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."
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.
A Careful look at The Diabetes-Heart Disease Tie-In
"You start seeing the difference remarkably early-between the ages of 30 to 35," Golden says. "There's a long period of exposure to higher blood pressure, and this might explain why 50 percent of all Type 2 diabetics already have heart disease by the time they're diagnosed." Golden, a diabetes epidemiologist and endocrinologist, is interested in identifying the risk factors for cardiovascular disease in diabetics and helping patients avoid those pitfalls.
In a separate study, Golden wanted to find out just what predisposes diabetics to atherosclerosis, the plaque buildup in the arteries that's an early sign of heart disease. To do it, she looked at the pre-diabetic period when the body begins to develop a resistance to insulin. Six classic signs mark insulin resistance-elevated insulin, glucose and high triglycerides; low levels of protective HDL (the good cholesterol); obesity and hypertension. Which ones, in which combinations, she wondered, were most likely to be associated with atherosclerosis?
She weeded out two culprits. "Those people who had hypertension coupled with high triglycerides were most likely to develop atherosclerosis."
As a result of her study, due to appear shortly in the medical journal Diabetes, Golden now makes sure her patients in the clinic understand that the key to living with diabetes is not just lowering their blood sugar, but also lowering their blood pressure and cholesterol-that's if they want to try to avoid heart disease.
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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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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.