Diabetes drugs must be targeted to ensure safety

Diabetes ResearchToday is World Diabetes Day – and there’s some great work being done at the Centenary Institute to understand and treat diabetes by Associate Professor Mark Gorrell and his team of liver researchers.

New research just published in the online journal PLOS ONE has confirmed that diabetes drugs and potential cancer therapies based on regulating the dipeptidyl peptidase (DPP) family of enzymes must be carefully targeted to avoid serious side effects, such as skin and intestinal damage.

Since the 1990’s Dr Mark Gorrell has been an advocate of drug targeting to safely treat diabetes. When enzyme-inhibiting drugs to treat diabetes were being developed, Dr Gorrell warned that care was needed to ensure the drugs targeted a specific enzyme, leaving other members of the enzyme family unaffected.

Thankfully, drug companies listened to this warning despite targeting being a disputed topic.

In 2005 Dr Gorrell ran an experiment designed to show that targeting is necessary to ensure drug safety – and his latest research has vindicated his hypothesis.

“Since 2005 the conversation of targeting in diabetes drugs was a controversial point, so it’s really gratifying to have a result after 6 years,” Dr Gorrell says.

The targeted inhibition of enzyme DPP4 activity is the basis of a leading drug treatment for diabetes. DPP4 inhibitors enjoy sales of about $6 billion a year and comprise about a quarter of the diabetes drug market. All licensed DPP4 inhibitors are DPP4-specific.

Inhibiting the action of another enzyme in the DPP family, DPP9, is also under investigation as a cancer therapy in adult humans.

Dr Gorrell and his researchers found that mice lacking an active form of the enzyme DPP9 die as newborns after developing quite normally to that point.

“If removing DPP9 activity is as dangerous for humans at an early age as it clearly is for mice, then DPP4 inhibitors really do have to be DPP4-specific. It’s possible that DPP9 is essential in humans too, and that its lack may cause problems in early infancy. But we’re only just starting to look at that possibility.”

Finding out just how critical DPP9 is to the survival of newborn mice—and the fact that its activity cannot be compensated by any other enzyme —“was unexpected,” Dr Gorrell says.

The importance of this research is reflected in the recent upsurge of interest in DPP9 inhibitors after evidence emerged that may be useful in cancer therapy. By dampening the activity of DPP9, some inhibitors are able to activate the immune system and slow down tumour growth.