protein target obesity and type 2 diabetes

Scientists have identified a key protein that could be used as a treatment target for obesity and type 2 diabetes.

The discovery, made during a series of studies led by Assistant Professor Anutosh Chakraborty of The Scripps Research Institute in Florida, has raised hopes that by eliminating the IP6k1 protein (inositol hexakisphosphate kinase-1) fats will be broken down more easily, helping weight loss and cutting the risk of obesity and type 2 diabetes.

The researchers observed that the IP6K1 protein promotes fat accumulation in animals by slowing the breakdown and expenditure of fat and encouraging weight gain.

"We found that the protein IP6K1 is a viable target in obesity and type 2 diabetes," said Chakraborty. "We also discovered that an inhibitor of the protein known as TNP decelerates what is known as diet-induced obesity and insulin resistance."

Deleting IP6k1 in the fat cells of animal models was found to enhance energy expenditure and protect them from diet-induced obesity and insulin resistance.

The expenditure of fat energy is preceded by a process called lipolysis which breaks down stored fat into free fatty acids and glycerol to be used as energy in cells. When IP6K1 was deleted, it was found to affect interaction with another regulating protein and enhanced the breakdown of fats.

To assses how the IP6KI pathway could yield future weight loss treatments, the team analysed the impact of an IP6K inhibitor known as TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine] on diet-induced obesity in animal models. TNP was found to significantly slow the onset of diet-induced obesity and insulin resistance.

"In addition, the compound facilitates weight loss and improves metabolic parameters when used in animals that are already obese," said Chakraborty.

The studies were published in The International Journal of Biochemistry and Cell Biology, Molecular Metabolism and, most recently, The Journal of Clinical Investigation

Diabetes is a serious condition that affects over 29 million Americans. Obesity also affects a large part of the United States population. A new scientific breakthrough may have found a way to prevent both of these disorders.

Researchers have isolated a protein that in the future may stop the development of diabetes.

According to the Centers for Disease Control and Prevention (CDC), over 36.5 percent of the American population are obese.
Obesity has been associated with a variety of serious conditions, such as heart disease, stroke, certain types of cancer, and type 2 diabetes.
Type 2 diabetes is also widespread, with the CDC reporting that more than 29 million Americans are living with the condition, and an additional 86 million have prediabetes.
Diabetes can lead to severe complications, and the illness is the seventh leading cause of death in the U.S.
While there is currently no cure for diabetes, scientists are investigating several possibilities, including pancreas transplantation and genetic manipulation.
Researchers at the Catholic University of Louvain in Belgium may have made a breakthrough by discovering a protein that could soon halt the development of diabetes and obesity in humans.

Researching the bacteria Akkermansia in mice

For the past 10 years, researchers led by Patrice Cani, a WELBIO researcher at the Louvain Drug Research Institute of the University of Louvain, and Willem de Vos, professor at the University of Wageningen in the Netherlands, have been working on a bacterium called Akkermansia muciniphila.
Akkermansia are one of the most common bacteria, accounting for 1-5 percent of the gut microbiota.
Cani and team have shown, for the first time, that Akkermansia muciniphila may be crucial in the fight against obesity and type 2 diabetes.
Researchers hypothesized about the key role of Akkermansia in 2007 and confirmed their hypothesis in 2013. Until then, it was known that type 2 diabetes and obesity are characterized by altered gut microbiota, inflammation, and gut barrier disruption, but the exact mechanism responsible for this was unknown.
In their 2013 study, Cani and team isolated Akkermansia muciniphila - a mucin-degrading bacterium that resides in the mucus layer. They noticed that levels of this bacterium were lower in obese rodents. They also administered an Akkermansia-based treatment to mice, which reversed several metabolic disorders.

Studying pasteurized Akkermansia in humans

Now, the researchers have decided to produce Akkermansia and test it on humans. The trials have been ongoing since December 2015 at the Saint-Luc clinics of the University of Louvain.
For now, researchers have shown that using the bacterium on humans is safe. However, the scientists still need to prove that the positive effects demonstrated in mice in 2013 also apply to humans.
During their research, Cani and team accidentally discovered that pasteurization has positive effects on Akkermansia:

"Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice."

Scientists were trying to facilitate the production of Akkermansia by finding a way to make it inactive without destroying its properties. Pasteurization was one such way, as it makes the bacterium stable and easier to administer.
However, after pasteurizing it, researchers found that its efficacy had doubled. Akkermansia became so effective that it prevented the development of the obesity and type 2 diabetes mice.
This is the first time that scientists have shown pasteurized Akkermansia effective against these metabolic conditions in mice.
Results were published in the journal Nature Medicine.

The benefits of the purified protein Amuc_1100*

In an attempt to understand why the bacterium was made so effective by pasteurization, researchers isolated a protein that can be found on the outer membrane of the bacterium.
Since pasteurization kills off everything in the bacterium except the protein, researchers hypothesized that this protein might be the reason for its effectiveness.
With the help of genetic engineering, scientists produced the protein Amuc_1100* and tested it on rodents. 

Results showed the protein Amuc_1100* was as effective in stopping diabetes and obesity as pasteurized Akkermansia.
As the authors note, their study demonstrates that Akkermansia muciniphila "retains its efficacy when grown on a synthetic medium" and is "compatible with human administration."
Amuc_1100* is known to be good for the immune system, as it blocks toxins from reaching the bloodstream and strengthens the immunity of the intestines.
In the near future, the protein Amuc_1100* could help prevent diabetes and obesity in humans, and later on it might also treat other conditions, such as inflammation of the intestine caused by stress, alcoholism, liver disease, or cancer. 

For the first time, researchers have determined how bromodomain (BRD) proteins work in type 2 diabetes, which may lead to a better understanding of the link between adult-onset diabetes and certain cancers.

The findings, which appear in PLOS ONE, show that reducing levels in pancreatic beta cells of individual BRDs, called BET proteins, previously shown to play a role in cancer, may also help patients who are obese and diabetic.
The research was led by Gerald V. Denis, PhD, associate professor of pharmacology and medicine at Boston University School of Medicine, who was the first to show that BET protein functions are important in cancer development.
Adult-onset diabetes has been known for decades to increase the risk for specific cancers. The three main members of the BET protein family, BRD2, BRD3 and BRD4, are closely related to each other and often cooperate. However at times, they work independently and sometimes against each other.
According to the researchers new small molecule BET inhibitors have been developed that block all three BET proteins in cancer cells, but they interfere with too many functions.
"The BET proteins provide a new pathway to connect adult-onset diabetes with cancer, so properly targeting BET proteins may be helpful for both," explained Denis, who is the corresponding author of the study.
He believes this discovery shows the need for deeper analysis of individual BET proteins in all human cell types, starting with boosting insulin and improving metabolism in the pancreas of adults who are obese.
"Without better targeted drugs, some ongoing cancer clinical trials for BET inhibitors are premature. These new results offer useful insight into drug treatments that have failed so far to appreciate the complexities in the BET family."