A study of the DNA of more than 55,000 people worldwide has shed light on how we maintain healthy blood sugar levels after we have eaten, with implications for our understanding of how the process goes wrong in type 2 diabetes.

The findings, published today in Nature Genetics, could help inform future treatments of type 2 diabetes, which affects around 4 million people in the UK and over 460 million people worldwide.

Several factors contribute to an increased risk of type 2 diabetes, such as older age, being overweight or having obesity, physical inactivity, and genetic predisposition. If untreated, type 2 diabetes can lead to complications, including eye and foot problems, nerve damage, and increased risk of heart attack and stroke.

Investigating the genetics of the response to ‘glucose challenge’

A key player in the development of type 2 diabetes is insulin, a hormone that regulates blood sugar – glucose – levels. People who have type 2 diabetes are unable to correctly regulate their glucose levels, either because they don’t secrete enough insulin when glucose levels increase, for example after eating a meal, or because their cells are less sensitive to insulin, a phenomenon known as ‘insulin resistance’.

Most studies to date of insulin resistance have focused on the fasting state – that is, several hours after a meal – when insulin is largely acting on the liver.  But we spend most of our time in the fed state, when insulin acts on our muscle and fat tissues.

It’s thought that the molecular mechanisms underlying insulin resistance after a so-called ‘glucose challenge’ – a sugary drink, or a meal, for example – play a key role in the development of type 2 diabetes. Yet these mechanisms are poorly-understood.

Professor Sir Stephen O’Rahilly, Co-Director of the Institute of Metabolic Science at the University of Cambridge, said:

We know there are some people with specific rare genetic disorders in whom insulin works completely normally in the fasting state, where it’s acting mostly on the liver, but very poorly after a meal, when it’s acting mostly on muscle and fat. What has not been clear is whether this sort of problem occurs more commonly in the wider population, and whether it’s relevant to the risk of getting type 2 diabetes.”

To examine these mechanisms, an international team of scientists used genetic data from 28 studies, encompassing more than 55,000 participants (none of whom had type 2 diabetes), to look for key genetic variants that influenced insulin levels measured two hours after a sugary drink.

The team identified 10 new loci – regions of the genome – associated with insulin resistance after the sugary drink. Eight of these regions were also shared with a higher risk of type 2 diabetes, highlighting their importance.

GLUT 4 in the frame.

One of these newly-identified loci was located within the gene that codes for GLUT4, the critical protein responsible for taking up glucose from the blood into cells after eating. This locus was associated with a reduced amount of GLUT4 in muscle tissue.

To look for additional genes that may play a role in glucose regulation, the researchers turned to cell lines taken from mice to study specific genes in and around these loci. This led to the discovery of 14 genes that played a significant role in GLUT 4 trafficking and glucose uptake – with nine of these never previously linked to insulin regulation.

Further experiments showed that these genes influenced how much GLUT4 was found on the surface of the cells, likely by altering the ability of the protein to move from inside the cell to its surface. The less GLUT4 that makes its way to the surface of the cell, the poorer the cell’s ability to remove glucose from the blood.

Dr Alice Williamson, who carried out the work while a PhD student at the Wellcome-MRC Institute of Metabolic Science, said:

What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work – and in particular how, when these mechanisms go wrong, they can lead to common diseases such as type 2 diabetes.”

Given that problems regulating blood glucose after a meal can be an early sign of increased type 2 diabetes risk, the researchers are hopeful that the discovery of the mechanisms involved could lead to new treatments in future.

Professor Claudia Langenberg, Director of the Precision Healthcare University Research Institute (PHURI) at Queen Mary University of London and Professor of Computational Medicine at the Berlin Institute of Health, Germany, said:

Our findings open up a potential new avenue for the development of treatments to stop the development of type 2 diabetes. It also shows how genetic studies of dynamic challenge tests can provide important insights that would otherwise remain hidden.”

The research was supported by Wellcome, the Medical Research Council and the National Institute for Health and Care Research.

Read more

• Williamson, A et al. Genome-wide association study and functional characterisation identifies candidate genes for insulin-stimulated glucose uptake. Nat Gen; 8 June 2023; DOI: 10.1038/s41588-023-01408-9