‘The key to avoiding the adverse effects of obesity is the maintenance of energy balance by limiting energy intake and maximizing expenditure through physical activity.’
This leads 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.
Genomes associated with insulin resistance
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.
The researches 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.
The 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.
This new study suggests thatamong 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.
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.
The large-scale genetic study is published in Nature Genetics