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 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 obese, 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.
A key player in the development of the condition 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 of insulin resistance to date 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.
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 new 10 loci – regions of the genome – associated it, and eight of these also shared a higher risk of type 2 diabetes, highlighting their importance.
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.
Dr Alice Williamson carried out the work while a PhD student at the Wellcome-MRC Institute of Metabolic Science. In May she joined the Precision Healthcare University Research Institute (PHURI) at Queen Mary University of London.
Dr Williamson 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.
The study was overseen by Professor Claudia Langenberg, Director of the Precision Healthcare University Research Institute at Queen Mary University of London, undertaken in her prior roles at the Berlin Institute of Health at the Charité (BIH) and University of Cambridge
Professor Langenberg, 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.
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