Back to Table of Contents | August 2011
Cover Story
Paths to a Cure
Researchers are going down many roads in their quest to cure diabetes.
By Jeanne Mettner
Each day, patients with diabetes painstakingly choreograph decisions about issues that people without diabetes take for granted—what and when to eat, when and how much to exercise, how to ensure that hypoglycemia doesn’t debilitate them, especially when they sleep. Type 1 diabetes, in particular, demands a vigilance that tries even the most conscientious, compliant patient. The body’s immune system turns on its own tissues, destroying the precious beta cells housed within pancreatic islets that the body needs to produce life-saving insulin. The disease takes a huge physical and emotional toll.
The good news for people in Minnesota is that they are surrounded by researchers who are dogged in their determination to find better treatments and even a cure for the disease. The University of Minnesota’s Schulze Diabetes Institute, which was launched in 2008 with a $40 million gift from the Richard M. Schulze Family Foundation, is unabashed about its goal of finding a cure. And last October, the Minnesota Partnership for Biotechnology and Medical Genomics launched an ambitious Mayo Clinic-University of Minnesota partnership to “prevent, optimally treat, and ultimately conquer diabetes.” “If the passion to find a cure were directly related to how quickly we could discover it, we would have found it 10 years ago—right here in Minnesota,” says Elizabeth Seaquist, M.D., an endocrinologist and director of the University of Minnesota’s Center for Diabetes Research. “I am very optimistic that something very good will come out of that kind of relentless dedication.”
Here are some of the paths that Minnesota researchers are taking on their quest to minimize the impact of type 1 diabetes in patients’ lives—or eliminate the disease altogether.
Innovations in Islet Cell Transplantation
For more than 40 years, pancreas transplantation has been a treatment option for patients with type 1 diabetes. University of Minnesota surgeons performed the first pancreas transplant in 1966 and have been world leaders in the field since. Numerous clinical trials have demonstrated the procedure’s effectiveness in restoring normal glucose levels and freeing patients from insulin injections. But while the procedure generally makes recipients diabetes-free, the risk for surgical complications is relatively high, so researchers have continued looking for alternatives.
In 1974, David Sutherland, M.D., Ph.D., led a team that performed the world’s first human islet cell transplant on a patient with diabetes, using cells from a deceased donor. Although the patient was not able to stop taking insulin, the team was undeterred.
Since then, investigators in Minnesota have been working to perfect the procedure to increase the length of time that patients remain free of insulin injections and further define protocols for bringing islet cells to patients with type 1 diabetes. University of Minnesota transplant diabetologist Bernhard Hering, M.D., scientific director of the University of Minnesota’s Schulze Diabetes Institute, has led eight clinical trials of islet transplantation. The protocol changes he implemented have markedly improved short-term and long-term outcomes in such patients. Ninety percent of the patients who undergo a transplant no longer require insulin injections and can enjoy a life no longer restricted by constant fear and worry. The procedure has stood the test of time; five years after transplant, more than 50 percent of patients remain insulin-independent—and 80 percent remain protected from severe hypoglycemia. Three of the first six patients who participated in Hering’s first clinical trial at the University of Minnesota between 2000 and 2002 have remained insulin-free and diabetes-free for 10 years (and counting). The protocol he published in 2005 has been adopted by the NIH’s Clinical Islet Transplant Consortium for the ongoing Phase III licensure trial of human islet medical products.
Hering says seeing the transformed lives of patients who’ve undergone successful human islet transplants has inspired him and others to seek ways to make islet transplant a possibility for more people. “Human-to-human islet transplantation has shown proof in concept, but even if we maxed it out, really only one or two thousand patients can benefit from it annually in the United States,” he explains. “To amplify access to islet cell transplant and make it accessible to many more populations, we need to develop an unlimited supply of insulin-producing cells for transplantation.”
Hering’s solution: using islet cells from pigs, the animals that supplied us with therapeutic insulin for six decades, before human recombinant insulin could be readily manufactured. Toward the end of the 1990s, Hering demonstrated that islet cells harvested from pig pancreases could reverse type 1 diabetes in mice. By February 2006, Hering showed that the therapy could yield long-term success in monkeys. “At that point, we realized that pig islets could most likely offer a new therapy with very profound implications for humans,” he says. “We started to build momentum.” Soon after, Hering helped create the Spring Point Project, a nonprofit that operates a 21,000-square-foot biosecure facility in western Wisconsin, where it is raising a population of medical-grade pigs.
Hering says University of Minnesota researchers are “getting close” to doing human clinical trials using transplanted pig islet cells. But he doesn’t want to speculate when those might begin. “We don’t want to rush. Every single time my team and I have done a clinical trial, the first person who has participated has shown a substantial benefit, so we are not going to do this without the utmost regard for our patients.”
Another potential way to create an unlimited supply of islet cells for transplantation is with stem cells. In the past few years, University of Minnesota researcher Meri Firpo, Ph.D., has been exploring how skin and other cells can be reprogrammed into a pluripotent state. Until recently, the only stem cells that were pluripotent—that is, able to evolve into different cell types, including islet cells—were embryonic stem cells. In her lab, Firpo has discovered that these reprogrammed cells, called induced pluripotent stem (iPS) cells, can be differentiated into insulin-producing cells.
