• A Careful look at The Diabetes-Heart Disease Tie-In
• Concocting Cells that Produce Insulin
• Unraveling the Mystery of Insulin Resistance
  
  Going National with Diabetes

By Anne Bennett Swingle

With 17 million Americans suffering from this once rare disease, Chris Saudek sounded a wake-up call during his year as president of the American Diabetes Association.

It's a side effect of prosperity," Christopher Saudek says, when he's asked about the rampant spread of diabetes. Saudek should know. As outgoing president of the American Diabetes Association, this endocrinologist has seen firsthand the sweeping grasp of this once rare condition. In the United States alone, diabetes affects more than 17 million people. Another 16 million Americans test with higher-than-normal blood glucose levels, putting them in a new category known as "pre-diabetic."

And while Type 1 diabetes, in which the body completely stops making insulin, the vital hormone that allows sugar to enter and fuel the cells, generally begins in childhood and is largely unavoidable, the far more common Type 2 diabetes has a lot to do with how people live. Specialists like Saudek are especially disconcerted by the fact that this once adult disease is today increasingly common among obese, inactive children. It even is reaching epidemic proportions among people in Third World countries as their populations become more sedentary and are exposed to Western dietary excesses.

Fighting the diabetes epidemic became Chris Saudek's personal crusade during his year as ADA president. He went on a campaign to raise public awareness about diabetes' link to heart disease and stroke. And when a major clinical trial revealed that proper eating habits and exercise can delay Type 2 diabetes, he spread the findings nationwide. (The trial, the Diabetes Prevention Program, had been conducted at 27 medical centers, including Hopkins, where Saudek was principal investigator.)

Saudek's message got a flood of attention. The diabetes outbreak earned top billing in national news (Time and Newsweek gave it the cover); The Journal of the American Medical Association published its first issue devoted entirely to diabetes; and Health and Human Services Secretary Tommy G. Thompson made diabetes prevention and management a priority.

Saudek, an affable, enthusiastic man who sails and plays the clarinet, has been publishing papers on diabetes ever since 1970, when he was a fellow at the Harvard Unit of Boston City Hospital. He's also spent years advancing the national understanding of the disease as a member of countless scientific panels and medical organizations. He joined the Hopkins faculty in 1981 and in 1984 founded the Johns Hopkins Diabetes Center, a patient education and treatment program he's directed ever since. In 1988, he also became director of Hopkins' General Clinical Research Center, the federally funded program that provides support for patient-based research.

Saudek remains interested in everything about diabetes. "But my roots," he says, "are in the clinic. It's fascinating to try to find the triggers for each person struggling with this disease. Some simply don't understand that diabetes is serious-that it can lead to complications like blindness, kidney-failure and amputations. Others know these things but need encouragement.

They don't need to be scared."

Saudek's own research has long focused on developing an artificial pancreas, the logical next step, he believes, to the external insulin pump, which has been available for at least 15 years. The external pumps deliver insulin into the body in precise amounts at pre-programmed times through a plastic tube and flexible needle inserted beneath the skin. The artificial pancreas will go even further. Designed for Type 1 diabetics whose immune systems have completely destroyed the pancreatic insulin-producing cells, it will consist of an implanted sensor, an information processor and a small pump that infuses insulin into the body. Night and day, it will measure the diabetic's blood glucose and deliver the correct insulin dosages for maintaining blood sugar at a constant level. And because it has an internal monitor, for the person with diabetes it will mean nothing less than at last not having to worry about injections or pricking a finger several times a day for a blood test to determine how much insulin is required.

The stumbling block to completing this project, Saudek says, has been the sensor. "You have to link it to the delivery system, and that's been very difficult." Currently in clinical trials and awaiting FDA approval, is just the implantable pump part of the artificial pancreas. Although it is inserted into the abdomen of patients and replenished every three months with insulin, the pump is not a fully automatic, artificial pancreas: patients must still check their own glucose levels and activate the pump. Still, Saudek's patients who already have this pump swear by it. And Saudek is convinced that the
implantable pump alone should be made available even without the sensor element. "It's a halfway step to the completely artificial pancreas," he says. "We just haven't taken that last step yet. But it will be done."

In June as his term as ADA president came to an end, Saudek addressed the crowd of specialists who'd gathered for the annual meeting and told them, "There is a rising tide of diabetes research." He noted that diabetes may have been recognized for some 3,500 years, but all the scientific and medical understandings about the disease have occurred in the last century. One hundred years ago, not even the foremost clinician of the day, Johns Hopkins' William Osler, understood much about the disease. Osler, in fact, told his students there was really only one thing that could limit the progress of diabetes: opium.

"But even then the tide was beginning to gather," Saudek said. "Today, I am convinced that we are riding an incredible wave of scientific progress that, if taken at the flood, could cure diabetes." (For examples of the scientific progress Saudek's talking about, see the three boxes accompanying this article that offer a look at key diabetes research now taking place at Hopkins).

Some of the research in this article has corporate ties. For full disclosure information, call the Office of Policy Coordination at 410-223-1608.

