New treatments for diabetes could be on the way, following a discovery about the mechanism of energy production in cells. A key enzyme in the process is stimulated by two molecules, not one, as previously thought. The finding unveils new targets for the treatment of type 2 diabetes. Often considered the cell’s energy regulator, the enzyme known as AMP-activated protein kinase (AMPK) helps “recharge” a cell by stimulating the creation of adenosine triphosphate (ATP), which then fuels the cell’s activities.
When ATP breaks down it becomes adenosine diphosphate (ADP) or adenosine monophosphate (AMP). Once ATP is depleted, AMP stimulates the phosphorylation of AMPK – the addition of a phosphate group to the enzyme. This triggers the production of more ATP. For decades it was thought that only AMP had the power to activate AMPK, as the enzyme’s full name suggests. AMP causes AMPK to change shape, exposing its “active site” and so making it more likely to be phosphorylated, or attaches itself to AMPK, making it more likely to be phosphorylated by other enzymes.
Now, Jonathan Oakhill and Bruce Kemp at St Vincent’s Institute of Medical Research in Melbourne, Australia, have found that ADP can also activate AMPK. By mixing ADP with the AMPK expressed in monkey kidney cells, the team found that ADP could coax phosphates to bind to AMPK, at a similar rate to AMP.
As far back as 1975, there have been studies showing that ADP could activate AMPK, but a later report refuted the evidence, claiming AMPK activation in these studies was in fact just caused by AMP which had contaminated the ADP experiments. The new finding provides a fresh target for the treatment of type 2 diabetes, which is characterised by insulin resistance or deficiency. When AMPK is activated in muscle cells, they become more sensitive to insulin. Creating drugs that amplify ADP’s actions on AMPK could improve sensitivity to insulin and treat diabetes, says Kemp.
“This could have big implications for the management of diabetes,” says Christopher Nolan at the Australian National University in Canberra. “If we had new ways to increase AMPK activity, we could have new ways to treat diabetes,” he says.