A Lundbeck Foundation researcher has headed a study to map activity in 80,000 different brain cells, which in animal trials have been proven to help control complicated blood sugar processes. This could have implications for treatment of type 2 diabetes in humans.
Researchers around the world reacted with amazement in 2016 to an article published in the prestigious scientific journal Nature Medicine, detailing trials with mice that had been genetically engineered to become type 2 diabetes patients.
In the article, a team of American researchers demonstrated that a single injection into the brain of a specific signal molecule found in mammals was sufficient to achieve permanent recovery of blood sugar levels in the diabetic mouse models.
The mice were then able to regulate their own blood sugar levels as normal, and they no longer had symptoms of type 2 diabetes. As Tune H Pers, associate professor and Lundbeck Foundation Fellow at the NNF Centre for Basic Metabolic Research at the University of Copenhagen, explains, the results were highly surprising for a number of reasons:
‘Primarily, of course, because the symptoms of type 2 diabetes disappeared completely. But the fact that this reaction resulted from an injection into the brain also caused a stir. Traditionally, the brain is not in the spotlight when it comes to diabetes research.’
Type 2 diabetes is one of the lifestyle diseases rapidly on the rise in many parts of the world. It is also costly in terms of human suffering and a burden on healthcare resources. For these reasons, too, the disease is of concern to many researchers.
Despite the fact that it is hardly a realistic proposition – even if purely for ethical reasons – to treat type 2 diabetes by injecting the brains of human beings in the way the researchers injected the genetically engineered mice, the American trials inspired other researchers to take a closer look at the novel signal molecule known as FGF-1.
Indeed, numerous questions remained unanswered after the American trials, and we need to address these if this signal molecule is to be useful in treating type 2 diabetes in humans in the future.
Among these, one question is of particular relevance: which cells and which functions stimulated the signal molecule in the diabetic mouse brains?
Tune Pers and his postdoctoral associate Marie A Bentsen decided to investigate, and, to this end, they gathered a team of colleagues from universities in Denmark and the USA. One of the members of the team is the man who spearheaded the American trial in 2016, Professor Michael W Schwartz from the University of Washington. Researchers from Spain and Thailand also participated.
The first phase of the mapping work is now complete, and Tune Pers and his colleagues were able to demonstrate in a scientific article, recently published in Nature Communications, how the 80,000 different neurons in the brains of the diabetic mouse models reacted to the signal molecule.
The 80,000 neurons were all localised in the hypothalamus, a region of the brain in mice, humans and all other mammals that controls, among other things, blood pressure, appetite and thirst.
“Like seeing all of the lights in the entire city”
If you want to delve into something extremely complicated then make a start on the hypothalamus, says Tune Pers who is investigating the role of the brain in the development of obesity and type 2 diabetes:
‘The hypothalamus has a number of so-called cores which act as control centres. They keep track of processes such as growth and weight, and in humans they also play a role in the timing of puberty and menopause. If you want a more detailed picture of how all these control centres work – and how they have the potential to interact – you need to look at the genetic regulation of their specialised cells. And that’s what our mapping of the 80,000 different neurons was all about.’
As part of the mapping process, Tune Pers and his colleagues repeated Michael Schwartz’ trials from 2016:
‘We used the exact same type of genetically engineered mouse model as used by Schwartz in the original trials. We initially divided the mice into two groups. All of the animals were then given a general anaesthetic and an injection in the hypothalamus. One group was given injections with the novel signal molecule, while the other received injections with a saline solution,’ Tune Pers explains.
The researchers then used a new technique to track the genetic activity in the hypothalami of the two groups of mice. This technique allows scientists to study the genetic activity in a single cell, to see how the cell’s genetic code commands it. And the technique can be used to collect and handle huge volumes of data when, as in this case, you have 80,000 different brain cells to study in all kinds of detail.
Tune Pers attempts to put this volume of data into perspective by using the image of flying over a large city at night:
‘From the plane, you can see lots of lights from buildings and streets below you, but you’re seeing only a small proportion of all the lights that are actually switched on. Imagine if you could look into all of the buildings, into all of the rooms, and down into all the basements; you’d see a great many more! And this is literally what we do with the new technique we’re using to map the genetic activity of the 80,000 different hypothalamus cells.’
Repeating the trial
The fascinating thing about Michael W Schwartz’ 2016 trial was that the signal molecule permanently relieved the injected, genetically engineered mice of their type 2 diabetes symptoms.
But, as Tune Pers explains, there was another remarkable aspect:
‘The obese mice lost no weight at all. This is what you’d expect, since obesity and type 2 diabetes are closely linked. About 80% of all people with type 2 diabetes are obese. It’s also a well-known fact that many patients reduce their symptoms, or can eliminate them altogether, if they lose weight. So, of course, when Marie Bentsen repeated Schwartz’ 2016 trial, it was exciting to see whether she would get the same results as he did. And she did,’ says Tune Pers:
‘Her experiments had exactly the same outcome: the mice given the signal molecule were relieved of all type 2 diabetes symptoms but remained obese. And there was no change at all in the control group that had been given saline solution.’
But what about the mapping of the genetic regulation of the 80,000 genes in the hypothalamus – what did that show?
One of the most significant findings of the mapping experiment was that the signal molecule only eliminates the symptoms of type 2 diabetes if a specific group of neurons are intact. Tune Pers explains:
‘We don’t yet have the details of how these neurons and the signal molecule are linked. And, so far, we can’t explain why the signal molecule eliminates symptoms of type 2 diabetes in the mouse models – without seeming to have any effect on their obesity. We’ll need to study this much more before it’s realistic to assume that the signal molecule could be used in some way to treat type 2 diabetes in humans.’ (end of text)