Doubling down on diabetes

Not everyone who is overweight develops adult-onset diabetes. The Winers believe they know why.

Identical twins Daniel and Shawn Winer first started working together as babies, appearing in commercials for products like Wet Ones and Spic and Span. (Identical twins make the best baby actors, Shawn says, because “if one cries, you can swap the other one in.”) Now they’re both medical doctors based at the Toronto General Hospital, and colleagues still mix them up today. “We’ll play tricks on people sometimes. It’s fun,” Dr. Shawn Winer says. “The only time it gets annoying is I do get called Daniel. It’s happened so often, I’ll just answer to it.” Dr. Daniel Winer calls himself and Shawn “big science geeks.”

Two high-achieving identical twins like the Winer brothers are unusual enough, but what’s even more remarkable is the actual work they’re doing. For a few years now, they’ve been collaborating on a big question: Why do so many overweight people develop type 2 diabetes? (Type 2, which tends to appear in adulthood, represents 90 per cent of all cases.) With obesity rates skyrocketing, diabetes is now one of the most common chronic conditions in Canada, and leads to everything from kidney problems and blindness to heart disease. About 3.7 million Canadians are living with all types of diabetes, but the Winers’ work could very well change our understanding of the condition—and maybe one day pave the way for a vaccine.

As a person gains extra weight, “their tissues stop responding as well to insulin, the hormone that keeps blood sugars in check,” Daniel says. To compensate for insulin resistance, the pancreas starts pumping out more insulin, but it eventually can’t make enough, burning out the system. The end result is type 2 diabetes. (In type 1 diabetes, which is more typically diagnosed in kids, the body’s immune system attacks and kills insulin-producing cells in the pancreas.) “We know obesity contributes to insulin resistance,” Daniel says, “but we don’t know how or why.” He and his brother are exploring an entirely new theory that suggests type 2 diabetes might not only be a metabolic disease, but something closer to type 1.

In 2007, when both were doing post-doctoral research—Dan at Stanford University in Palo Alto, Calif., and Shawn (who also holds a Ph.D.) at the Hospital for Sick Children in Toronto—they’d chat on the phone, “brainstorming ideas,” Dan says. “It helped keep us close.” Shawn’s research focused on autoimmune diseases like type 1 diabetes, and they both thought it might be worth taking a closer look at type 2, which isn’t classified the same way. Even so, obesity seems to cause a state of chronic inflammation in the body, suggesting the immune system is mounting some kind of response. Previous studies have shown how, as fat builds up, the blood supply that feeds it eventually can’t keep up, and some fat cells start dying off. This triggers the immune system to clean up the dead cells—and in the process, the Winers’ latest work suggests, it also seems to build antibodies that attack the body’s own tissues.

In their new study, published in April, the Winers’ team—with Dr. Edgar Engleman, Dan’s former post-doc supervisor at Stanford—fed lab mice a high-fat, high-calorie diet. Some of these mice were genetically engineered so they couldn’t produce “B cells,” the white blood cells that make antibodies to fight infection. Remarkably, even though these mice got fatter, they never became insulin resistant or diabetic. This followed a 2009 study by the team, which showed that blocking an immune response in inflammation (this one from so-called “T cells”) prevented a group of lab mice from developing diabetes.

In the April study, the team also looked at a group of 32 overweight people, all with different levels of insulin sensitivity. They found that those with insulin resistance made antibodies to attack their own tissues, while those who were just as overweight­—but not insulin resistant—didn’t make the same antibodies. In fact, a small number of obese people never do develop type 2 diabetes or insulin resistance; for some reason, it seems, their immune system doesn’t react in the same way.

“We are in the process of redefining one of the most common diseases as an autoimmune disease, rather than a purely metabolic disease,” Daniel Winer said as he announced their latest results. Engleman added that their work will “change the way people think about obesity, and will likely impact medicine for years to come.” That doesn’t seem to be an exaggeration: redefining type 2 diabetes as not only a metabolic disease, but one with an autoimmune component, could have massive implications for the way it’s treated.

Today, nearly all type 2 diabetes drugs “treat the consequences, but not the causes, of the disease,” Daniel says. Their work suggests that drugs to modify the immune system could be helpful. They looked at one in particular, called anti-CD20, which is used to treat autoimmune diseases like rheumatoid arthritis (when the body’s immune system attacks the joints). When this drug was given to mice prone to developing type 2 diabetes, their blood sugar levels went back to normal. It sounds promising, but it’s unlikely that strong immune-suppressing drugs like anti-CD20 will ever be used to treat diabetes, since they have serious side effects, Daniel says. Even so, their work raises the hope that one day—if researchers can pinpoint certain protective antibodies—someone could make a vaccine. Daniel thinks it will happen in the future: “I strongly believe that there will be a vaccine to prevent the development of insulin resistance,” he says. Until then, he adds, it’s best to stick with diet and exercise.

At 35 years old (Shawn is two minutes older), the Winers are still relatively early into their careers, and it’s impossible to predict what they’ve yet to find. Engleman, who calls them both “real characters,” expects big things: “Much of their career lies ahead of them, and it’ll be interesting to see what unfolds.” The Winers are now setting up a lab at the Toronto General Hospital, where they’ll continue to collaborate closely on their research. “We’re going to work together, pretty much forever,” Dan says. And they’re not quite so identical anymore, he adds, because Shawn just cut his hair.




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