Drug Deals Diabetes a One-Two Punch

17 July 2003 (All day)

Activated. A glucokinase (right) enhancer tackles two major defects found in diabetes.

People with type II diabetes can't respond properly to insulin and end up with too much glucose in their blood, which can damage blood vessels and other tissue. Now a novel strategy has drastically reduced blood sugar levels in rodents, sparking hope that it could become a powerful tool for controlling diabetes.

Insulin is a hormone that shuttles glucose into cells. When the pancreas makes too little insulin or the body responds to it improperly, cells don't absorb enough glucose and blood sugar levels soar. The problem is compounded by the liver's tendency, in diabetes patients, to churn out excess glucose. There's no perfect therapy, but most drugs tackle the problem by increasing insulin production or enhancing cells' sensitivity to insulin. In severe cases, patients rely on insulin injections.

Molecular pharmacologists Joseph Grippo, Joseph Grimsby, and their colleagues at Hoffmann-La Roche in Nutley, New Jersey, pursued a different strategy. They focused on an enzyme called glucokinase, which regulates two key functions that go awry in diabetic patients: secretion of insulin by the pancreas and overproduction of glucose by the liver. Boosting glucokinase activity, they believed, might normalize both--something no diabetes drug can do.

Using a molecular screen, Grippo and his colleagues dug a glucokinase activator out of a haystack of 120,000 candidate molecules. The researchers tested the activator on islet cells, the pancreatic cells that secrete insulin. The drug coaxed rat islet cells to release insulin, and rat liver cells responded, too; the drug blunted their tendency to release glucose.

Diabetic mice given the activator responded dramatically. With a single oral dose of the drug, their blood sugar levels plummeted by half; in some cases they dropped below normal. Injecting animals with an almost identical molecule that doesn't activate glucokinase had no effect, the group reports in the 18 July issue of Science.

The drug's ability to target the pancreas and the liver simultaneously "is a potential big plus," says Alan Cherrington, a physiologist at Vanderbilt University in Nashville, Tennessee. But, says Robert Rizza, an endocrinologist at the Mayo Clinic in Rochester, New York, the activator's novelty comes with some risk. The main worry, he and others say, is that the drug might lower blood sugar levels too much. Grippo believes that careful dosing would help users steer clear of side effects.

Related sites
Information on type II diabetes
Diabetes clearinghouse at NIH

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