BETHESDA, MD—Much of the discussion surrounding diabetes concerns day-to-day treatment and how a patient can manage symptoms and keep the disease from progressing. Rarely does anyone discuss the possibility of a cure. Speaking on the campus of the National Institutes of Health here last month, Dr Christopher Saudek did just that. A researcher at Johns Hopkins University and director of the Comprehensive Diabetes Center, Dr Saudek outlined the different approaches that researchers are taking in the search for a cure. He also pointed out that the definition of a cure is not a fixed point.

“There are various ways to conceptualize a cure,” Dr Saudek noted. “One is a simple procedure, device, or drug that eliminates diabetes permanently. One is a periodically repeated procedure, device, or drug that eliminates diabetes. or a procedure, device, or drug that has risk and morbidity but also eliminates diabetes.” These devices and drugs could make diabetes forgettable, allowing patients to go about their daily lives with no conscious acknowledgement of their disease, he added. And there are devices that could make diabetic self-care much easier than it is now. Parsing the word “cure” is not a trivial question, Dr Saudek declared. “[This question] drives our resources and expectations. Do we plan research looking for the sudden dramatic cure, or an incremental one?”

Biological Approaches

Doctor Saudek divided the current research initiatives into two areas: biological approaches and mechanical approaches. The most invasive and radical example of the former has been whole-organ pancreas transplantation, a more common procedure than might be expected, with 400-500 occurring in the US every year. While the procedure can be a short-term solution to glucose control, the long-term prognosis is poor. “The 10-year graft survival is under 50% and doesn’t seem to be improving,” Dr Saudek explained. “It’s a long and difficult surgical procedure with significant morbidity.”

Since a full organ transplant isn’t a solution, researchers have been examining the viability of islet transplantation. Islets are clusters of cells that exist within the pancreas. These clusters include beta cells that make insulin. Insulin is the hormone that helps the body use glucose for energy, and must be taken daily by those with type 1 diabetes and by those with a more progressed type 2 diabetes. In islet transplantation, the cells are taken from the pancreas of a deceased organ donor, purified, processed, and transferred to the diabetic patient. Once implanted, the beta cells in these islets begin to make and release insulin. Researchers hope that this process will help people with type 1 diabetes treat the condition without daily injections.

The breakthrough for islet transplantation came in 2000, when seven patients with type 1 diabetes survived islet cell transplantation and showed immediate improvement in blood glucose and insulin production. “It’s a simple infusion procedure, but each of these patients required more than one and in some cases three infusions of islets,” Dr Saudek explained. “That is a major barrier when you think of waiting lists for one organ, and in this case you need two or more whole organ donors for [infusion].” A follow-up in 2006 showed that the patients had a loss of insulin independence within a year, needing a follow-up transfusion. “That certainly took the blush off the rose of the idea that islet transplants were going to be a ready cure,” Dr Saudek said.

Another potential use for islets is the implantation of sequestered islets. Islets are placed in microcapsules that could then be infused into the patient. Glucose goes through the wall of the capsules and insulin should be released, but antibodies would be blocked from entering. A clinical study on mice in 2009 showed that glycemia greatly improved following implantation of sequestered islets. “If you can encapsulate islets, then you can think of transplanting xenotransplants,” Dr Saudek explained. “If you’re not going to be destroying the foreign body, you can think of using pig islets or beef islets that can be put inside these capsules. And if you have this infinite supply of islets, you’d be much more ahead of the game than having to harvest them out of humans.”

There is also research into the regeneration of beta cells. One rat regeneration model showed post-partial pancreatectomy beta cell regeneration, as if the rat were regrowing its pancreas following surgery. Researchers hypothesized that pancreatic ductal cells were the progenitors of new beta cells, and follow-up research demonstrated this to be true.

There is also research underway on adult stem cells and the possibility of taking pancreatic cells and turning them into beta cells. “Anything you can do to augment your beta cell supply [is a research target]” Dr Saudek said. “If you can regenerate islets endogenously, you can theoretically cure all diabetes.”

Mechanical and Surgical Approaches

For type 2 diabetes, the most effective surgical approach has been bariatric surgery—using methods to constrict or shrink the stomach to allow for only minor intake of food. Weight loss over one 2-year study period was around 20% of body weight. In that study, there was remission of type 2 diabetes in 73% of the participants. “I think we have to admit, it was effective,” Dr Saudek said. “I still think we have to talk it over with the patient.And I wouldn’t recommend it for anyone with BMI under 35.And I wouldn’t recommend you start talking about it for people over 40. And they have to understand what it does…it changes your whole approach to food. You can’t eat in large amounts. If losing the weight is more important than having normal eating patterns to food, then it’s a viable approach.”

Mechanical approaches to glucose control are all variations on the insulin pump. The external insulin pump, which is partially dependent on how it is programmed, is not always accurate. A variation on the external pump is a simple, cheap-er pump worn on the arm or the abdomen that communicates with an external palm device. This pump is disposable and thrown away every 3 days or so. There are also implantable insulin pumps, more common in Europe than in the United States. In this case, there is a refill procedure where insulin is injected through the skin and into the pump.

One relatively new system uses a continual glucose-monitoring device with a sensor applied to the skin that sends read-outs to a handheld device. “It’s a niche market now for people who are very involved in their diabetes. The technology is by no means perfect, but it’s an interesting approach to care now,” Dr Saudek said. The long-range goal for this system is a fully-implanted closed loop insulin delivery system, with an intravenous glucose sensor mated to the pump with a mathematical algorithm linking the two. The sensor tells the pump when insulin injection is needed.

“Everybody asks when you talk about glucose pumps and glucose sensing, why can’t you make it automatic? It sounds easy. It’s not,” Doctor Saudek declared. “Even the linking algorithms, which we thought were going to be the easiest part of that, are not so easy. For example, the blood glucose normally goes up very rapidly when you start a meal. [So] if you only do it based on blood glucose, how does that blood glucose sensor know that the insulin shooting up is the two Lifesavers you just ate or the Thanksgiving dinner you just ate? And that seems to be a very critical distinction.” The answer might be to design a way for the patient to tell the internal pump that he or she is eating a large or small meal and for the sensor to take that into consideration. “So, closing the loop is the Holy Grail of mechanistical approaches,” Dr Saudek said.

Doctor Saudek added that there is no way to predict when any of these still-in-the-works approaches will be available to patients and said, “In the meantime, we need to take advantage of what is available, which is a great deal, to avoid complications, and be ready as each step comes across.” As for the initial question of how researchers should define the idea of a “cure” for diabetes, Dr Saudek opined, “I think it’s naïve to believe that any of these approaches is going to have a headline one day saying ‘Diabetes Cured.’ I think it will be incremental.”

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