New Chemical May Lead to Oral Insulin Equivalent
Pharmaceutical researchers have found the first simple molecule that, given by mouth, can mimic the action of insulin in diabetics, a discovery that could eventually free millions of people from the burden of injecting insulin two or more times a day.
Isolated from a fungus growing on the leaves of a plant collected outside Kinshasa, Congo, the chemical controls blood glucose levels in mice specially bred to develop diabetes, the team reports in today’s Science. Researchers have high hopes that it or a closely related chemical will do the same thing in humans.
Insulin helps cells throughout the body use glucose for energy and store it for future use, but it produces no effects if taken orally because it is a protein that is broken down in the stomach.
An estimated 1 million Americans have Type 1, or insulin-dependent, diabetes and must take the hormone every day. Many of the 15 million Americans with Type 2, or adult-onset, diabetes must also inject insulin, as do many of the 175 million diabetics worldwide.
If the new chemical is shown to work as well in humans as it does in mice, “the potential is enormous,” said Dr. Arthur Rubenstein of Mt. Sinai Medical Center in New York City.
“Conceptually, the idea that a simple molecule can replace insulin is dramatically important,” said Dr. Gerald Bernstein of Beth Israel Medical Center in New York, president of the American Diabetes Assn. “This is a very exciting opportunity.”
Officials from Merck Research Laboratories, which discovered the chemical, would not speculate on when it might be tested in humans. Although they observed no adverse effects in the mouse experiments, Merck researchers will have to do much more toxicological testing before the substance can be given to humans.
“The point is to demonstrate that this novel approach [to treating diabetes] works,” said endocrinologist Bei Zhang, leader of the Merck team. “It’s way too early to project how or when it might get into clinical trials.”
Type 1 diabetes occurs when insulin-secreting cells in the pancreas are destroyed by an individual’s immune system, for reasons that are not clear. If insulin is not administered, the diabetic can quickly develop symptoms, including coma, and die.
Insulin delivered by injection is a $3-billion-a-year industry, but many researchers are looking for less painful and more convenient ways to deliver the drug.
Early clinical trials of an inhaled form of insulin have been successful, but some diabetics consider that approach more cumbersome than injections. Researchers are also trying to modify insulin so it can survive passage through the stomach, but that has not yet been very successful.
Type 2 diabetes has a variety of causes, but the ultimate problem is either that the pancreas does not produce sufficient insulin--even though insulin-secreting cells are intact--or that cells throughout the body are resistant to insulin’s effect.
This adult-onset form of diabetes can be treated with diet, exercise and a variety of drugs that stimulate insulin production and uptake. But the drugs have some side effects, including nausea, vomiting and tingling of the hands and feet. One such drug, called Rezulin, has recently been linked to 43 cases of liver failure.
If the new Merck chemical can mimic insulin without having serious side effects, it will be valuable in treating both forms of the disease.
“This is the first chemical we’ve seen that does this,” said Dr. Robert Goldstein, vice president for research of the Juvenile Diabetes Foundation International. “This looks to be a unique approach to the issue, and is thus very exciting.”
In their search for new drugs, pharmaceutical companies frequently travel the world, looking for new plants, bacteria and fungi. They then test them in screening systems to determine whether they have biological effects.
The anti-cancer drug Taxol, for instance, was isolated from the Pacific yew tree and the anti-rejection drug cyclosporin from a soil fungus.
The new insulin mimic is produced by a fungus called Pseudomassaria that was collected years ago outside Kinshasa. Chemicals secreted by the fungi were tested by researchers in Merck’s Spanish subsidiary as part of an ongoing search for chemicals that could stimulate cells to take up glucose.
When the fungal extract showed a strong effect in the preliminary screening, Merck chemist Gino Salituro sorted through the hundreds of chemicals the fungus secreted and identified one, called L-783,281, that was responsible for the effect. He determined its structure and found it to be, surprisingly, a type of chemical that is not like any drug now used to treat diabetes.
“From looking at its chemical structure, you would not think it has any obvious biological activity,” said Merck’s David Moller, co-leader of the team.
But when Zhang and Moller tried L-783,281 in diabetic mice, they found that it controlled blood glucose levels as well as any drug now used.
Equally important, its action seems to be specific for stimulating glucose uptake by cells. It does not seem to affect a variety of other biological pathways that are often activated by insulin-like molecules, producing unwanted side effects.
“It was quite well tolerated at the doses used to give glucose lowering,” Zhang said.
L-783,281 itself may not be the chemical that eventually makes it into clinical trials. When a new biological agent is found, it is standard procedure at drug companies to make dozens or even hundreds of derivatives in an effort to find chemicals that are even more powerful.
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Possible Pill for Diabetes
Scientists have discovered a simple molecule that regulates glucose use and storage just like insulin. Unlike insulin, the molecule can be taken orally.
Diabetes
Diabetes occurs in two forms. In Type 1 diabetes, the insulin-secreting cells of the pancreas have been destroyed and insulin must be given by injection. In Type 2 diabetes, also called adult-onset diabetes, either the insulin-secreting cells do not produce enough insulin--even though they are intact--or cells become resistant to its effects.
