The researchers used mouse cell lines to analyse particular genes in and around these loci to explore for additional genes that may play a role in glucose regulation.
Digital Desk: A study of over 55,000 people's DNA from around
the world has given insight on how humans maintain appropriate blood sugar
levels after eating, with implications for our knowledge of how the process
goes awry in type 2 diabetes.
The findings, which were published today in Nature Genetics,
could help guide future treatments for type 2 diabetes, which affects over 4
million individuals in the United Kingdom and over 460 million people
worldwide.
Older age, being
overweight or obese, physical inactivity, and genetic susceptibility all
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 regulates blood sugar - glucose -
levels, is a major player in the development of the illness. People with type 2
diabetes are unable to properly manage their glucose levels, either because
they do not secrete enough insulin when glucose levels rise, such as after
eating a meal, or because their cells are less susceptible to insulin, a
condition known as "insulin resistance."
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Most insulin resistance
research to far have concentrated on the fasting state - that is, several hours
after a meal - when insulin is primarily working on the liver. However, we
spend the most of our time in the fed state, during which insulin effects on
our muscle and fat tissues.
The molecular mechanisms behind insulin resistance following a 'glucose
challenge' - such as a sugary drink or meal - are thought to play a significant
role in the development of type 2 diabetes. Nonetheless, these mechanisms are
poorly understood.
An multinational team of scientists looked for important genetic
variations that influenced insulin levels measured two hours after a sugary
drink using genetic data from 28 research including over 55,000 subjects (none
of whom had type 2 diabetes).
Following the sugary drink, the researchers discovered ten additional
loci - or sections of the genome - connected with insulin resistance. Eight of
these regions also had a higher incidence of type 2 diabetes, emphasising their
significance.
One of these newly discovered loci was found within the gene that codes
for GLUT4, a crucial protein that transports glucose from the blood into cells
after eating. This locus was linked to lower levels of GLUT4 in muscle tissue.
The researchers used mouse cell lines to analyse particular genes in and
around these loci to explore for additional genes that may play a role in
glucose regulation. This resulted in the identification of 14 genes involved in
GLUT 4 trafficking and glucose uptake, nine of which had never previously been
related 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 ability
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 ability to take glucose from
the blood.
Dr. Alice Williamson, 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 indicator of an elevated risk of type 2 diabetes, the researchers are
optimistic that uncovering the mechanisms involved can lead to innovative
treatments in the future.
"Our findings open up a
potential new avenue for the development of treatments to stop the development
of type 2 diabetes," said 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 in Germany. It also demonstrates how genetic studies of
dynamic challenge tests can provide vital information that would otherwise be
buried."
Wellcome, the Medical Research
Council, and the National Institute for Health and Care Research all provided
funding for the study.
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