Dr. Aaron Vinik likes to dream big. In his ideal vision of the not-so-distant future, people with diabetes and its sometimes crippling side effects return to health, reducing or even stopping their multiple daily insulin injections and blood tests. He imagines patients rising up from wheelchairs and throwing away crutches, celebrating the easing of pain and regaining feeling in their limbs, and living as long as people who never had the disease at all.
As director of research at the Strelitz Diabetes Institute at Eastern Virginia Medical School (EVMS), Vinik has led the school’s aggressive effort to decode diabetes and develop a variety of new treatments for the disease. In recent years, he and other scientists at EVMS have turned the Norfolk center into a national hot spot for diabetes research.
I’m the eternal optimist: I want to see a cure for diabetes in my lifetime,” Vinik says.
“I’m hoping for a day when patients never have to take insulin again. But if we can get them down to less frequent insulin doses and less frequent blood monitoring—and if we can eliminate some of the complications—I’d consider that an outstanding success. I know it would make a tremendous difference to the many patients I’ve met over the years.”
Ongoing research projects at EVMS are attacking diabetes from a number of angles. These efforts are aimed at developing therapies that might reverse one type of diabetes, trying to halt cell and nerve damage, creating anti-inflammatory medications to protect against blood vessel damage and better understanding the link between obesity, diabetes and heart disease.
“This research is truly homegrown,” says David Taylor-Fishwick, an associate professor of internal medicine at EVMS and director of the Cell, Molecular and Islet Biology Laboratory at the center. “We are taking new approaches to diabetes with the knowledge we’ve gained over the past 10 years. It’s a very exciting time to be working here.”
A Powerful and Complex Enemy
Diabetes mellitus is a broad term for a group of conditions marked by problems with producing or using insulin, a hormone made by cells in the pancreas called beta cells. If insulin production is compromised, or if cells lose sensitivity to this hormone, cells can’t convert sugars from food into the energy needed for movement, growth, cell repair and other functions. Over time, high blood sugar levels—or glucose levels—also damage vital organs.
More than 23 million people in the United States—roughly eight percent of the population—are diabetic, according to the American Diabetes Association. Another 59 million have higher-than-normal blood sugar levels that put them at risk for developing the full-blown disease. Complications of diabetes can include heart disease, stroke, blindness, kidney failure, limb amputation, severe nerve damage, poor concentration and fatigue. On average, diabetics live five to 10 years less than people without the disease, according to EVMS; each year, more than 1,500 Virginians and 210,000 Americans die from it.
Many other diabetics suffer a greatly diminished quality of life. Even those who keep their glucose levels under control and stay relatively healthy typically have to follow an intense daily schedule of finger pricks and diet monitoring, along with relying on insulin injections, oral medications or an implanted insulin pump.
The two main forms of diabetes, Type 1 and Type 2, are very different diseases. Type 1 diabetes, often diagnosed in children and young adults, is an autoimmune disorder in which the body’s own immune system turns against healthy beta cells and destroys them. A genetic predisposition or an environmental trigger such as a virus may set that progressive attack into motion, although doctors don’t know for sure.
In Type 2 diabetes, the most common form of the illness, the body either stops producing enough insulin or loses the ability to use it efficiently. Top risk factors are obesity, age, family history and race; African-Americans and Hispanics, for example, are more vulnerable than Caucasians. Unlike Type 1 diabetes, Type 2 may be reversible with improved diet, exercise and weight loss.
EVMS researchers are taking aim at both forms of diabetes. Some of the therapies under examination also potentially could help fight other autoimmune diseases such as lupus and rheumatoid arthritis. “We would love to create therapies with multiple uses,” says Dr. Jerry Nadler, professor and chair of internal medicine at EVMS and director of the Strelitz Diabetes Center.
“Our goal is to help as broad a population of patients as possible.”
Generating New Beta Cells
Dr. Vinik has led EVMS’ drive to create a treatment that would generate new insulin-producing cells in the pancreas. Those new cells would come from a patients’ own tissue, meaning their bodies wouldn’t reject the cells as foreign. The effort is built on Vinik’s discovery of a gene called islet neogenesis associated protein, or INGAP, a compound that stimulates immature cells in the pancreas to produce insulin.
Early clinical trials of a synthetic version of INGAP, done at EVMS and other locations, showed it could reverse diabetes in 40 to 50 percent of animals. Published reports of human trials also have demonstrated promising results in both Type 1 and Type 2 patients, including some return of insulin secretion in Type 2 diabetics. Additional benefits for Type 1 diabetics were higher levels of C-peptide, a compound that can help prevent nerve damage and kidney problems, and lower levels of hemoglobin A1c, another change that lowers the risk of complications.
Synthetic INGAP, now branded as ExsulinTM by a Minnesota-based pharmaceutical development company called Exsulin Corp., is being tested in a new trial at both the Mayo Clinic and Canada’s McGill University. Each site has enrolled two patients to date, and others have expressed interest in participating, Vinik reports. The current focus is on Type 1 diabetes; with twice-daily injections, researchers again hope to show the therapy can raise C-peptide levels, lower hemoglobin A1c levels and reduce insulin requirements in patients. The study is expected to take about a year and if it’s a success, the U.S. Food and Drug Administration should approve the treatment for clinical use, Vinik says.
