Researchers have discovered a cell surface receptor that is essential for adipose tissue responding properly to insulin. When the receptor is inactivated, the response to insulin is insufficient. However, a researcher says that it may be possible to stimulate the receptor – thereby protecting against the development of type 2 diabetes.
Globally, researchers are searching for new ways of treating people with type 2 diabetes or ensuring that they do not develop it at all.
Much of this research involves people, but many major breakthroughs originate in studies of mice and fruit flies. Researchers made an interesting discovery that may eventually prevent people from developing type 2 diabetes.
The researchers identified a receptor on the surface of adipose tissue cells that promotes sensitivity to insulin and thus the uptake of glucose from the blood.
This may eventually lead to the development of new treatments to increase the signalling of this receptor to maintain insulin sensitivity, thereby keeping type 2 diabetes at bay.
“Activating insulin sensitivity through this receptor could help to ensure that blood glucose never rises to the level leading to the development of type 2 diabetes. This is the potential of our discovery,” explains a researcher behind the study, Kim Rewitz, Professor, Department of Biology, University of Copenhagen, Denmark.
The research, which included researchers from Novo Nordisk A/S and others, has been published in Nature Communications.
The reason why some people develop type 2 diabetes
People who develop insulin resistance often develop type 2 diabetes.
Insulin is a signalling molecule that promotes the uptake of glucose from the blood.
Insulin resistance causes the body’s muscle and adipose tissue to become less sensitive to insulin, impairing these tissues from taking up glucose.
When blood glucose increases and is not removed from the blood, the beta cells in the pancreas respond by making more insulin.
These processes are part of the body’s system for controlling blood glucose, but if the insulin-producing cells increase the production of insulin for too long, they can deteriorate, resulting in type 2 diabetes, in which the body cannot effectively reduce blood glucose by itself.
Studied fruit flies
Kim Rewitz and colleagues screened fruit flies for receptors and hormones that affect insulin sensitivity.
The researchers extensively knocked out fruit fly genes to examine how this affected glucose tolerance and insulin signalling.
Although fruit flies and humans differ greatly, most of the mechanisms for controlling blood glucose, including insulin signalling, are conserved across most animal species. Research on fruit flies can therefore be an excellent starting-point for understanding human biology.
Hormone controls cross-talk between muscles, adipose tissue and the brain
The researchers identified bursicon, a hormone that affects the balance of blood glucose. When they knocked out the gene for bursicon, the fruit flies became more insulin resistant.
Further investigation revealed that bursicon has a key role in the cross-talk between muscles, adipose tissue and the brain.
When muscle cells can sense the presence of more glucose, they send a signal to the brain’s neurons, which start producing more bursicon.
Bursicon has two functions: signalling the fruit fly’s beta cells to secrete more insulin and signalling the adipose tissue to promote insulin sensitivity.
This is similar to simultaneously closing the windows and turning up the heat on a cold day. An effective response is therefore best ensured by initiating several processes at the same time – and bursicon fulfils this in mediating the body’s insulin response.
“These processes enable animals to very rapidly adapt to more glucose being available. Glucose is an excellent energy source, but it must be stored in the muscles and adipose tissue. Bursicon helps to ensure this,” says Kim Rewitz.
Receptor is key to insulin resistance
The research also revealed that bursicon works through a leucine-rich repeat–containing G protein–coupled (LGR) receptor. This discovery is interesting because LGR receptors are well conserved across all animals, including humans and other mammals.
In mice and humans, the corresponding receptor is called LGR4. The researchers then knocked out the gene for the LGR4 receptor with a gene-silencing technology in adipose tissue cells from mice and examined how this affected the cells’ sensitivity to insulin.
Without the LGR4 receptor, 60–70% of the proteins that are usually activated in response to insulin were not activated at all in cells lacking LGR4 and thus leading to the development of insulin resistance in fat cells.
For a person, this would likely correspond to severe insulin resistance and being well on the way to having type 2 diabetes.
Developing new medicine
According to Kim Rewitz, the LGR4 receptor may be the key to developing new medicine to maintain insulin sensitivity in adipose tissue and perhaps also other tissues such as the muscles, thereby counteracting the development of type 2 diabetes.
One obvious advantage is the fact that this is a cell surface receptor, since most medicines have been developed to work on these types of receptors.
The goal would be to stimulate LGR4 on the adipose cells to enhance the effect of insulin and the absorption of glucose from the blood.
This would not only reduce blood glucose but could potentially even prevent people from developing type 2 diabetes altogether.
“This type of receptor may be an obvious target for producing drugs to treat type 2 diabetes. I am not aware of other and more obvious drug targets for insulin resistance, which is thought to be the main cause of type 2 diabetes. Therefore, our next goal is also to examine what happens in adipose tissue and muscle cells and then in experimental animals if we treat them with something that activates this receptor. This will be the first step on the journey to discover whether we can use this receptor for developing a new type of drug,” concludes Kim Rewitz.
