IOS extra: pheromones & diabetes

How do pheromones affect the lives of animals from moths to fish and even humans? What can a rare mutation tell us about diabetes and how to treat it?

These were the topics discussed in the third edition of our regular series of science podcasts, Inside Oxford Science: you can listen here or download it from iTunesU.

In OxSciBlog’s Inside Oxford Science Extra (IOS Extra) we delve deeper into the issues behind the podcast with extra info and links…

Stimulating smells
As far back as Ancient Greece people had noticed the behaviour of dogs in heat suggesting that ‘invisible sexual messages’ were being communicated but, as Tristram Wyatt of the Department of Zoology tell us, there were some pretty odd ideas about how this might happen – everything from sounds below human hearing to infrared radiation.

It wasn’t until 1959 that such notions were definitively put to rest when the first pheromone was chemically identified by Adolf Butenandt ‘Pheromone’ was a term coined by Peter Karlson and Martin Lüscher that same year from the Greek ‘pherein’ (to transport) and ‘hormone’ (to stimulate). Tristram explains that a good definition of a pheromone would be: ‘a chemical released by an individual that has an effect on the behaviour or physiology of another member of that species’ – although we’ll see that some creatures use pheromones ‘illegally’.

Butenandt called the pheromone he identified bombykol after the silk moth Bombyx mori that produces it – females secrete it to attract a mate.

The lengths he had to go to show just how difficult it was then to isolate enough of the pheromone to identify: Butenandt needed 500,000 silk moths for his experiment – some had to be imported from as far away as Japan.

A key to identification was the telltale sign male moths make – as part of a bioassay – fluttering their wings if bombykol is present.In the 50 years since Butenandt’s discovery many more animals have been shown to use pheromones: from elephants to goldfish, mice to lobsters.

Deception and debate
Not all users play fair, however, with examples such as the bolas spider, which synthesises moth pheromone to lure male moths to their deaths and even plants get in on the act with orchids attracting male wasps.

Social insects are amongst the most sophisticated users of pheromones: and whilst such chemical signalling does not approach the complexity of language it does enable them to mark trails, raise the alarm and coordinate attacks on intruders.

Do humans have pheromones?

Tristram tells us this is still a controversial question although work by scientists including Martha McClintock at the University of Chicago suggests that they do – and that pheromones are behind an effect in which women’s menstrual cycles become synchronised – the first human pheromone has yet to be chemically identified.

Finding human pheromones is an enormous challenge. For one thing many pheromones are not only present in very small amounts but are often a combination of molecules.

Another difficulty is the complexity of human behaviour – unlike moths we don’t (usually!) flutter our wings when we smell a sexually attractive scent, so finding a way of determining when a candidate pheromone is affecting humans is hard.

Strangely there is very little serious research going on into human pheromones, Tristram comments: ‘For some reason it’s very sexy on the Internet but not very sexy for funding agencies.’ More about this work here.

Diabetes from birth
Basic research into the role a protein plays in insulin secretion has ended up having a striking impact on the lives of people with a rare form of diabetes.

Insulin is produced by the beta-cells of the pancreas and is used by the body to reduce the blood sugar level after a meal. Diabetes - characterised by abnormally high blood sugar - results when the body doesn’t produce enough insulin, or becomes resistant to its action. So it is essential to understand exactly how a rise in the blood sugar concentration leads to the release of insulin in order to determine what goes wrong in diabetes.

Over 25 years ago, soon after she had first arrived in Oxford, Frances Ashcroft discovered that a protein known as a potassium channel is crucially important for insulin release. This potassium channel sits in the cell membrane and acts as a tiny gated pore. When it is open, insulin is not released and when it is closed insulin is secreted by the beta-cell.  Frances showed that glucose caused the channel to shut, so stimulating insulin secretion.

Subsequently, she and others (including Patrik Rorsman, who is also now at Oxford) showed that the sulphonylurea drugs used to treat type-2 diabetes cause insulin secretion by closing the channel. Even at the time it was clear that mutations in the genes that code for the channel proteins might cause diabetes if they caused the channel to be more open. But the gene was unknown and it took many years to identify the DNA sequence that coded for the channel. In 1995, Frances identified clones of the genes involved (Kir6.2) which enabled the search for mutations associated with the diabetes.

Starting in 2004, Andrew Hattersley, an Oxford alumni now at Peninsula University Exeter, discovered that mutations in Kir6.2 are associated with a rare form of diabetes that manifests at birth or shortly after, known as neonatal diabetes. Frances showed that the mutant channels are no longer closed by glucose and, importantly, that sulphonylurea drugs can still shut them.

Replacing insulin
Patients with neonatal diabetes had previously been treated with regular insulin injections, but the discoveries of Frances and Andrew suggested they might respond to sulphonylurea drugs. This turned out to be the case for 90 per cent of patients with mutations in the potassium channel and more than 400 have now been able to switch from insulin injections to one or two sulphonylurea tablets daily. This has had a dramatic effect on the quality of life of both patient and parent - and a considerable improvement in the patient’s clinical condition.

Some children with severe potassium channel mutations don't just have diabetes: they also have epilepsy, muscle weakness and developmental delay, so that they walk and talk late for their age. This is because the potassium channel is also found in muscle and brain cells.

Insulin cannot help the extra-pancreatic effects of the channel mutations but, as Frances describes, the sulphonylurea drugs do. Within a few days or weeks of drug therapy, the children start to walk and talk. Although most of them never fully catch up, the hope is that if they are given the drug early enough the neurological problems can be prevented.

As Frances says this is an extremely unusual story: it’s very rare for a research scientist to see their work contribute towards such an improvement in people’s health within their working lifetime.

One of the reasons this was possible was that the sulphonylurea drugs were already being used to treat type 2 diabetes, so that no new drug needed to be developed and tested.

Even so, it's worth bearing mind that it took a long time. Although it two only a year or two from discovering potassium channel mutations caused neonatal diabetes to implementation of a new therapy, the ability to do so was based on twenty years of fundamental research by many scientists across the world. 

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