A large-scale genetic study has provided strong
evidence that the development of insulin resistance -- a risk factor for type 2
diabetes and heart attacks and one of the key adverse consequences of obesity
-- results from the failure to safely store excess fat in the body.
Overeating and
lack of physical activity worldwide has led to rising levels of obesity and a
global epidemic of diseases such as heart disease, stroke and type 2 diabetes.
A key process in the development of these diseases is the progressive
resistance of the body to the actions of insulin, a hormone that controls the
levels of blood sugar. When the body becomes resistant to insulin, levels of
blood sugars and lipids rise, increasing the risk of diabetes and heart
disease. However, it is not clear in most cases how insulin resistance arises
and why some people become resistant, particularly when overweight, while
others do not.
An
international team led by researchers at the University of Cambridge studied
over two million genetic variants in almost 200,000 people to look for links to
insulin resistance. In an article published today in Nature
Genetics, they report 53 regions of the genome associated with
insulin resistance and higher risk of diabetes and heart disease; only 10 of
these regions have previously been linked to insulin resistance.
The researchers
then carried out a follow-up study with over 12,000 participants in the Fenland
and EPIC-Norfolk studies, each of whom underwent a body scan that shows fat
deposits in different regions of the body. They found that having a greater
number of the 53 genetic variants for insulin resistance was associated with
having lower amounts of fat under the skin, particularly in the lower half of
the body.
The team also
found a link between having a higher number of the 53 genetic risk variants and
a severe form of insulin resistance characterized by loss of fat tissue in the
arms and legs, known as familial partial lipodystrophy type 1. Patients with
lipodystrophy are unable to adequately develop fat tissue when eating too much,
and often develop diabetes and heart disease as a result.
In follow-up
experiments in mouse cells, the researchers were also able to show that
suppression of several of the identified genes (including CCDC92, DNAH10 and
L3MBTL3) results in an impaired ability to develop mature fat cells.
"Our study
provides compelling evidence that a genetically-determined inability to store
fat under the skin in the lower half of the body is linked to a higher risk of
conditions such as diabetes and heart disease," says Dr Luca Lotta from
the Medical Research Council (MRC) Epidemiology Unit at the University of
Cambridge. "Our results highlight the important biological role of
peripheral fat tissue as a deposit of the surplus of energy due to overeating
and lack of physical exercise."
"We've
long suspected that problems with fat storage might lead to its accumulation in
other organs such as the liver, pancreas and muscles, where it causes insulin
resistance and eventually diabetes, but the evidence for this has mostly come
from rare forms of human lipodystrophy," adds Professor Sir Stephen
O'Rahilly from the MRC Metabolic Diseases Unit and Metabolic Research
Laboratories at the University of Cambridge. "Our study suggests that
these processes also take place in the general population."
Overeating and
being physically inactive leads to excess energy, which is stored as fat
tissue. This new study suggests that among individuals who have similar levels
of eating and physical exercise, those who are less able store the surplus
energy as fat in the peripheral body, such as the legs, are at a higher risk of
developing insulin resistance, diabetes and cardiovascular disease than those
who are able to do so.
"People
who carry the genetic risk variants that we've identified store less fat in
peripheral areas," says Professor Nick Wareham, also from the MRC
Epidemiology Unit. "But this does not mean that they are free from risk of
disease, because when their energy intake exceeds expenditure, excess fat is more
likely to be stored in unhealthy deposits. The key to avoiding the adverse
effects is the maintenance of energy balance by limiting energy intake and
maximising expenditure through physical activity."
These new
findings may lead to future improvements in the way we prevent and treat
insulin resistance and its complications. The researchers are now collaborating
with other academic as well as industry partners with the aim of finding drugs
that may reduce the risk of diabetes and heart attack by targeting the
identified pathways.
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