Researchers are investigating the mechanism in the brain enabling a single injection of a peptide to cure type 2 diabetes in rodents. Evidence indicates that people may have a similar mechanism, says a researcher.
A few years ago, a research group in the United States discovered that a single injection of fibroblast growth factor 1 (FGF1) into the brain of rodents led to a sustained diabetes remission.
FGF1 is a peptide that appeared to have the capacity to restore normal control of blood glucose in diabetic rodents.
The researchers knew they had found an interesting and unknown mechanism that could potentially become an important target in combatting the worldwide diabetes epidemic.
A new study by researchers from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen now shows which cells in the brain interact with FGF1 to cure diabetes in rodents.
The discovery may launch a whole new approach to treating people with type 2 diabetes.
“Although the brain has not traditionally been the main focus of treatment targeting type 2 diabetes, our research clearly shows that targeting the brain and how it communicates with the liver can potentially not only treat people with type 2 diabetes in a novel way but also completely cure them,” says Tune H. Pers, Associate Professor and Group Leader, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
The discovery has been published in Nature Communications.
Could the brain be the source of type 2 diabetes?
Tune H. Pers’ research addresses a controversial theory.
Broadly speaking, he thinks that targeting the brain and not the pancreas and its insulin-producing beta cells could lead to major advances in treating people with type 2 diabetes.
“Our theory is that people have type 2 diabetes because a regulator in the brain does not send the right signals to the pancreas and other relevant parts of the body. The beta cells regulate blood glucose, but they are in part controlled by the brain. For example, the brain can be misled into thinking that blood glucose is too low, leading to an increase in blood glucose via the pancreas and liver. Since the brain has the capacity to ensure that the blood glucose is in equilibrium, we think that treatments targeting the brain could have long-term benefits” , explains Tune H. Pers.
Danish-American collaboration provides new insight
In the groundbreaking experiments with rodents, the United States researchers did not discover why the treatment with FGF1 was effective.
Tune H. Pers and postdoctoral fellow Marie A. Bentsen therefore reached out to his colleagues across the Atlantic, because he and his group are experts in discovering the mechanisms in the brain that influence the development of obesity and metabolic diseases.
In the new study, the transatlantic research collaboration found what actually happens in the brain when FGF1 is injected into mice.
Investigated 75,000 brain cells and 20,000 genes
The researchers compared the activity of the genes in various types of brain cells in mice treated with FGF1 versus those not treated.
In this extremely comprehensive study, the researchers examined the expression of 20,000 genes in 75,000 brain cells and took 3 years to comprehensively analyse their data.
The results showed that FGF1 specifically suppresses the activity of Agouti-related peptide (AgRP) neurons in the hypothalamus of the brain. AgRP neurons are already known, because they are very strongly linked to appetite regulation and can be a determining factor for whether people become overweight through the melanocortin 4 receptor (MC4R).
If MC4R is disrupted, people can become severely obese in childhood, which is obviously a huge problem.
The researchers also found that the FGF1 injection downregulated the AgRP neurons not for a few hours but for more than 6 weeks.
“This study shows that FGF1 injected into rodent brains affects biological systems that affect their weight by downregulating AgRP neurons and MC4R – in addition to regulating blood glucose. This is a completely new discovery,” says Tune H. Pers.
MC4R important for human metabolism
Although the experiments involved rodents, Tune H. Pers explains that they are relevant for treating people with type 2 diabetes.
People with type 2 diabetes have three well-known genetic mutations. One is in the MC4R gene, and according to Tune H. Pers, this is exciting because people with this mutation have an increased risk of developing diabetes without an increased risk of becoming severely obese.
In further experiments, the researchers investigated what happened to mice when they knocked out the MC4R gene and discovered that injecting FGF1 into the brain did not affect high blood glucose.
“This clearly indicates that MC4R regulates blood glucose and not just appetite and the development of severe obesity,” explains Tune H. Pers.
Resetting the brain’s own regulation
Tune H. Pers explains that an especially interesting perspective in targeting the brain is that restoring the brain’s ability to properly sense and regulate blood glucose would provide a very effective treatment option that potentially would not rely on regular properly dosed treatments.
For example, treating diabetes with insulin requires just the right amount, since both too high and too low blood glucose can be dangerous.
In contrast, a single injection of FGF1 appears to simply restore rodents’ ability to self-regulate blood glucose.
This therefore suggests that FGF1 simply enables the brain and hypothalamus to do exactly what they were once designed for: to ensure glycaemic equilibrium.
“Instead of constantly regulating blood glucose with medication, you could return to enabling the body to regulate itself. This applies to the brain’s ability not only to regulate blood glucose but also to regulate body weight. The smart thing about this approach is that it indicates that a drug can reset the internal systems that regulate both obesity and poor blood glucose control in type 2 diabetes,” concludes Tune H. Pers.