Diabetes Newsletter
May 3, 2010

Worth Quoting
"It doesn't hurt to be optimistic. You can always cry later. "

--Lucimar Santos de Lima

In This Issue
• Tight Blood Sugar Control May Not Harm Diabetics
• Wounded Soldier Spared Diabetes With Emergency Transplant
• Artificial Pancreas for Type 1 Diabetes Moves Closer to Reality

Tight Blood Sugar Control May Not Harm Diabetics

WEDNESDAY, April 28 (HealthDay News) -- The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was abruptly halted in 2008 when researchers noticed an increase in deaths in the group of type 2 diabetics who were being intensively treated to bring their blood sugar levels down to near-normal levels.

Now, a new analysis of data from that study has concluded that a rapid lowering of blood sugar (glucose) levels was not the cause of the increased risk of mortality.

However, even though the researchers were able to exclude intensive diabetes management from their list of suspects, they still aren't clear what factors may have played a role.

"The original question underlying the study was, would rapid lowering of blood glucose be an explanation for the excess mortality rates?" said study author Dr. Matthew Riddle, a professor of medicine at Oregon Health and Science University in Portland.

"The answer was no. People who rapidly lowered their A1C didn't have excess deaths," Riddle said. In fact, "it was the ones who couldn't bring their A1Cs down that had increased mortality."

A1C is a test that can estimate two to three months of blood sugar control. The American Diabetes Association recommends that most people with diabetes try to maintain an A1C of 7 percent or less, which translates to an average blood sugar reading of about 154 milligrams per deciliter.

In the ACCORD trial, which included more than 10,000 people with type 2 diabetes, the intensive management group was trying to achieve an A1C level of less than 6 percent, which is a normal level. Most people with type 2 diabetes have significantly higher A1C levels, according to background information in the study.

The reason lowering A1C is important is that other studies have shown that for each 1 percent increase in A1C levels, there's a 15 percent to 20 percent higher risk of cardiovascular disease. And, in addition, as A1C levels rise, so do the risks of kidney disease, eye disease and nerve damage.

To achieve A1C levels of less than 6 percent, most people with type 2 diabetes would need a combination of medications and aggressive lifestyle changes, such as losing weight and exercising a lot more often.

Initially, the ACCORD study was scheduled to last for almost six years, but the study was stopped during the third year when the researchers discovered the increased death rate. At the time, there were 257 deaths in the intensive group vs. 203 deaths in the usual treatment group.

When Riddle and his colleagues re-examined the data, they found that people in the intensive treatment group who still had higher A1Cs were most at risk of mortality.

Results of the study were published in the May issue of Diabetes Care.

"We need to know what it is about those who couldn't lower their glucose levels that puts them at greater risk. We need to find more specific red flags for clinicians to look for," said Riddle.

He added that although most people would like a standard set of goals and advice for everyone with type 2 diabetes, "there's no one-size-fits-all approach. There are different treatments for different groups, and we need more sophisticated assignment to subgroups for treatment."

"I think what this paper reveals is that it was not simply the low A1Cs or improved glucose control that account for the higher death rates, and that's reassuring. It shows that many people can safely achieve good glucose control," explained Dr. David Kendall, chief scientific and medical officer for the American Diabetes Association.

"It appears that those who continued to attempt medication titration and other changes without success are most at risk. Their diabetes may be more challenging somehow or there may be other barriers that we're not yet aware of," said Kendall.

The bottom line, said Kendall, is that there's no reason to change target recommendations for glucose control for most people.

Riddle said that doctors may need to suspect an increased risk of potential problems in people who don't have significant improvement in diabetes control after six months or so on aggressive treatment, and that the researchers would continue to try to tease out what factors contributed most to the increased risk of death.

In the meantime, Riddle pointed out that "treatment of type 2 diabetes early in the game, when it's easier to get good glucose control, should have a high priority." He added that many people in the ACCORD trial had been diagnosed with diabetes years earlier and were already suffering from diabetic complications.

More information

Learn more about type 2 diabetes and its management from the U.S. National Library of Medicine.


Wounded Soldier Spared Diabetes With Emergency Transplant

WEDNESDAY, April 21 (HealthDay News) -- In the first operation of its kind, a wounded soldier whose damaged pancreas had to be removed was able to have his own insulin-producing islet cells transplanted back into him, sparing him from a life with the most severe form of type 1 diabetes.

