How Do Humans Maintain a Healthy Blood Sugar Level After Meals?

A study of more than 55,000 people’s DNA from around the world has given insight into how humans maintain appropriate blood sugar levels after eating, with implications for the current understanding of how the process goes awry in type 2 diabetes.

The results, which were published today in Nature Genetics, could assist in guiding future therapies for type 2 diabetes, which affects over 4 million individuals in the United Kingdom and over 460 million people globally.

Older age, being overweight or obese, physical inactivity, and genetic susceptibility contribute to an increased risk of type 2 diabetes. Type 2 diabetes, if left untreated, can cause complications such as eye and foot difficulties, nerve damage, and a higher risk of heart attack and stroke.

Insulin, a hormone that controls blood sugar or glucose levels, is a significant factor in the development of the disease.

People with type 2 diabetes are unable to control their blood sugar levels properly, either because they do not secrete enough insulin when blood sugar levels rise, such as after eating, or because their cells have become less responsive to insulin, a condition known as “insulin resistance.”

The majority of studies on insulin resistance so far have concentrated on the fasting state, which is the period of time following a meal when insulin is primarily working on the liver.  However, when food is consumed, insulin operates on the fat and muscle tissues -  this is where the majority of time is spent.

Type 2 diabetes is assumed to be significantly influenced by the molecular mechanisms behind insulin resistance following a so-called “glucose challenge,” such as consuming a meal or beverage that is high in sugar. These processes, however, are not well understood.

We know there are some people with specific rare genetic disorders in whom insulin works completely normally in the fasting state, where it is acting mostly on the liver, but very poorly after a meal, when it is 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 is relevant to the risk of getting type 2 diabetes.”

Sir Stephen O’Rahilly, Professor and Co-Director, Wellcome-MRC Institute of Metabolic Science, University of Cambridge

A multinational team of researchers analyzed genetic data from 28 studies, including more than 55,000 volunteers (none of whom had type 2 diabetes), to search for important genetic variations that affected insulin levels measured two hours after a sugary drink to investigate these processes.

Following the sugary drink, the scientists discovered 10 additional loci, or sections of the genome, linked to insulin resistance. It is important to note that eight of these areas also have a greater incidence of type 2 diabetes.

One of these recently discovered loci was found inside the gene that codes for the essential protein GLUT4, which is in charge of bringing glucose from the blood into cells after a meal. This locus was linked to a decrease in GLUT4 levels in muscle tissue.

The researchers used cell lines derived from mice to investigate certain genes in and around these loci to search for new genes that may contribute to glucose control. As a result, 14 genes crucial for GLUT 4 trafficking and glucose absorption were found, nine of which had never before been connected to insulin control.

Further research revealed that these genes altered the amount of GLUT4 located on the cell’s surface, most likely via modifying the protein’s capacity to migrate from within the cell to the cell’s surface. The less GLUT4 that reaches the cell’s surface, the worse the cell’s capacity to take glucose from the blood.

What is 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.”

Dr. Alice Williamson, Lecturer, Chemistry, University of Sydney

Given that issues managing blood glucose after a meal can be an early indicator of an elevated risk of type 2 diabetes, the researchers are optimistic that uncovering the processes involved can lead to innovative therapies in the future.

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.”

Claudia Langenberg, Professor and Director, Precision Healthcare University Research Institute (PHURI), Queen Mary University of London