Pushing for a Diabetes Cure
It was in May 1923 that the New York Times published an article boldly announcing that diabetes had been cured. "Its conquest is a feather in the cap of science," the paper proclaimed. The subject of the report was the discovery of insulin, which was indeed a medical miracle. But although this hormone has saved countless lives over the past nine decades, it is of course not a true cure. Diabetes remains a chronic disease and, while manageable, lasts a lifetime.
All people with type 1 diabetes and many with type 2 must take insulin every day and regularly monitor blood glucose levels to make sure they don't go too high or too low. Even with meticulous attention, diabetes still can cause complications like heart disease, vision problems, nerve damage, and kidney ailments, shortening lives.
So what would a real cure look like? In short, it would permanently return a person's blood glucose levels to normal without a continuing need for medication. Researchers are working on a variety of ingenious approaches to make this a reality in the not-too-distant future. Here's where things stand today.
The two main kinds of diabetes—type 1 and type 2—are quite different in origin, although people with both diseases face the same challenge: keeping blood glucose in a healthy range. Type 1 is an autoimmune disease, in which the body attacks its own cells, destroying the cells in the pancreas that make insulin. In type 2, the pancreas makes at least some insulin, but the body is unable to use it properly. Both diseases have significant genetic origins in addition to environmental influences. But a cure for people with type 1 might not stop type 2, and vice versa.
Type 2 diabetes is far more common than type 1, affecting more than 90 percent of the nearly 26 million people with diabetes in the United States alone. Unlike type 1, type 2 can sometimes be prevented or at least delayed through healthy eating, exercise, and weight loss. If public-health campaigns to curb the obesity epidemic are successful, the number of people with type 2 could shrink. Significant weight loss can put type 2 into remission but may not be a permanent solution.
A true cure for type 2 would have to deal with two facets of the disease: insulin resistance and inadequate insulin production. Getting damaged pancreatic cells to regenerate could help with insulin production, but the body's resistance to insulin is less well understood and may be the more difficult problem to solve.
One promising research avenue into a cure for type 2 (but not type 1) stems from an interesting side effect of gastric bypass surgery: The diabetes of most people with type 2 who have this weight-loss surgery goes into remission even before they begin to shed pounds. This suggests that some hormonal or other factor in the body, apparently triggered by the surgery's reconfiguring of the digestive tract, is capable of holding type 2 diabetes in check. Researchers are eagerly following up this discovery in their pursuit of a cure.
Type 1: A Unique Challenge
Ninety years after the discovery of insulin, scientists still don't really know what causes type 1 diabetes. "We know nothing about the origin of any autoimmune disease," including type 1, says Pedro Herrera, PhD, professor at the University of Geneva in Switzerland. To make matters worse, he adds, "There are probably no two patients [who are] alike."
Genetics are certainly involved, but genes are only part of the story. Not everyone at high genetic risk for type 1 develops the disease, so it must have an environmental trigger. The list of suspects includes viruses, foods, intestinal bacteria, and sun exposure, but nothing is certain. Identifying a trigger and developing a treatment based on that could prevent new cases of type 1. Still, that wouldn't cure the diabetes of people who already have the disease.
Once type 1 is triggered, the body starts down an irreversible path that ends in the eradication of most of its beta cells. These cells in the pancreas alone have the capacity to make insulin, the hormone that escorts glucose from the blood into the cells to provide energy. The annihilation of the beta cells stems from a breakdown in the way the immune system differentiates between the body and foreign intruders. This disconnect is true of all autoimmune diseases. In type 1 diabetes, the beta cells are attacked as if they were any other foreign body, such as harmful bacteria or a transplanted organ. As the beta cells are obliterated and insulin levels plummet, blood glucose rises and type 1 becomes fully established.
A Bionic "Cure"?
This device, which already exists in various experimental versions, combines a continuous glucose monitor, an insulin pump, and a computer algorithm that calculates appropriate doses of insulin from blood glucose measurements. By taking over the jobs of monitoring glucose and dosing insulin, the artificial pancreas not only promises to make living with diabetes less of a burden but may also perfect blood glucose control. The result would be to reduce the risk for diabetes complications and remove the constant threat of hypoglycemia (low blood glucose).
The artificial pancreas has been called a "functional cure," but even if it can be made to correctly dose insulin 24/7 for a person with diabetes, it still wouldn't cure the disease. The underlying illness would still be present in people using the technology. But having an artificial pancreas may someday feel very much like a cure to people now forced to manage their diabetes continuously.
In its earliest incarnations, which may become available in the next few years, the artificial pancreas will most likely be clunky and not very cure-like. Users would still need to wear the device, calibrate it frequently, and deal with its maintenance. In the future, researchers may develop a care-free implantable device that could really allow people to forget they have a chronic disease. By then, though, scientists might be on the verge of a true cure that would render the machine obsolete.
