Blood sugar fix: can novel drugs rescue insulin-making cells?

Twenty years ago, scientists discovered an unusual substance made by cells lining the intestines. It would have gone unnoticed except for one remarkable quality: The compound, called glucagon-like peptide 1 (GLP1), acted as a hormone, inducing cells in the pancreas to churn out insulin. Scientists promptly realized that GLP1 had strong potential. People with diabetes could certainly use it because they either manufacture too little insulin or need extra insulin to get by. Plus, GLP1 appeared safe, since it's a natural compound circulating in everyone's body. The finding seemed too good to be true.

Alas, it was. GLP1 turned out to have a half-life of mere minutes in the bloodstream. A compound so ephemeral has little value as a drug. So, researchers set aside GLP1 and its dazzling prospects for years until John Eng of the Veterans Affairs Medical Center in the Bronx, N.Y., discovered a form of the peptide that has longer-lasting effects.

Eng had been looking for hormones in animal venoms when he came across a component of Gila monster saliva that bears a chemical resemblance to GLP1. He tested the compound on guinea pig cells and found that it latches onto the same receptor molecule that GLP1 does.

Eng named the mysterious compound exendin-4, fashioned a synthetic version of it, and patented it for use against diabetes. When Eng injected exendin-4 into diabetes-prone mice, it lowered the animals' blood-glucose concentrations for up to a day.

Other scientists have now taken note of this strategy. An American Diabetes Association meeting in New Orleans in June featured a raft of long-lasting versions of GLP1, some being tested in diabetes patients for the first time. Early results show the compounds controlling blood sugar and curbing appetite. If this success is borne out in long-term trials, the experimental compounds could represent a new class of drugs for type 2, or adult-onset, diabetes.

Laboratory findings also reported at the meeting suggest that GLP1 not only revs up the insulin-making beta cells of the pancreas but also refurbish these cells and possibly spawn the growth of new ones. Says Riccardo Perfetti of Cedars-Sinai Medical Center in Los Angeles, "GLP1 doesn't just paint the house, it rebuilds it." If GLP1 mimics also have those effects, these substances would go well beyond current therapies, which concentrate on wringing every last molecule of insulin out of beleaguered beta cells or injecting extra insulin into the body.

VITAL CELLS Insulin directs the body to process glucose, the simple sugar that delivers energy to cells via the bloodstream. Too much insulin causes low blood sugar, which induces shaking and sweating and can be fatal. Too little insulin makes for high blood sugar, the hallmark of diabetes.

People with type 1 or juvenile-onset diabetes, stop making insulin early in life when a misdirected immune onslaught kills off their beta cells. People with type 2 diabetes usually retain beta cells into adulthood. But at some point, their bodies begin to ignore, or resist, insulin's message. Then beta cells must make more and more insulin to have an effect. Eventually, the overwhelmed beta cells start to commit suicide, sending blood sugar concentrations soaring.

Many middle-aged people with type 2 diabetes initially can control the condition by watching their diets, but they later need to take oral medication, such as Glucophage (metformin), to spur the remaining beta cells to make more insulin. In time, these patients often require insulin injections, as people with type 1 diabetes do.

Beta cells rely on an array of molecular signals to do their job, and GLP1 appears central to the program, Perfetti says. Some evidence suggests that supplies of GLP1 arriving in the pancreas are diminished in people with type 2 diabetes. So in a series of recent laboratory studies, Perfetti and his colleagues obtained beta cells and other pancreas tissue from type 2 diabetes patients and tested whether extra GLP1 would have an effect.

GLP1 inhibits cell suicide among these overwrought beta cells, the researchers found. Moreover, GLP1 exposure boosts the number of beta cells, perhaps by inducing nascent cells in the pancreas to develop into beta cells, Perfetti says. GLP1 switches on genes encoding insulin within the nucleus of the beta cells and initiates other actions that make beta cells more robust.

Tests on rats show beta cells with adequate supplies of GLP1 make needed insulin when glucose concentrations rise, a demonstration that proper signaling has been restored in the pancreas.

The peptide seems capable of "making new beta cells appear and preventing old beta cells from dying," says Daniel J. Drucker of the University of Toronto. "We don't yet have the human evidence of that, but that's the excitement that's underlying this field."

VERSATILE VERSIONS When Eng in 1996 presented his data showing that synthetic exendin-4 showed a benefit in diabetes-prone mice, Amylin Pharmaceuticals of San Diego took note. Since then, the company and several other research groups have begun testing long-lasting GLP1 mimics in people with type 2 diabetes. Like GLP1, the experimental drugs seem to have the uncanny capability to trigger only enough insulin production for efficient glucose metabolism. They switch on insulin secretion by beta cells when blood-glucose concentrations rise after a meal.

Amylin's Alain D. Baron reported at the June diabetes meeting that exenatide, the synthetic version of exendin-4, lasts 6 hours in type 2 diabetes patients. Twice-daily injections of the drug induced significant blood-glucose declines in roughly half of 63 patients who had insulin resistance so severe that oral medication had failed them.

What's more, the activity of exenatide doesn't shut off completely when it's no longer detectable in the blood, Baron notes. "Clearly, the drug has an effect above and beyond the time it's administered," he says.

Exenatide caused nausea in some patients, but this side effect faded after several weeks, Baron adds.

If exenatide works as well in a larger study, it might substitute for insulin injections. Amylin is working with Eli Lilly and Co. of Indianapolis to develop a long-acting, slow-release version contained in injectable biodegradable polymer beads.

At the same meeting, the drug company Novo Nordisk of Bagsvaerd, Denmark, presented promising results in diabetes patients receiving injections of a GLP1 mimic called NN2211. Ten diabetes patients showed higher beta cell sensitivity to glucose when getting NN2211 than when receiving a placebo.

Two other GLPl-based drugs enlist the services of albumin, a blood protein with a long half-life. One, a GLP1 mimic called CJC-1131, links with albumin in the blood to increase the drug's durability. Montreal-based ConjuChem is now testing CJC-1131 in people, says Drucker. Although, tests haven't yet established how long its effects last, he would like eventually to see a version that might be given weekly.

The other drug that relies on albumin is called Albugon. Scientists at Human Genome Sciences of Rockville, Md., bioengineered it from the genes for GLP1 and albumin. Albugon lasts roughly 11 hours when injected into mice and 3 days when given to monkeys, says Adam C. Bell, one of the drug's developers.

The way that GLP1--and the drugs patterned after it--appropriately switch on insulin secretion by beta cells only when blood-glucose concentrations rise would give such therapy a great advantage over current injected insulin, Bell says.

"The body has evolved an intricate system to sense intake of energy," Drucker explains, and gut cells making GLP1 and other compounds are an integral part of it. "Turning some of these gut hormones into drugs may, in fact, open us up to new treatments for diabetes," he says.

"To promote the formation of new beta cells and prevent the death of susceptible beta cells--that may well transform the way we think about the natural history of diabetes," Drucker says.

Baron predicts that Amylin Pharmaceuticals will next year apply to the Food and Drug Administration for approval for exenatide.