Type 2 diabetes is in the process of being redefined as an autoimmune disease rather than just a metabolic disorder, said an author of a new study published in Nature Medicine this week, the findings of which may lead to new diabetes treatments that target the immune system instead of trying to control blood sugar.
As part of the study the researchers showed that an antibody called anti-CD20, which targets and eliminates mature B cells in the immune system, stopped diabetes type 2 developing in lab mice prone to develop the disease, and restored their blood sugar level to normal.
Anti-CD20, available in the US under the trade names Rituxan and MabThera, is already approved as a treatment for some autoimmune diseases and blood cancers in humans, but more research is needed to see if it will work against diabetes in humans.
The researchers believe that insulin resistance, the hallmark of type 2 diabetes (unlike type 1 diabetes where it is the insulin-producing cells that are destroyed), is the result of B cells and other immune cells attacking the body’s own tissues.
Co-first author Daniel Winer, now an endocrine pathologist at the University Health Network of the University of Toronto in Ontario, Canada, started working on the study as a postdoctoral scholar at Stanford University School of Medicine in California, USA. He told the press that:
“We are in the process of redefining one of the most common diseases in America as an autoimmune disease, rather than a purely metabolic disease.”
“This work 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,” he added.
The discovery brings type 2 diabetes, until now considered to be more of a metabolic disease, closer to type 1 diabetes, where the immune systems attacks and destroys the insulin-producing cells in the pancreas.
Type 2 diabetes occurs when the tissues of the body gradually become more and more resistant to insulin, the hormone that mops up dietary glucose and transports it to cells to convert into energy.
We don’t know what causes the tissues to become resistant to insulin in type 2 diabetes, but we know it is linked to obesity and often runs in families.
Co-first authors of the study along with Daniel Winer are his twin brother Shawn Winer, of the Hospital for Sick Children at the University of Toronto, and Stanford research associate Lei Shen. The senior author is Stanford pathology professor Edgar Engleman who is also director of Stanford’s Blood Center.
A few years ago, Daniel and Shawn Winer started thinking that immune cells, including T cells (involved mostly in cell-mediated immune responses) and B cells (involved mostly in antibody responses), can cause inflammation in the fatty tissue that surrounds and protects internal organs.
Feeding mice a high-fat, high-calorie diet leads to this type of inflammation, as a result of fat cells growing faster than the blood supply (a similar thing happens in humans with type 2 diabetes). So the fat cells begin to die off, spilling out their contents, which the immune system clean-up cells, the macrophages, come along and mop up.
“This immune reaction causes havoc in the fatty tissue.”
By studying the reaction more closely, the researchers found it involves not only the macrophages, but also the T cells and the B cells, which gradually inhibit the ability of the remaining fat cells to respond to insulin, causing fatty acids to seep into the blood.
Too high a level of fatty acids in the blood leads to fatty liver disease, high cholesterol, high blood pressure and even more insulin resistance in the body.
To test their ideas at the time (a 2009 paper also in Nature Medicine with Shawn Winer as first author describes this early work) the researchers fed lab mice on a high-fat, high-calorie diet, so that within a few weeks they began to grow obese and their blood sugar began to rise. But when the researchers blocked the action of the T cells, the cells in the immune system that trigger responses inside the cells in tissue, the mice did not go on to develop diabetes.
So they started investigating B cells, the cells that work by stimulating T cells and by producing antibodies. They were interested in B cells because the antibodies they make not only protect the body from infection, but can also cause disease.
For this part of their work they genetically engineered mice to lack B cells, then put them on the high-fat, high-calorie diet and found they did not go on to develop insulin resistance. But when they injected these same mice with B cells or antibodies from obese, insulin-resistant mice, their ability to metabolize glucose diminished and their fasting levels of insulin went up.
To see if such an effect occurs in humans, the researchers then studied 32 overweight people, matched for age and weight, and differing only in their sensitivity to insulin.
They found that those with insulin resistance were making antibodies against some of their own proteins, wheras the ones who were not insulin resistant did not have those antibodies.
Daniel Winer said this was “highly suggestive” that the development of insulin resistance in humans involves the body targeting its own proteins.
“It really links the concept of insulin resistance to autoimmunity,” he explained.
Winer thinks that it may be possible one day to develop vaccines against type 2 diabetes, ones that trigger protective rather than harmful immune responses, “if we could identify a panel of antibodies that might protect against developing insulin resistance,” he conjectured.
In a final step of the study, the researchers tested the effect of a mouse counterpart to the FDA-approved anti-CD20 antibody Rituximab in mice fed on the high-fat, high-calorie diet for 6 weeks. They showed that the anti-CD20 latched onto mature B cells and targeted them for destruction.
However, the anti-CD20 did not stop new B cells being made: after an initial period of treatment, the mice improved their ability to metabolize glucose and their fasting levels of insulin went up, but after a while, such as in one treatment that lasted 40 days, they began to develop insulin resistance again as new batches of B cells were generated.
The researchers cautioned against jumping to conclusions that Rituximab will work in the same way in humans, especially if their type 2 diabetes is already established.
Engleman said even though their findings “strongly suggest that immune modulation should be considered as a potential human therapy”, until we can prove these effects in humans and successfully test therapies in clinical trials, “diet and exercise are still the best ways to prevent type-2 diabetes in humans”.
Funds for the research came from National Institutes of Health. Daniel and Shawn Winer, the Stanford University and The Hospital for Sick Children in Toronto, have filed joint patent applications in connection with the use of B cells and other agents as described in the studies.
“B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.”
Daniel A Winer, Shawn Winer, Lei Shen, Persis P Wadia, Jason Yantha, Geoffrey Paltser, Hubert Tsui, Ping Wu, Matthew G Davidson, Michael N Alonso, Hwei X Leong, Alec Glassford, Maria Caimol, Justin A Kenkel, Thomas F Tedder, Tracey McLaughlin, David B Miklos, H-Michael Dosch & Edgar G Engleman.
Source: Stanford School of Medicine (press release 17 Apr 2011).
Written by: Catharine Paddock, PhD