Clock-setting chemical discovered

Scientists have discovered a chemical that can alter the activity of the body clock and might hold the key to a new treatment for diabetes...

Almost without exception, cells in the body show synchronised patterns of biochemical activity that follow a 24h cycle. In the majority of cases, this is achieved by a family of genes that function like a DNA domino effect with one gene switching on a second, which feeds back and turns off the first.

This cycle takes about a day to complete, and the gene products themselves also control the activities of large numbers of other genes concerned with metabolism, enabling cells to optimise their activities to meet the demands of the body.

But it's becoming increasingly clear that a range of diseases, including diabetes, are directly linked to this circadian clock going off kilter, while shift-work is also well-known to have long-term serious health consequences.Scientists are therefore searching for chemicals that can manipulate the clock to reduce these risks.

Now, writing in Science, University of California San Diego scientist Steve Kay and his colleagues have identified a small family of carbon-ring-based molecules called carbazoles that appear to be able to do this.

Kay and his team made the discovery by testing over 60,000 different compounds on dish-cultured cells that had been genetically engineered to produce a coloured label whenever one of their clock genes became active. By looking for changes in the expression levels of the label, they were able to spot chemicals capable of targeting the clock system.

One substance, KL001, was particularly potent and had the effect of slowing down the clock cycle by binding to 2 of the genetic cogs in the body clock, CRY 1 and 2, and preventing them from being broken down.

In the liver, these genes help to regulate control of blood sugar levels by altering the activity of glucose-producing biochemical pathways. Predicatbly, adding the KL001 drug to cultured liver cells stopped them responding to hormone signals that would normally elevate blood sugar, suggesting that this mechanism might hold the key to a new way to control diabetes...