“Things are moving along very nicely,” he says. “Not many drugs are fast-tracked in medicine, especially in the diabetes world, because of concerns over complications. However, we don’t feel complications will be an issue here because we’re using a compound that naturally occurs in humans. We hope these beta cells will survive in your body for life—that there will be no autoimmune attack whatsoever because the body will consider them ‘self.’ ”
Protecting Healthy Beta Cells From Destruction
Another major investigation for Vinik is a stem cell treatment that would use bone marrow cells from healthy adults to stop the destruction of pancreatic (beta) cells in newly diagnosed diabetics. Doctors can retrieve those cells from donors simply by drawing blood and running it through a cell sorting machine. “[Bone marrow cells] are cells that circulate in the blood at all times, policing the body and looking for sites of injury,” Vinik says. “If we can introduce them within a couple of months of a patient developing Type 1 diabetes, we’re hopeful they can stop destruction of beta cells and preserve remaining beta cells.”
In a recent small trial, some patients with Type 1 diabetes were able to virtually stop taking insulin after receiving three stem cell infusions over a three-month period, Vinik says. However, he cautions that researchers still need to analyze more data and follow patients for a longer period of time to be able to posit that the treatment led to that result.
“This wouldn’t address the millions of people with established diabetes,” he says, “but I have high hopes for people who are still within a couple of months of their diagnosis.”
One problematic aspect of diabetes is an inflammatory process within the body that helps destroy beta cells. While INGAP could prove to be a stand-alone treatment, some researchers feel that regenerating beta cells within a toxic environment may not be enough, especially in patients with more advanced diabetes.
“Here’s an analogy: you are blowing up balloons in a room with friends who are holding pins,” Taylor-Fishwick explains. “You can blow more balloons up, but they won’t last very long if your friends are trying to pop them. We want to dampen down the response of those friends. We want to create new cells that are stable and can hang around and do their job.”
A research team led by Dr. Nadler is studying an enzyme called 12-Lipoxygenase, or 12-LO, that plays a role in that destructive process. In animal models, deleting the gene that produces 12-LO prevented the development of Type 1 diabetes at a rate of nearly 100 percent, Nadler says. EVMS researchers also have established that the same enzyme is at work in humans. “We have successfully identified a vital step in the development of Type 1 diabetes, and we are hopeful that blocking this enzyme could hold the key to engineering breakthrough new treatments,” Nadler says. Targeting 12-LO production also may help guard against heart disease, which kills roughly 80 percent of diabetics, he adds.
Nadler is working with a two-year, $472,683 grant from the Juvenile Diabetes Research Foundation and collaborating with a chemistry professor at the University of California, Santa Cruz. During that time period, he hopes to narrow a large number of compounds down to one or two promising ones that could go into further testing. At least initially, the therapy would be delivered via injection.
Taylor-Fishwick, meanwhile, has a three-year, $1.1 million grant from the Department of Defense Peer Reviewed Medical Research Program to test experimental drugs that, like Vinik’s work, might reduce immune system attacks that lead to Type 1 diabetes. His team is using a drug called Lisofylline and related molecules to block interleukin-12, a protein that triggers the harmful autoimmune response. “By targeting interleukin-12 signaling, we hope to redirect the immune system, not wipe it out,” he says. Taylor-Fishwick also hopes to develop compounds into an oral pill. “That would be very helpful with patient compliance,” he says. “Not surprisingly, there is a global preference for pills over injections—although certainly if an injection worked, people would do it.”
Regenerating Nerve Cells
At least half of all diabetics have some form of nerve damage, or neuropathy, according to the American Diabetes Association. That can cause everything from pain and numbness in the hands and feet—a leading cause of limb amputations—to heart and digestive disorders, to balance problems and falls. In fact, nerve damage can occur in every organ system in the body.
Keeping blood sugar levels stable is crucial to preventing neuropathy, and doctors also have developed medications to help diabetics manage pain. EVMS, in fact, licensed and patented a formula of supplements called NeutriNerve, which has been shown to improve symptoms.
But researchers now want to go a step further: Vinik would like to prompt the body to re-grow nerve cells, just as he would do with insulin-producing cells. “The same thing we’re trying to do in the pancreas, we want to do in the peripheral nervous system,” he says. “It has been considered heretical to say these cells could grow back, but in animal models we can get nerves to re-grow.”
One of the school’s current priorities is working with a naturally occurring protein called vascular endothelial growth factor, or VEGF. Researchers have completed a small study on humans with a synthetic version of VEGF and saw evidence of nerve fiber re-growth, Vinik says. The next step—researchers hope—will be to confirm those early results in a large, multi-center study that likely will take at least two years to complete.
Into The Future
EVMS continues to release new data on a regular basis. Just last month, for example, researchers announced preliminary findings on a gene called STAT4 that appears to play a role in insulin resistance as well as artherosclerosis, or thickening of artery walls. With follow-up studies planned, the ultimate goal is to develop a drug to block or inhibit that gene.
“Basically, it appears that [with insulin resistance], excess STAT4 is working in hyper-drive, leading to inflamed fat which can produce these problems,” Nadler says. “This is significant because prior to this study, no one knew that STAT4 was involved in insulin resistance or artherosclerosis.”
Sharing information and collaborating with other leading researchers in the field is a priority. Over the next two months, Nadler estimates that EVMS representatives are scheduled to make 15 presentations at major medical conferences. The school also continues to pursue grant funding for more studies on ongoing or brand-new treatment plans.
Says Vinik about his plans after decades of research, “I’m not done yet.”
Diabetes Research At EVMS Currently Includes:
- Developing therapies that may reverse one type of diabetes by prompting cells in the patient’s own pancreas to produce insulin – the hormone needed to convert sugars from food into energy
- Creating anti-inflammatory medications to protect healthy insulin-producing cells and possibly guard against heart disease
- Using bone marrow cells from healthy donors to stop the destruction of pancreatic cells in newly diagnosed diabetics
- Testing treatments that may lead to re-growth of nerve cells damaged by diabetes
- Further investigating the link between obesity, diabetes and heart disease
- Developing therapies that may help fight other diseases that involve an immune system attack, such as rheumatoid arthritis and lupus