancers and autoimmune disorders.
The researchers also tested blood samples from 32 obese humans. Half had insulin resistance. Those who were insulin-resistant had a distinct set of antibodies compared to the antibodies found in those without insulin resistance. This, according to Winer, suggests the possibility of developing a vaccine for type 2 diabetes based on what appear to be protective antibodies in those who are obese but not insulin-resistant.
Pointing out the mice and the human volunteers were all male, Winer said it’s not clear if these findings are applicable to women. He also noted that anti-CD20 is not benign ‒ it dampens the immune system and can cause significant side effects, it’s not certain if it would ever be used for type 2 diabetes because other treatments are available.
Sources: Stanford News, HealthDay, Nature Medicine