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Dissecting drug side effects offers hope (2011)

Researchers from the Maurice Wilkins Centre have discovered how a common class of medicines causes diabetes-like symptoms, and their work suggests a promising way of managing these side effects.

All medications have side effects, and studying them can point to better ways to manage disease. Professor Peter Shepherd and Dr Greg Smith at The University of Auckland investigate diabetes-like side effects associated with antipsychotic agents such as clozapine and olanzapine that are commonly used to treat schizophrenia. 

“Antipsychotic medications are widely prescribed internationally – in New Zealand alone around 30,000 people take these drugs – and side effects of weight gain and diabetes are a concern for many patients,” says Peter. 

“These side effects are well recognised but affect people variably, with some people experiencing severe effects and other people none at all,” says psychiatrist Dr Wayne Miles, Clinical Associate Professor at The University of Auckland. “Understanding the biochemical reasons that the side effects occur may eventually help to make treatment more tolerable.” 

Rates of diabetes – or “type-2 diabetes” as the most common form is more accurately known – are on the rise in New Zealand and around the world. “Most of the increase in type-2 diabetes is thought to be due to lifestyle factors, in particular obesity, but in some cases diabetes can be caused by drugs used to treat other conditions,” Peter explains. 

Since diabetes in the wider population is most often linked with obesity, it had been assumed that weight gain over a period of time in people taking antipsychotic medications was causing their diabetes-like symptoms. 

In laboratory studies published from 2008 to 2011, however, the New Zealand researchers showed that common antipsychotic medications trigger diabetes-like symptoms very rapidly, by directly altering the levels of key hormones, and that this occurs independently of any weight gain. 

They showed in animal studies that the medications rapidly suppressed levels of the hormone GLP-1, which in turn increased levels of a second hormone – glucagon. They went on to show that restoring GLP-1 function could overcome many of the side effects of the drugs. 

The work suggests that managing diabetes-like side effects in people on antipsychotic medications may require a different approach from standard diabetes care. It also points to a possible method of reversing diabetes in this group, by correcting the hormonal imbalance caused by their medication – for example using recently-discovered drugs that activate the GLP-1 system. 

The researchers are now extending these studies into humans with a clinical trial funded by the Health Research Council of New Zealand. Ultimately they hope this work will not only reduce the side-effects of current antipsychotic drugs, but also open up new routes to improved drugs for both schizophrenia and diabetes.