“The reason that iPS cells are so exciting is because they allow us to transplant patients’ own cells back into their bodies, versus what is done now, which is to take the islets or pancreas from cadavers,” she explains. “The major drawback is that iPS cells may not be as safe as embryonic stem cells because we are genetically modifying the cells to make them pluripotent, and that may increase the risk of these iPS cells causing cancer.”
Currently, Firpo is putting iPS cells to the test in animal models. After collecting skin-cell samples from patients with and without type 1 diabetes, she reprograms them, first turning them into iPS cells and then differentiating those cells into pancreatic precursor cells, which are transplanted into diabetic mice. Although Firpo won’t disclose the results of the research because she has not yet published her data, she is confident that the strategy will be clinically useful.
Gauging when and if iPS cells might be used in the clinical setting is difficult. The current challenges, Firpo says, are twofold: 1) determining which iPS cells are better—those from the patient’s own body (autologous) or those from another donor (allogeneic) and 2) ensuring the safety of introducing genetically re-engineered cells into the body. Among others is the concern about cancer risk. “The reason it is so hard to predict whether we will be able to use iPS cell therapy is because it is a completely new field, and given the fact that these cells are genetically modified, we don’t know what safety standards we need to meet in order for the FDA to approve them,” she says. “The limiting factor is not the proof of concept but what needs to be done to ensure safety. Once we have that answer, we may have a slightly better idea of how long it will take before this therapy gets to the clinic.”
Managing the Immune Response
Regardless of how effective a transplant or cell therapy is in reducing the burden of diabetes, the key to ensuring the success of those therapies in humans will be managing the body’s immune response. At the University of Minnesota, researchers are working on immunoreactivity from two angles: 1) stifling the autoimmune response in people with type 1 diabetes and 2) suppressing the body’s immune response to a friendly foreign body such as transplanted islet cells or a pancreas.
The fact that type 1 diabetes is an autoimmune disease that kills patients’ own insulin-producing cells presents a critical challenge to those attempting to find a cure. A therapy won’t be considered successful unless that autoimmune attack can be stifled. For researcher Brian Fife, Ph.D., a professor in the university’s department of medicine and a member of the Center for Immunology, the definition of a cure for type 1 diabetes is two-pronged: “It essentially involves 1) restoring the body’s supply of insulin-producing cells (beta cells) and 2) deactivating the part of the immune system that causes the body to attack its own beta cells. … The fundamental purpose of my research is to understand why the immune system is attacking itself and then develop ways to counteract that process.”
In the case of type 1 diabetes, the immune system views its own insulin-producing cells as a threat, and in doing so, signals T cells to attack the islet cells, which eventually destroys the body’s ability to produce insulin. Since 2001, Fife has been fine-tuning a way to turn off only the diabetes-causing T cells—effectively training them to be tolerant of islet cells—without turning off the T cells that protect the body from real threats such as viruses.
“Each T cell is like a specific lock and key for a particular protein; it only targets the cells that it recognizes,” Fife says. “Our strategy is to re-educate the T cells, so they no longer attack and destroy the islet cells; thus in effect, you turn off that process of self-destruction.” Fife has proven the concept in mice. After turning off T cells in mice with new-onset type 1 diabetes, half were cured and returned to normal glycemic levels. The remaining 50 percent had improved glycemic function but did not return to normal presumably, Fife speculates, because they needed to replenish their stores of insulin-producing cells that were destroyed in the original attack. “The advantage of our treatment approach is that you could use the patient’s own (autologous) blood cells to induce the immune system’s tolerance to the islet cells. The injected cells are decorated with islet targets and inactivated, rather than genetically altered, thus eliminating any risk of the cells releasing viruses or developing tumors,” he says.
Like Firpo, Fife hesitates to say when his research results could be applied in a clinical setting, but he and his group are currently working with samples from patients with type 1 diabetes. His technique for inducing tolerance could ultimately be used with the introduction of cell-based treatments such as Firpo’s iPS cell therapy. “I believe the research we are doing is certainly on the path to finding a cure,” Fife says. “If you can effectively silence the immune system and then replace the lost beta cells, that would constitute a cure in my mind.”
As Fife works to prevent the immune system from attacking itself, Pratima Pakala, Ph.D., another University of Minnesota diabetes researcher, is focusing on therapies that can suppress the body’s rejection of a transplanted islet cell or pancreas, thus minimizing a transplant patient’s need to take anti-rejection medications. “Even though they continue to improve, today’s immunosuppressive drugs definitely affect quality of life; they increase patients’ susceptibility to infection, to cancer, to reactivation of viruses; and overall, those risks affect a patient’s ability to take the medication, which increases the risk of rejection of transplanted organs,” Pakala says. “The aim of our research is to better control the body’s immune response to organ transplant by increasing the body’s regulatory T cells, which help suppress transplant rejection.” Regulatory T cells are sparse in the average human, comprising only about 1 to 2 percent of total lymphocytes.