Taming the Immune System
To cure type 1, says Herrera, "we'll have to deal with the immune system." That won't be easy, however, because the system is quite sophisticated. "The human body has evolved to fight a great diversity of enemies," he adds.
Researchers are working to develop treatments, sometimes called diabetes "vaccines," to persuade a wayward immune system to welcome beta cells back into the fold. The idea behind a diabetes vaccine is that by targeting specific components of the immune system, rather than suppressing the system in general, the body can be coaxed into tolerating beta cells. "If you systemically suppress the immune system, you can 'cure' diabetes," says Matthias von Herrath, MD, a professor at the La Jolla Institute for Allergy and Immunology in California. But the disastrous result would be to kill the patient in the span of a few months as the immune system was rendered defenseless against invaders, including common-cold germs. So the aim is to alter just the parts of the immune system that are detrimental to beta cells, while preserving the parts that keep people healthy.
Various experimental approaches have been tested. Some suppress specific immune system cells, such as T cells that target beta cells. Others attempt to acclimate the body to beta cells by, for example, exposing it to insulin or related substances, taken orally or nasally. The latter approach is similar to trying to cure an allergy by slowly introducing a person to allergens until the body stops reacting to them.
Before being given to people, diabetes vaccines are first tested in mice with diabetes, often with great success. "We have cured diabetes in mice" many times, says von Herrath. In humans, some vaccines seem to preserve beta cell function, at least for a time. But in the end, all have so far come up short. The latest disappointment, announced in May, was a treatment called GAD65. It showed promising results in early trials but ultimately failed to save the beta cells of people with newly diagnosed type 1.
But hope is not lost. Several trials are under way, and the solution may lie in optimizing drug delivery. "We know from mice that the precise dose, route, and frequency play a role, so why wouldn't they play a role in humans?" asks von Herrath. Experimenting with different combinations is easy in laboratory animals. But human studies are slow and expensive.
Another challenge is that the immune system gets better at destroying beta cells over time. So a diabetes vaccine may work on someone at first but then become ineffective. "Once the first immune response is triggered, then there are additional responses," von Herrath says. "With time, things get worse and worse." This is one reason why people newly diagnosed with type 1 are the focus of most studies; they are thought to be less tough to treat than those who've had diabetes for a long time.
Rather than tweak the immune system as diabetes vaccines try to do, one remarkably successful experiment suggests that type 1 can be cured by hitting the reset button on the entire immune system. A 2009 study published in The Journal of the American Medical Association reported that a majority of 23 people with newly diagnosed type 1 who had their old broken immune system replaced with a new one continued to produce insulin for more than two years after the treatment.
To do this, researchers harvested particular cells—precursors to immune system cells—from the people with type 1 and then killed off their immune system with drugs. Finally, they reintroduced the harvested cells into the people to establish new immune systems. These reborn immune systems had never encountered the type 1 "trigger" and appeared to leave the beta cells alone. It's unclear how lasting a solution this will be for recipients of the new immune systems , but the scientists say that, so far, this is the only treatment shown to be capable of reversing type 1 diabetes in humans. The side effects were mostly mild, with the most serious being a couple of cases of pneumonia that were treated successfully with antibiotics. Even so, the process required an average 19-day hospital stay.
Bringing the Beta Back
Even if the immune systems of people with type 1 could be tamed, there would still be the issue of resurrecting the beta cells to start producing insulin again. Two general strategies are being investigated for regenerating beta cells. "There's the approach of growing the beta cells outside the body and having to transplant them into individuals," says Alexander Rabinovitch, MD, associate director of the Sanford Project, a research center focused on diabetes. "The other approach would be to treat a person with type 1 diabetes with drugs that would stimulate the individual's own cells to develop into new beta cells." This could also help type 2s who have lost beta cell function because of the wear and tear of years of insulin resistance.
One source of beta cells for transplantation is the pancreases of deceased organ donors, though animal sources like pig pancreases are also being explored. These beta cells can be transplanted either along with the whole pancreas or in small clusters of cells called islets. At present, in part because of the scarce supply of donated organs (there are only about 1,500 suitable donors a year), only a few people are typically considered for transplants. "For the vast majority of patients who come to me because they want a transplant, I have to conclude that they just need better diabetes care," says Jose Oberholzer, MD, director of the Islet and Pancreas Transplant Program at the University of Illinois Medical Center at Chicago. "The 10 percent who have fully tried everything and have an excellent endocrinologist, then I would consider transplantation."
Transplanting a pancreas is more invasive surgically than transplanting islets, but it is also the more established procedure. Researchers are still trying to determine the best ways to isolate islets from donor pancreases and implant them into a patient's liver (the pancreas is too hostile an organ to accept cell transplants). There, they set up shop and start producing insulin. "Normally, it will take a few days or weeks until the islets are fully functional. During that time, you slowly are weaned off insulin," says Oberholzer. "Transplant recipients feel like they have been cured of diabetes."
