Researchers say they have discovered a family of molecules that acts on a key gene involved in blood sugar control, a finding that could lead to more effective diabetes treatment.
Glucokinase gene activity stimulated
The molecules increase the activity of the gene that produces glucokinase, which is the most important member of a family of kinases that maintain normal glucose levels in the body, says Joseph Grippo, vice president for metabolic diseases at the Hoffman-La Roche Inc. and lead author of a report on the discovery in the July 17 issue of Science.
What makes these molecules look interesting is that glucokinase acts in two ways to keep blood sugar under control, Grippo explains. It is activated when blood sugar levels rise above normal after a meal, increasing insulin secretion
from the pancreas and stimulating the process of glucose metabolism in the liver. It is inactivated just as quickly, when blood glucose levels drop to normal.
Thus, we could control two very important points in the process of blood sugar control, Grippo says.
A single mode of action
Today's diabetes drugs all have a single mode of action. For example, the sulfonylureas, the most widely used medications to control blood sugar, are effective because they increase insulin production. Metformins reduce production of glucose. Many patients now are given more than one drug to achieve this dual action.
Like the sulfonylureas and other oral medications, the prospective new medications would be useful only for type 2 diabetes, in which the body can still produce some insulin. Type 1 diabetes requires insulin injections because the pancreas cannot produce the critical hormone.
Decade-long effort bears fruit
In the latest study, the Hoffman-La Roche investigators screened a library of 120 000 compounds to come up with others that increased glucokinase activity. Then they synthesised variants on that compound that were even more effective. Work with mice and rats with rodent versions of type 2 diabetes showed the compounds increased insulin secretion as well as glucose metabolism. The work was done in collaboration with Dr Franz Matschinsky, a professor of biochemistry and biophysics at the University of Pennsylvania School of Medicine who did much of the work establishing the importance of glucokinase.
It has been a decade-long effort, Matschinsky says. They got wind of the work, and then we began to talk, he recalls. He says he is still working intensively on glucokinase. I am very involved in the whole concept.
Longer-term testing to follow
The newly reported work is just the beginning of a long effort that may or may not produce a usable medication, Grippo says. The next step is longer - and longer-term testing, he says. It has been effective in mice up to nine months with no loss of activity, which is very exciting for us. Early studies with dogs have also shown promising results, he adds.