Malaria drug turns alpha cells into insulin-producing organs, platypus venom key to treatment
CRISPR editing in pancrea reduced tissue death, increased insulin secretion, researchers find.
For decades, researchers have been trying to replace the insulin cells of the pancreas that are destroyed by the disease. Groundbreaking research may have found a way to genetically transform alpha cells into insulin-producing beta cells.
Type 1 diabetes is characterized by the inability of the pancreas to produce insulin. More specifically, the body’s own immune system stops recognizing the beta cells normally responsible for producing insulin. Instead, it attacks and destroys them.
Without insulin – which normally “tells” the body to start reducing the levels of glucose – the blood sugar cannot enter the cells, where it is normally transformed into energy. As a result, glucose gets stuck in the bloodstream, leading to diabetes.
Now, researchers from the CeMM Research Center for Molecular Medicine in Austria seem to have found the missing link, giving hope of a cure for type 1 diabetes.
A team of researchers – led by Stefan Kubicek, group leader at CeMM – examined the role of a variety of approved drugs on alpha and beta cell transformation. Their findings were published in the journal Cell.
In addition to beta cells, alpha cells and three other types of cells form the islets of Langerhans in the pancreas, where they are responsible for regulating blood sugar levels.
While beta cells help signal a reduction in blood sugar, alpha cells do the opposite, by producing glucagon. However, alpha cells are flexible: they can transform into beta cells. In cases of extreme beta cell depletion, alpha cells have been shown to turn into insulin-producing beta cells, with the help of an epigenetic regulator known as Arx.
Also, with the help of the CRISPR/Cas9 gene scissors, researchers at Lund University Diabetes Centre in Sweden have managed to “turn off” an enzyme that proved to play a key role in the regulation of the diabetes-associated TXNIP gene. The results are decreased cell death and increased insulin production in the genetically modified pancreatic beta cells.
In a recent study, researchers have conducted an investigation on a group of enzymes, histone acetyltransferases (HATs), which play a crucial role in the regulation of the TXNIP gene that, in cases of high blood sugar levels, leads to beta cell death and reduced insulin production.
The study was published in International Journal of Biochemistry & Cell Biology.
The researchers compared donated insulin -producing pancreatic islets from type 2 diabetes patients with those from healthy people and discovered that the gene activity of HAT enzymes is twice higher in diabetic cells than in the healthy ones. Following this discovery, the goal was to remove the genetic function of the enzyme to study its effect on diabetes. And this proved to be successful.
Using CRISPR/Cas9, the researchers were able to remove a sequence in the genetic code that controls the function of the HAT enzyme in insulin-producing cells from rats. This resulted in reduced TXNIP gene activity, and thereby reduced cell death and increased insulin production.
Also, Australian researchers have discovered remarkable evolutionary changes to insulin regulation in two of the nation’s most iconic native animal species – the platypus and the echidna – which could pave the way for new treatments for type 2 diabetes in humans.
The findings, now published in the Nature journal Scientific Reports, reveal that the same hormone produced in the gut of the platypus to regulate blood glucose is also surprisingly produced in their venom.
The research is led by Professor Frank Grutzner at the University of Adelaide and Associate Professor Briony Forbes at Flinders University. The hormone, known as glucagon-like peptide-1 (GLP-1), is normally secreted in the gut of both humans and animals, stimulating the release of insulin to lower blood glucose.
But GLP-1 typically degrades within minutes.
In people with type 2 diabetes, the short stimulus triggered by GLP-1 isn’t sufficient to maintain a proper blood sugar balance. As a result, medication that includes a longer lasting form of the hormone is needed to help provide an extended release of insulin.
Meanwhile, Kubicek said: “Arx regulates many genes that are crucial for the functionality of an alpha cell. Preceding work of our collaborator, Patrick Collombat’s team showed that a genetic knockout of Arx leads to a transformation of alpha cells into beta cells.”
So, at this point, researchers knew that they needed Arx to transform the cells, but they did not know whether there were other factors in the human organism that influenced the process.
To investigate this, Kubicek and team designed alpha and beta cell lines and isolated them from their environment. They analyzed the cells and demonstrated that a deprivation of Arx is enough to give a cell its alpha identity, and no other factors from the human body are required.
Now, scientists were able to test the effects of a wide range of approved drugs on cultured alpha cells using a specially designed, fully automated assay.
Researchers found that artemisinins – a group of drugs commonly used to treat malaria – had the same effect as a loss in Arx.
In other words, artemisinins transformed pancreatic alpha cells into functional, insulin-producing beta-like cells.
“With our study, we could show that artemisinins change the epigenetic program of glucagon-producing alpha cells and induce profound alterations of their biochemical function,” explains Kubicek.
The way this happens is through the activation of GABA receptors.
The effect of GABA in rodents and humans
GABA is a major neurotransmitter produced by islet beta cells. It works as a transmitter within the islet cells, where it regulates the secretion and function of the islet.
Artemisinins reshape alpha cells by binding to a protein called gephyrin. This protein activates the GABA receptors, which are like central switches of the cellular signaling. At the end of a longer chain of biochemical reactions, GABA triggers the production of insulin.
Kubicek’s study confirms previous mouse studies that have shown GABA to help transform alpha cells into beta cells. One of these studies is led by Patrick Collombat and is published in the same issue of Cell.
The beneficial effects of artemisinins were shown not only in isolated cell line experiments, but also in model organisms. Kubicek and team showed that the malaria drug increased beta cell mass and improved homeostasis in zebrafish, mice, and rats.
It is very likely that the same effect will happen in humans, say the authors, because the molecular targets for artemisinins in fish, rodents, and humans are very similar.