Yet, even when transplants work, the cure is temporary. Pancreas transplants fail after an average of 10 years, about the same as other organ transplants, Oberholzer says. With islets, the reprieve from insulin injections may be even shorter. "We are preparing a paper that shows that 6 out of 10 patients are still off insulin after five years" with islet transplants, says Oberholzer. This is major progress, he adds; in the past, only 20 percent of patients had functioning islets for that long.
Part of transplants' growing success is due to better immune suppression, a necessary part of any transplant to avoid its rejection by the body. However, powerful immunosuppressant drugs can have severe side effects, such as kidney toxicity, infections, and cancer. Nor is the suppression totally effective. Transplanted islet cells in people with type 1 face failure in two ways: the normal tissue rejection that accompanies all transplants and the autoimmune response that caused diabetes in the first place.
The donor shortage and other problems with transplants have prompted researchers to try to make beta cells in laboratories from stem cells. These cells, if they receive the right chemical signals, can develop into other types of cells, in a process called differentiation. If scientists can discover the correct signals, stem cells have the potential to provide a limitless source of insulin-producing beta cells for people with diabetes.
Much research has centered on politically controversial embryonic stem cells. Culled from embryos left over after in vitro fertilization procedures, embryonic stem cells can differentiate into any type of cell in the body. Their potential to treat type 1 diabetes was demonstrated in a 2008 study in Nature Biotechnology. In the study, embryonic stem cells were converted to functional beta cells and used to cure diabetes in mice.
Researchers are also trying to produce beta cells from adult stem cells, a less controversial source. The drawback is that adult stem cells have a more limited capacity to differentiate than their embryonic counterparts. Even so, attempts have been made to turn these and other adult stem cells into insulin producers. The experiments have been less successful than those using embryonic stem cells.
One advantage of using stem cells instead of donor cells for transplants is that the body won't necessarily reject them as foreign. Yet there's a good chance that a beta cell derived from a stem cell will still fall victim to the autoimmune attack that is central to type 1 diabetes. Another risk with stem cells, particularly embryonic ones, is that they'll form cancerous tumors.
Enclosing therapeutic cells in a membrane might solve both problems by protecting healthy insulin-producing cells from the immune system while walling off potentially cancerous cells. This strategy, an active area of research, is called encapsulation. Encapsulated beta cells would essentially function as a bioartificial pancreas. This technology involves placing cells inside a microscopic envelope, ideally made out of a material that the body ignores. It would need to have pores large enough to let glucose in and insulin out but small enough to keep the therapeutic cells inside and hostile immune system cells at bay.
The idea is not new. In 1980, researchers demonstrated that diabetic rats could be cured with encapsulated beta cells. But researchers have struggled to find just the right material for the envelope, its appropriate placement in the body, and the best cell types to create a viable system.
The Inside Route
Rather than make beta cells outside the body for transplant, some researchers are trying a more direct route. They believe it may be feasible to transform cells already in the pancreases of people with diabetes into insulin producers.
Some drugs aimed at regenerating beta cells are already being tested in humans. For example, Rabinovitch is heading up a study to see if a combination of the diabetes drug sitagliptin (Januvia) and the acid reflux medication lansoprazole can treat people with newly diagnosed type 1. "In mice with autoimmune diabetes, the drug combination alone succeeded in regenerating beta cells," says Rabinovitch, though how it worked isn't well understood.
The evidence suggests that functioning beta cells exist in the pancreases of people with type 1, just not in sufficient numbers to stave off diabetes. "Physicians have known for years that when they look at the pancreases from long-term patients, they find a few beta cells," says Herrera. These cells may somehow have survived the immune system's attack. But Herrera thinks it's more likely that "the pancreas is creating new beta cells all the time." Herrera's research team found that mice without beta cells spontaneously make new ones, enough to normalize blood glucose levels. "The majority of these beta cells were in fact alpha cells that had been reprogrammed to produce insulin," says Herrera.
His lab is currently in hot pursuit of the chemical signals that turn alpha cells, pancreatic cells that make glucagon (a hormone that raises blood glucose levels), into beta cells. "Ideally, what I would like to have is a drug or compound that could be delivered, in this case, directly into alpha cells to make them start making insulin in people with type 1 diabetes," he says.
This research also suggests that if the malfunctioning immune system could be corrected, then the pancreases of people with type 1 would heal themselves. If the underlying autoimmune cause of type 1 diabetes could be snuffed out, beta cell regeneration might be unnecessary.
A full understanding of diabetes genes could lead to as yet unfathomable strategies for curing type 1 and type 2 diabetes. To date, researchers have linked dozens of genes to type 2 diabetes. How these genes activate the disease is not yet understood, but some experts believe that they may hold the key to the origins of insulin resistance or solve the mystery of why beta cells fail in some people with insulin resistance, but not others.
Scientists are blazing many possible paths to a cure. But it remains unclear which strategy, if any, will be successful and how long people will have to wait for the burden of diabetes to be lifted. Whatever the route, there's a good chance that the next time the New York Times heralds a cure, it will be for real.