Concocting Cells that Produce Insulin

For six years, molecular biologist Michael Shamblott worked to harness the embryonic stem cells developed here in the famed lab of John Gearhart. Then he began to wonder just how the powerful new cells he'd cultivated in a petri dish could be used to cure a person.

Shamblott's answer came from the cells themselves. He was struck by the fact that when the lab's so-called embryonic germline (EG) cells, a basic form of stem cell, were transplanted into mice with compromised immune systems, some clearly were transformed into insulin-producing cells. "To me, this was the most surprising, profound result we got," Shamblott says.
And so Shamblott was drawn to the problem of diabetes. and the idea of producing islet cells, which produce insulin and regulate blood sugar. Thanks to the new "Edmonton Protocol," which relies on a steroid-free immuno-suppressive drug regimen to control rejection, we didn't have to be concerned about whether the cells matched the patient," explains Shamblott.
But it takes two to three pancreas donors to come up with enough islet cells for one recipient, so obtaining a plentiful source of islet cells remained the big problem. Some stem-cell biologists were trying to create precise replacements for the beta cells within the islets that produce the insulin. Shamblott focused on engineering a beta-cell substitute, something he calls a glucose responsive insulin producing cell, or GRIP.

"It doesn't have to be just like an islet, or just like a beta cell," he says. "There's been a strategy in this field to take cells and push them through the natural course of development in a dish. But it's pretty complicated-too complicated-to end up with an islet. So, we're not trying to redo development; we're trying to produce cells that can cure diabetics. And GRIP defines exactly what we're looking for."

To create this new type of cell, Shamblott is adding the genes to the EG cells that they need to express in order to have GRIP function. He's also manipulating the cell's environment-the matrix upon which it sits and the media, or liquid, it sits in-by adding and subtracting the factors that appear to either support or impede GRIP function.

Finally, Shamblott is injecting the cells into diabetic mice. Surprisingly, not into the pancreas but under the kidney capsule or, more typically, into the spleen, which is small and flat and easy to examine to see what happens. "These cells could go anywhere and work, as long as they have blood," he explains. "They just need to know what the glucose level is and produce insulin and get it into the bloodstream. One of the great things about diabetes is that it's a disease that doesn't occur in just one part of the body, so it's not subject to location."

The transplanted cells have matured in the mice. "They've been surprisingly powerful," Shamblott says. "We haven't found the right combination of numbers to make the animals recover, but we have shown that our human cells not only are capable of producing insulin, but also are able to process it."

This past May, when the Bush administration quietly removed some of the government roadblocks to stem-cell research, the first-ever NIH grant award based on the use of EG cells went to Shamblott's diabetes project.

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Unraveling the Mystery of Insulin Resistance

Gerald Hart, with postdocs Keith Vosseller and Lance Wells.

It has an ugly sounding name, "oh-gluck-nack," but in many ways this simple sugar, the O-linked beta-N-acetylglucosamine, or O-GlcNAc, is a beautiful and mysterious thing, for it appears to have led scientists to a major, mechanistic reason for insulin resistance. O-GlcNAc can build up on proteins inside cells, and it is this extra sugar coating on proteins, says Gerald Hart, director of biological chemistry, that causes cells to develop insulin resistance.

Eighteen years ago, Hart's lab discovered that simple sugars are used all the time in the nucleus and cytoplasm to turn proteins on and off. Now, Hart suggests, proteins loaded up with too many of these simple sugars can't be controlled properly by their cells. The work underscores the importance of glycosylation, or the attachment of a sugar to a protein, as a way cells control proteins' activities, in addition to elucidating resistance. "These cells developed insulin resistance," Hart emphasizes, "simply because their proteins had more than the normal number of sugar tags."

O-GlcNAc is added to proteins by one enzyme and removed by another. By selectively blocking that removal, Hart and postdoctoral fellows Lance Wells and Keith Vosseller and professor of biological chemistry Daniel Lane-hoped to load up proteins with sugar without adding extra sugar, as others have done to create insulin resistance. "We wanted to see the effect of glycosylation itself, so we used a molecular sledgehammer to increase the amount of sugar bound to proteins," says Hart.

Sure enough, the blocker, a molecule called PUGNAc, increased the amount of O-GlcNAc bound to proteins, and the cells stopped responding to insulin. Wells and Vosseller identified two proteins in the insulin-signaling pathway that were more glycosylated than normal: beta-catenin and insulin receptor substrate-1 (IRS-1)."Our experiments show that increasing O-GlcNAc on proteins is, by itself, a cause of insulin resistance, rather than an effect or a coincidence," says Vosseller.

"Cells don't respond to insulin itself," Hart explains. "Instead, a whole cascade of events, set in motion by insulin, eventually causes cells to take in sugar. We now have an explanation of how sugar can affect these signals." And, if key proteins laden with sugar are indeed present in patients with diabetes, finding a way to remove extra sugar tags may one day help treat or prevent the disease.

-Joanna Downer