Two professors at the University of Dundee have combined their scientific expertise to crack an important scientific problem. Their research, published this week in Journal of Biology, may lead to the development of improved drugs to treat diabetes.
Dario Alessi, working at the Medical Research Council Protein Phosphorylation Unit (in Dundee), and Grahame Hardie, at the Wellcome Trust Biocentre, (Dundee,) have discovered that a tumour suppressor called LKB1 is the long sought after enzyme that switches on AMPK, an enzyme important in regulating the level of glucose in the blood.
High blood glucose levels are a hallmark of diabetes. These levels are reduced by AMPK, which increases the rate at which glucose is transported from the blood and into muscle, and decreases the production of glucose in the liver. Drugs that can switch on AMPK, such as Metformin (also called Glucophage), are therefore commonly used to treat Type II diabetes. Until now, it was not clear how these drugs exerted their effects, but the researchers have now found that Metformin does not work if there is a deficiency of LKB1. This suggests that the drug activates AMPK via LKB1.
This fundamental new understanding of how AMPK is switched on in the body is likely to stimulate the development of improved drugs to treat Type II diabetes, which are better than Metformin at normalising blood glucose and which lack its unpleasant side effects that include stomach and intestinal problems.
Remarkably, a lack of LKB1 activity is known to be the cause of Peutz-Jeghers Syndrome, a rare inherited disease that predisposes people to many types of cancer. The discovery that LKB1 switches on AMPK therefore raises the possibility that AMPK is also important in preventing cancer and that drugs that activate AMPK may be useful for the treatment of some cancers, as well as diabetes.
Commenting on their discovery Grahame Hardie said: "The idea that LKB1 might switch on AMPK came from work I did on a related system in the simple single-cell organism, brewer's yeast with another colleague in Dundee, Mike Stark. The idea that LKB1 might be the key was a genuine 'Eureka' moment, especially when I realized that Dario Alessi already worked on it and had all of the expertise necessary to test the idea. I immediately went down the corridor to see him. That was late one afternoon, and by lunchtime the following day we had done the first successful experiment to prove the idea. If I had been working somewhere else I would probably still be struggling to do it. This shows the benefit of working in a major biomedical research centre like Dundee, where the whole is much more than the sum of its parts.
This was an extraordinary and totally unexpected result that has important implications for our general understanding of diabetes and cancer. It also demonstrates the strength of this area of research in Dundee and the importance of scientific collaboration blending the complementary expertise and knowledge from our laboratories to discover the function of the LKB1 enzyme and identify it as the long sought after enzyme that activates AMPK."
Eleanor Kennedy, Research Director at Diabetes UK said: "This is an exciting development. It holds out the prospect of new treatments which give better control of diabetes. This could mean real improvements in the lives of people with the condition. We know that good control of your diabetes reduces the risk of the long term effects such as heart disease, blindness, kidney disease and amputations. Diabetes UK looks forward to seeing whether this research can make that more possible."
The paper goes live on the Journal of Biology website today (24/9/03) at 5pm. A preview paper for press can now be viewed at http://jbiol.com/press
Contact Dario Alessi 01382 348058
Grahame Hardie 01382 344253 or 344719
By Jenny Marra, Head of Press 01382 344910 j.m.marra@dundee.ac.uk