New Drug Targets Liver and Pancreas
posted 07/29/03

Researchers said on Thursday they had found a new class of drugs that might attack diabetes on more than one front -- and that could be taken as a pill.

They have only tested the drugs in rats and mice so far, meaning years of development are needed, but said the medications could offer an alternative to some of the drugs that many diabetes patients must take.

"At this point in time, this type of drug will not allow us to replace insulin," cautioned Joseph Grippo, a vice-president at Swiss drug giant Roche who led the research. The drug is targeting type-II diabetes populations before they get to insulin.

Patients with type II diabetes make too little insulin and have too much glucose in their systems. The new compound stimulates the pancreas to release more insulin and keeps the liver from producing too much glucose. Diabetes patients often take two drugs for this -- sulfonylureas and metformin. Roche's drug, known by the experimental name RO-28-1675, is a glucokinase enzyme activator. It acts on GK, an enzyme that diabetes researchers have known about for years.

The glucokinase enzyme is the body's first step in breaking down or metabolizing glucose.
"When the enzyme is functioning normally, GK helps the body maintain glucose levels by controlling the release of insulin from the pancreas as well as the disposal of glucose in the liver."

HOPES FOR HUMAN TESTS WITHIN A YEAR
In 1992 researchers discovered a mutation in the GK gene caused a certain type of diabetes called maturity onset diabetes of the young type 2. But, it did not seem like a good target for a drug. "In order to make it effective you have to activate the enzyme. If you look at many of the drugs out there the activators are rare. Most drugs inhibit enzymes.

But when Roche scientists started screening through a library of compounds -- a common way to look for drugs -- they found one that seemed like it would activate GK.

Reporting in the journal Science, they said it worked both in lab dishes and in mice.
Grippo said they hope to get approval to start testing it in people within a year.

"There have not been that many new drugs for the treatment of diabetes ever discovered, and this one is unique in its mechanism of action," said Mark Magnuson, a researcher at Vanderbilt University in Nashville, Tennessee who worked with GK for years. "No one ever thought we would find a drug that directly targets the enzyme and activates it," Magnuson added in a statement.

One big question is whether early treatment with drugs can prevent the development or progression of type-II diabetes. A class of drugs called TZDs or glitazones, which includes GlaxoSmithKline's Avandia, are being tested with prevention in mind. Grippo said the new Roche drug would not compete with these drugs, but said its mechanism of action might help prevent the deterioration of the pancreatic cells that produce insulin.

"If we catch people early enough, it will possibly have some benefit," Grippo said. "It's something we will look for."

Source: Diabetes In Control Dot Com.

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