In November 2009, 21-year-old Senior Airman Tre Porfirio was serving in a remote area of Afghanistan when an insurgent who had been pretending to be a soldier in the Afghan army shot him three times at close range with a high-velocity rifle.

After undergoing two surgeries in the field to stop the bleeding, Porfirio was transferred to the Walter Reed Army Medical Center in Washington, D.C. As part of the surgery in the field, a portion of Porfirio's stomach, the gallbladder, the duodenum, and a section of his pancreas had been removed.

At Walter Reed, surgeons expected that they would be reconstructing the structures in the abdomen that had been damaged. However, they quickly discovered that the remaining portion of the pancreas was leaking pancreatic enzymes that were dissolving parts of other organs and blood vessels, according to their report in the April 22 issue of the New England Journal of Medicine.

"When I went into surgery with Tre, my intention was to reconnect everything, but I discovered a very dire, dangerous situation," said Dr. Craig Shriver, Walter Reed's chief of general surgery.

"I knew I would now have to remove the remainder of his pancreas, but I also knew that leads to a life-threatening form of diabetes. The pancreas makes insulin and glucagon, which take out the extremes of very high and very low blood sugar," Shriver explained.

Because he didn't want to leave this soldier with this life-threatening condition, Shriver consulted with his Walter Reed colleague, transplant surgeon Dr. Rahul Jindal.

Jindal said that Porfirio could receive a pancreas transplant from a matched donor at a later date, but that would require lifelong use of immune-suppressing medications. Another option, Jindal said, was a transplant using Porfirio's own islet cells -- cells within the pancreas that produce insulin and glucagon. The procedure is known as autologous islet cell transplantion. Such a procedure had never been done in this type of situation, Jindal said.

"I called one of my colleagues in the transplant field, Dr. Camillo Ricordi [chief of cellular transplantation at the University of Miami Diabetes Research Institute], and he was ready to give it a try. We had about half the pancreas left, which we removed and sent to Miami, as we would an organ for donation," said Jindal.

In the meantime, because it was the evening before Thanksgiving and many people had gone home early, Ricordi had to re-assemble a team of technologists to harvest Porfirio's islet cells. Islet cell transplantation was initially developed with the hope of curing type 1 diabetes. And, while it's temporarily helpful for those with the disease, the autoimmune attack that caused diabetes in the first place eventually destroys the transplanted cells as well. Researchers have also used islet cell transplants to help people with chronic pancreatitis.

"I was concerned," said Ricordi. "It was the first time we'd done a remote procedure where there isn't a human cell processing center on the receiving end. But, I thought no matter, what we could give back in islet cells would be a good help. I didn't predict that we'd be able to get him off insulin therapy completely."

Less than 24 hours later, the harvested islet cells were back at Walter Reed, ready to be infused into Porfirio. According to Ricordi, the procedure to infuse the islet cells into the liver is relatively simple. They're infused into the portal vein in the liver, and then they "seed in" the liver and eventually take up their own blood supply from that organ. Once in place, these cells begin producing insulin and glucagon.

"I want to say it was three days after the surgery before it all hit me what was going on," said Porfirio. "It's amazing that they could do something like that."

Said Walter Reed's Shriver: "We sort of made this up on the fly. It took three people with strong expertise to come up with this plan on Thanksgiving eve, and six technologists willing to give up their time to help a wounded warrior. Seeing Tre alive now and getting well is really the payoff."

Remarkably, Porfirio's blood sugar levels are now normal and he doesn't require any insulin therapy. He still has several more surgeries to go, according to Shriver, in addition to the 15 major procedures he's also had to reconstruct other areas of his abdomen.

In March, Porfirio was back in the hospital for a much happier occasion, the birth of his first son.

And the improvised transplant procedure may one day lead to a new treatment approach that might "prevent diabetes and secondary complications if even a small portion of [the] pancreas can be salvaged," the doctors wrote in the journal.

More information

For more on Tre Porfirio's story, watch this video from the Diabetes Research Institute.


Artificial Pancreas for Type 1 Diabetes Moves Closer to Reality

WEDNESDAY, April 14 (HealthDay News) -- The first human trials of the latest design of an artificial pancreas for people with type 1 diabetes found the device worked without causing low blood sugar (hypoglycemia).