Pakala and her group have shown that they can extract regulatory T cells from the blood of monkeys, grow them in culture for 21 days to increase their quantity, and then reinfuse them into the blood. “In a very recent study we just concluded, we found that this expansion of regulatory T cells could protect the islet cell graft from rejection,” Pakala says. “Interestingly, we also found that we could remove all the chemical immunosuppressive drugs that would be used in the clinical setting.” In addition to extending the survival of the islet cell grafts, the animals maintained normal glucose levels for more than 180 days—and in one case, almost a full year.
Currently, Pakala and her team are running a protocol in which monkeys are kept on a low dose of the immunosuppressive drug rapamycin. At the end of one year, they will review the data and approach the Food and Drug Administration to get an opinion regarding whether to apply for investigational new drug status, which would move the therapy into clinical trials.
Pakala hesitates to call regulatory T-cell therapy a cure for type 1 diabetes. “It is primarily meant to replace immunosuppressive drugs and support an islet cell replacement product,” she says. “The islet cell replacement source becomes the cure, and regulatory T-cell expansion will be the supplemental therapy that supports the ability of the islet cell replacement to work for a long period of time.”
Closing the Loop
Mayo Clinic endocrinologist Yogish Kudva, M.B.B.S., knows that finding a cure for diabetes is the ultimate goal. But he says the significant advances that arise before the monumental discoveries are made are also valuable. “By literal definition, a cure has to be when you develop a therapy that prevents the patient from worrying about the disease at all,” Kudva says. “But there are levels below ‘cure’ that can limit self-management such that a patient experiences a vast improvement in quality of life.”
Kudva sees the closed-loop system, or artificial pancreas, technology he is working on with fellow Mayo endocrinologist Ananda Basu, M.B.B.S., M.D., as a significant advancement. Although there are different versions of the artificial pancreas, the main components of any closed-loop system are a continuous glucose monitor, a central processing unit that reads glucose measurements, and an automatic insulin pump that delivers doses of insulin according to the blood glucose reading generated.
After their research revealed that physical activity after meals lowers glucose levels in people with type 1 diabetes, Kudva and Basu decided to add ancillary tools such as a physical activity monitor to the artificial pancreas system in hope of fine-tuning precisely how much insulin each patient needs. Clinical trials of this modified artificial pancreas will likely begin in November. In an inpatient setting, a handful of participants will use an artificial pancreas system that combines a continuous glucose monitor, insulin delivery system, activity monitor, and a computerized algorithm that mimics the body’s natural process of monitoring and responding to glucose levels in the bloodstream. “We believe detection of physical activity—and modeling of its effect on glucose dynamics—is vital to designing an automatic insulin delivery system because we know now that physical activity enhances insulin action,” Kudva says. “Ultimately, the computerized algorithm makes the decision-making process simpler for the patient—not a cure, as I mentioned, but a reduction in the self-management activities that often create so much disruption in the lives of patients with diabetes.”
Meanwhile, the artificial pancreas is currently being evaluated in clinical trials throughout the country. In these trials, which are generally conducted in inpatient settings, the patient wears the device for three to seven days and all the while is monitored to determine the effectiveness of the therapy. Some studies have also been done outside of the hospital setting. In Minnesota, researchers at Park Nicollet’s International Diabetes Center (IDC) have shown that after one year, insulin-pump therapy augmented with a continuous glucose monitoring device more effectively lowered hemoglobin A1c levels than multiple daily insulin injections in patients 7 to 70 years of age who had poorly controlled type 1 diabetes. A report on that study was published in the July 22, 2010, New England Journal of Medicine. “Moving toward an artificial pancreas, which some consider a mechanical cure for diabetes, is a stepwise process,” says Richard M. Bergenstal, M.D., endocrinologist and executive director of the IDC. “Combining a glucose sensor and an insulin pump is step one; soon we will start a study with an insulin pump that can shut off the delivery of insulin if the glucose is dangerously low; and eventually the hope is the pump will be programmed to increase the insulin if the glucose is definitely high.”
The Cure Conundrum
Although diabetes researchers are taking different approaches to finding a cure and even define the term somewhat differently, all seem to understand that what matters most is improving the lives of patients. The university’s Meri Firpo says she has talked with dozens of people with type 1 diabetes. “Of course, there is a range of what ‘cure’ means to them; but for most of these patients, cure means not having limitations on life because of their disease, even if that means they may have to take anti-rejection medication the rest of their lives,” she says, adding that she hopes that if iPS cell therapy is found to be safe and effective, patients could regard it as a cure. Fellow researcher Bernhard Hering notes that recipients of islet cell and pancreas transplants speak of their disease in the past tense. “They say, ‘When I had diabetes, I had to endure this; I had to do this.’ They no longer refer to themselves as a patient with diabetes.” And, he says, before a transplant, patients say they spent a huge amount of time making plans for getting through the day with their diabetes. “Now, they are making plans for the next 20 years.” MM
