Type 1 and type 2 diabetes are generally thought of as different diseases with separate causes converging on a single life-threatening failure to control blood glucose levels. In an emerging story, recent evidence shows the two pathologies may have more overlapping aspects than previously realized. This may mean some treatments for one disease could work on the other and lead to better therapies for both.
In type 1, formerly known as juvenile diabetes, the body’s immune system attacks and gradually destroys the insulin-making beta cells located within pancreatic islets. In type 2 diabetes, once called adult-onset, the beta cells ultimately collapse from working hard to overcome increasingly insulin-resistant fat, muscle, and other tissues.
In a new twist, researchers seeking better ways to slow down or reverse type 1 diabetes also may have to contend with insulin resistance, a problem usually associated with type 2 diabetes, suggests a paper from HMS researchers in the Aug. 7 Proceedings of the National Academy of Sciences.
“To cure type 1 diabetes, it will not be enough to halt the destructive T cell–dependent autoimmune attack on islets,” said Terry Strom, senior author of the study. “We think, in addition, it will be necessary to restore proper insulin signaling, and the means to do that is to eliminate the curious inflammatory state in muscle, fat, and other insulin-sensitive tissues.” Strom directs the Transplant Research Center at Beth Israel Deaconess Medical Center and is an HMS professor of medicine and surgery.
“This is an important step in understanding the pathologies of the diseases,” said Marc Donath, professor of endocrinology and diabetes at University Hospital Zurich. Donath has found evidence of type 1–style beta cell destruction in type 2 diabetes in some people and mice. “And there is more overlap between type 1 and type 2 than believed until now. The current classifications are becoming less useful clinically. Diabetes is a multi-factorial disease. In some cases, there may be a little more of that. In others, there may be a little more of this.”
In their study, the researchers concocted a three-drug cocktail designed to eliminate the autoimmune-activated T cells that destroy the islets in mice with type 1 diabetes. The formula translates recent scientific advances into an experimental treatment. Down the hall, for example, Xian “Sean” Li, HMS associate professor of medicine, had discovered that activated effector T cells, the nemesis of beta cells and diabetes researchers, can be driven to suicide by a growth factor, interleukin-2. IL-2 first stimulates the growth and then kills the T cells. (In a bonus, it nurtures tissue-protective T cells.)
This “power mix,” as the BID team calls it, contains an IL-2 agonist to promote suicide of autoimmune effector T cells while strengthening the cadre of protective T cells. The second component in the regimen is a mutated form of interleukin-15, a protective factor that would otherwise save the effector cells from death by IL-2. To both molecules, the researchers added a piece of antibody that extends their longevity in the mice from minutes to days. Topping off the mix is rapamycin, a conventional immunosuppressant that blocks T cell proliferation at a step that does not compromise the ability of IL-2 to promote suicide of tissue-destructive T cells.
The researchers injected the cocktail over four or two weeks into mice with newly established type 1 diabetes. At that stage of disease in people and in mice, about three quarters of the beta cells have been destroyed. Yet, a month after treatment stopped, 55 of the 60 mice boasted normal blood sugar without added insulin. By then, most of the afflicted control animals on insulin but not power mix had died. The benefits lasted through the follow-up year, or more than half the mice’s lives, according to lead author Maria Koulmanda.
In the first analyses, the protocol seemed to work by the expected molecular mechanisms. It reset the immune system to tolerate, not obliterate, the remaining beta cells. To test the tolerance, Koulmanda destroyed the remaining beta cells about six months after treatment. She replaced them with islet cells from non-diabetic mice in the same nonobese diabetic (NOD) strain. In other treated mice, she transplanted islet cells from a different mouse strain. Normally, transplants within the same strain are rejected only by autoimmunity, and transplants between strains are rejected by the normal immune function.
“Islets from the foreign strain were rejected, but there was no destruction of transplanted beta cells from the same strain,” said Koulmanda, director of nonhuman primate research in the BID Transplant Research Center and an HMS assistant professor of surgery. That means “we don’t have a blanket immunodeficiency because the mice are capable of rejecting an allograft.”
Scientists have long tried to induce tolerance in the NOD mouse after disease has set in. The researchers achieved this milestone and found more interesting results lurking in their data.
The source of the normal blood sugar levels had stumped the scientists. “In my own fantasy life, I thought the [five- to seven-week] period between treatment cessation and disease remission was required for the healing of the damaged islets,” Strom said. But only 25 percent of the islet cell mass remained in the recovered mice, according to an analysis in the lab of co-author Susan Bonner-Weir, HMS associate professor of medicine at Joslin Diabetes Center.
They were at a loss to explain how normal blood sugar levels were restored without regeneration of the islet beta cells. The study started four years ago. In the meantime, last year, Stanford University immunology researchers reported insulin resistance–gene expression in NOD mice. Using an insulin tolerance test akin to the human test, Koulmanda also found insulin resistance in NOD mice with new disease, but not in mice treated with the triple therapy.
Blinded follow-up testing in the BID lab of Jeffrey Flier, the George C. Reisman professor of medicine and now dean of the HMS Faculty of Medicine, showed faulty insulin signaling in resistant untreated mice. The triple therapy regimen corrected a subtle form of inflammation also found in type 2 diabetes. The inflammation renders insulin unable to trigger phosphorylation of the insulin receptor and other downstream molecules.
“This is a key step in identifying the importance of insulin resistance in type 1 diabetes,” Koulmanda said. “With this study, we’re showing for the first time you can change insulin resistance to insulin sensitivity in type 1 diabetes. The remnant beta cell mass becomes sufficient to maintain euglycemia. Perhaps the same situation pertains to people.”
Strom speculatively credits the mutant interleukin-15 for the unanticipated effect on insulin resistance. It turns out that IL-15 stimulates the outpouring of pro-inflammatory cytokines from monocytes and macrophages, which are emerging as important players in the type 2 diabetes inflammatory crosstalk.
Strom and Koulmanda are interested not only in the role of inflammation in creating insulin resistance but in the possibility of remodeling inflammatory conditions within islets as a means of creating T cell tolerance. Many promising T cell therapies may have failed to reverse type 1 diabetes because they did not address problems in the broader inflammatory milieu.
In an unpublished follow-up study targeting only the inflammation and ignoring the T cells, the researchers found equally promising outcomes in diabetic mice. Even better, the test drug has been used in people for other conditions for nearly a decade. The power mix, on the other hand, contains an immunosuppressive agent with known severe side effects and two other molecules whose toxicity in people is unknown. Both studies have conditional approvals for safety and efficacy trials in adults with new onset type 1 diabetes through the Immune Tolerance Network, funded by the Juvenile Diabetes Foundation and National Institutes of Health.
No one knows what, if any, role that insulin resistance plays in human type 1 diabetes, but evidence is mounting for its importance as a therapeutic target. “We have neglected the aspect of insulin resistance in type 1 diabetes,” said Kristina Rother, a pediatric endocrinologist at the National Institute of Diabetes and Digestive and Kidney Diseases. “Reducing insulin resistance in type 1 diabetes may not lead to an immediate cure, but it will enhance treatment.”