Ideally, this type of automated device would finally free people with type 1 diabetes from the insulin injections that many require each day, while relieving them of the constant need to check blood sugar levels and monitor the food they eat accordingly.

The device, produced through a collaboration of experts from Boston University, Massachusetts General Hospital and Harvard Medical School, delivers two hormones that are deficient in type 1 diabetes -- insulin, which keeps blood sugar levels from going too high after a meal, and glucagon, a naturally occurring hormone that prevents blood sugar levels from dropping too low.

Because the device doesn't rely on human input, it's called a "closed-loop" system.

"A bi-hormonal closed-loop system is feasible and it can give you good average blood sugar readings," explained one of the device's designers, Edward Damiano, an associate professor of biomedical engineering at Boston University, and the father of a son with type 1 diabetes.

"What we've developed is automated decision-making software that uses a mathematical formulation to infuse varying amounts of insulin and glucagon when needed," he explained.

Type 1 diabetes is a disease in which the body's immune system -- which normally protects you from infections and other diseases -- turns against healthy cells. In type 1 diabetes, the immune system attacks beta cells in the pancreas, effectively destroying the body's ability to produce insulin and control blood sugar levels.

What many people don't realize, however is that beta cells aren't the only ones damaged by the autoimmune attack. Alpha cells, which produce the hormone glucagon, are also damaged. Damiano's colleague, Dr. Steven Russell from Harvard, said, "There is a functional deficiency in alpha cells in type 1 diabetes and they don't work properly. They don't secrete glucagon as they should, so an extra level of security is lost and you can wind up with hypoglycemia that can be scary and even life-threatening."

That's why they decided to add glucagon to their artificial pancreas to give it an added level of protection, said Russell.

In the current version of the device, the researchers tracked blood glucose via a special sensor placed into a vein. Future versions of the device will use currently available continuous blood glucose monitors (CGMs), but for this trial the researchers wanted an extremely accurate way to measure blood sugar levels so that the only variable was the mathematical formulation used to program the delivery of insulin and glucagon.

Eleven people with type 1 diabetes were included in the initial tests, and were studied in 27-hour experiments. During that time, they were hooked up to the artificial pancreas and given carbohydrate-rich meals (carbohydrates are transformed into glucose in the body).

The device responded to the rise in blood sugar levels by administering insulin. In six people, the device achieved an average blood glucose level of 140 milligrams per deciliter (mg/dl), which is well within the American Diabetes Association guidelines for care. However, five people absorbed the insulin much slower than expected, and ended up with low blood sugar levels serious enough to require intervention with additional food.

The researchers were surprised by the significant difference in blood sugar absorption rates, but went back and adjusted the mathematical formulation, and retested the device in a second experiment. This time, they achieved an average blood glucose level of 164 mg/dl, which is slightly higher than the ADA's goal. However, there were no instances of hypoglycemia that needed intervention.

The researchers said that people using the pump would rid themselves of the need for daily injections. Instead, they might just need to change the pump site every three days, and the glucose-monitoring site once per week. No one-site integration of hormone delivery and glucose monitoring has been developed yet, although that's the ultimate goal.

In the next trial, the researchers hope to deliver at least some of the insulin prior to a meal, which is the standard treatment. Damiano said this may be accomplished with a pre-meal button, and the user could just choose whether they were having a small-, medium- or large-carbohydrate meal.

The next set of trials will also test a device that includes insulin only, because it would likely be available faster. The reason is that glucagon is currently only FDA-approved in a freeze-dried form as an injectable rescue medication. It's not FDA-approved yet for delivering through an insulin pump in tiny doses, as it would be in an artificial pancreas. Both Damiano and Russell think it could be possible to have an insulin-only closed-loop system available for use by patients within five years or so.

"The goal of an artificial pancreas is to try to restore normal physiology as closely as possible, and this study demonstrates that this technology is real, and it's good in real people," said Aaron Kowalski, assistant vice president for glucose control research and research director of the Artificial Pancreas Project for the Juvenile Diabetes Research Foundation (JDRF). "We've talked for many years about the theoretical potential of a closed-loop system, and now we see the real potential. These technologies are going to be built into real systems and will have the potential to transform the management of diabetes."

Results of the study were published in the April 14 issue of Science Translational Medicine.

More information

Learn more about the artificial pancreas from the Juvenile Diabetes Research Association.