Written by:
EVP and President BioPharmaceuticals R&D, AstraZeneca
VP Centre for Genomics Research, AstraZeneca
SVP and Head of Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
Close to one in 16 people worldwide is affected by diabetes mellitus and the number is rising rapidly1. The clinical management of diabetes is often complicated by other factors and illnesses such as obesity, liver and kidney diseases2. Current treatments focus on managing symptoms instead of seeking to target the underlying causes directly. We are following the science to uncover new treatment approaches that could help many more people to live their lives free from diabetes.
Just a spoonful of sugar
Diabetes is a metabolic illness that results from a failure to correctly process sugar. As such, people with diabetes often need to carefully control when and how much sugar they eat.
The science of diabetes hinges on the hormone insulin which is made in the pancreas. When we eat, the amount of sugar in the blood rises. The pancreas detects this change and releases insulin into the blood. Insulin is detected by cells in the liver, muscles and fat tissues, causing them to take up sugar from the blood and convert it into other molecules which store energy until it is needed.
People with diabetes either have type-1 diabetes where they do not produce insulin, or type-2 where their bodies stop responding to insulin. Type-1 diabetes is usually diagnosed during childhood and can be treated with insulin injections. Most people with diabetes (around 95%) have type-2, which is linked to an inactive lifestyle or high body weight1. Type-2 diabetes is more typical later in life, although it is increasingly being seen in children mostly due to rising childhood obesity3. In addition, some people develop a form of diabetes when they are pregnant called gestational diabetes, which usually resolves after giving birth.
Is there a gene for diabetes?
Although there is clear evidence that some people are genetically much more or less likely to develop one type of diabetes or the other, it has been hard to pinpoint the exact genes that affect the risk of type-1 and type-2 diabetes4.
Collecting information on human genetics is now much easier than it has ever been. Worldwide, there are many projects that have focused on gathering genetic data on large numbers of people to help us gain deeper insights into the relationships between our genes and complex diseases like diabetes. With this in mind, in 2016 we set ourselves a bold ambition to analyse two million genomes by 2026 through our integrated genomics initiative5. Our aim is to leverage ongoing advances in genome technologies to uncover new disease insights and expand the therapeutic world that is available to those with chronic diseases. The information we gather using these approaches will be key to identifying the most appropriate genetic target for subpopulations of patients.
In a recent study our scientists shared some of the results of this work in which they studied diabetes using over 800,000 samples from across several genomic data collections, including the UK Biobank (450,000), Mexico City Prospective Study (MCPS; 100,000) and FinnGen (260,000).
There are many reasons to expect differences when comparing genetics from groups of people from the UK, Mexico and Finland, so finding a genetic change that appears to prevent diabetes in all these groups of people is particularly exciting. Starting with the UK Biobank, our scientists found that people that were unable to make a protein called MAP3K15 could be up to 35% less likely to develop diabetes, both type-1 and type-2. Given the many differences between the types of diabetes, it is unusual to find a single gene that affects the risk of both.
Putting MAP3K15 on the map
After finding a link between diabetes and MAP3K15 in people from the UK, our scientists then went on to show the same pattern in samples from MCPS and FinnGen. They also dug deeper into the data to show that losing MAP3K15 protects people from diabetes no matter their body mass index (BMI). This too is unusual, since people with a higher BMI are much more likely to develop type-2 diabetes.
But what is MAP3K15 and how does it prevent diabetes? The simple answer is that this is the vital next step for our research. We know that the pancreas, where insulin is made, is one of the parts of the body where the gene that produces MAP3K15 is normally active. We also know that MAP3K proteins generally help cells to communicate by responding to chemical signals6. Our hope is that MAP3K15 could be an effective target for treating diabetes and data from the UK Biobank, MCPS and FinnGen show that there are thousands, if not millions, of people worldwide who have low levels, or a total lack, of MAP3K15 and are otherwise healthy.
Overall, we have shown that MAP3K15 is potentially a safe target for the prevention, and possibly treatment, of both forms of diabetes. If this proves to be the case following further pre-clinical research, then a medicine targeting MAP3K15 could transform diabetes healthcare, helping to stop the rapidly rising number of cases worldwide so that more people can live better, healthier lives.
