Diabetes Research

Type 1.

It promises to be a simple and elegant strategy to heal diabetes type 1; replacing the destroyed beta-cells in the bodies of patients with newly-produced insulin-secreting cells. For years, researchers around the globe tried various approaches with stem or adult cells in order to induce this transformation. Their effort lead to a fundamental understanding of the molecular mechanisms involved in the development of beta cells, however a compound capable of doing the trick was missing.

Then a team coordinated by Stefan Kubicek, Group Leader at CeMM, eventually got a lead. In their latest study published in Cell, they showed that artemisinins hit the bulls eye. With a specially designed, fully automated assay, they tested the effects of a representative library of approved drugs on cultured alpha cells and found the malaria drug to do the required job. “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,” Stefan Kubicek explains.

Alpha- and beta cells form together with at least three other highly specialised cell types the so-called islets of Langerhans in the pancreas, the body’s control centres for the regulation of blood sugar. Insulin, the hormone produced by beta cells, signals to reduce blood glucose, while glucagon from alpha cells has the opposite effect. But those cells are flexible. Previous studies showed that alpha cells can replenish insulin producing cells following extreme beta cell loss. The epigenetic master regulator Arx was identified as the key molecular player in the transformation process.

“Arx regulates many genes that are crucial for the functionality of an alpha cell,” says Stefan Kubicek. “Preceding work of our collaborator, Patrick Collombat’s team showed that a genetic knock out of Arx leads to a transformation of alpha cells into beta cells.” This effect however, was only observed in live model organisms; it was completely unknown if additional factors from the surrounding cells or even distant organs play a role. To exclude those factors, Kubicek’s team together with the group of Jacob HecksherSorensen at Novo Nordisk, designed special alpha and beta cell lines to analyse them isolated from their environment. They proved that loss of Arx is sufficient to confer alpha cell identity and does not depend on the body’s influence.

With those cell lines, the researchers at CeMM were now able to test their compound library and found artemisinins to have the same effect as an Arx loss. In close collaboration with research groups at CeMM lead by Christoph Bock and Giulio Superti-Furga as well as the group of Tibor Harkany at the Medical University of Vienna they managed to elucidate the molecular mode of action by which artemisinins reshape alpha cells.  The compound binds to a protein called gephyrin that activates GABA receptors, central switches of the cellular signalling. Subsequently, the change of countless biochemical reactions lead to the production of insulin. Another study by Patrick Collombat, published in the same issue of Cell, shows that in mouse models, injections of GABA also lead to the transformation of alpha into beta cells, suggesting that both substances target the same mechanism.

In addition to the cell line experiments, the effect of the malaria drug was also shown in model organism. Stefan Kubicek´s team and their collaborators (Martin Distel, CCRI Wien; Dirk Meyer, Leopold-Franzens-Universität Innsbruck; Patrick Collombat, INSERM Nice; Physiogenex, Labege) observed an increased beta cell mass and improved blood sugar homeostasis in diabetic zebrafish, mice and rats upon artemisinin delivery. As the molecular targets for artemisinins in fish, rodents and humans are very similar, chances are high that the effect on alpha cells will also occur in humans. “Obviously, the long term effect of artemisinins needs to be tested,” says Stefan Kubicek. “Especially the regenerative capacity of human alpha cells is yet unknown. Furthermore, the new beta cells must be protected from the immune system. But we are confident that the discovery of artemisinins and their mode of action can form the foundation for a completely new therapy of type 1 diabetes.”

Type 2.

Researchers at Florida State University’s biomathematics program are using a mix of math and technology in an ambitious search for a cure to Type 2 diabetes.

New research by mathematics Professor Richard Bertram has successfully reactivated oscillations in insulin-producing pancreatic beta cells, one of the first necessary steps to resurrecting the dormant cells and restoring the production of insulin.

The problem for people living with diabetes is their pancreatic cells either don’t make any insulin, or they don’t make enough to control blood sugar, causing dangerous hyperglycemia — high blood glucose. About 30 million Americans live with diabetes; 95 percent have Type 2 diabetes.

Bertram’s trendsetting research published in the journal PLOS Computational Biology with graduate student and lead author Joseph McKenna, is a breakthrough that takes another step toward the goal of finding a cure for Type 2 diabetes.

“There’s no one else using this combination of tools,” Bertram said. “It’s nice to be doing scientific work gaining insights that no one else is gaining because we have the right collaboration with the right tools.”

The right tools include Bertram’s own mathematical models along with unique “microfluidic devices.”

The right collaboration includes Michael Roper, an associate professor in the Department of Chemistry and Biochemistry, who dreams up and then builds, the precision devices that bring Bertram’s math models to life.

Bertram’s equations can simulate many potential biological responses. Researchers test those predictions in an experimental lab with a glass microfluidic device; beautiful in the simplicity of its outer appearance but also daunting in the complexity of its inner design.

The device, about the size of a credit card, is etched with microscopic channels that can deliver perfectly measured and controlled amounts of a glucose liquid solution to dormant pancreatic beta cells, which form clusters called islets. Researchers perform varying experiments on mouse islets using microfluidic devices.

“They’re made a lot like computer chips are made,” Roper said. “The device allows either one or several islets to be placed within it. Then we can deliver very accurate glucose levels to these cells in a very controlled manner.”

By delivering accurate glucose levels to pancreatic islets in the lab, researchers can test how insulin-producing beta cells get turned off and whether they can be reactivated.

With Roper’s microfluidic device, researchers delivered tiny doses of glucose, about one microliter or 1/1000th of a raindrop, to the dormant pancreatic beta cells of mice. When those controlled doses were administered in rhythmic pulses of exactly the right size and frequency, mimicking a healthy body, they triggered inherent oscillators in the islet cells. That caused the cells to vibrate and secrete insulin in a “healthy” fashion.

The experiment is a valuable milestone in Bertram’s long quest to better understand the disease and it’s a good example of how the intersection of math and biology can advance that goal.

He’s also focused on why tissues throughout the body become insulin resistant, causing pancreatic islets to wear out and eventually shut down. When that happens, a person has the disease.

Now, Bertram and Roper and their team of FSU researchers, look to the future using a fascinating mix of math and new technology to help lead the search for a cure.

“We can think of this as making progress toward that goal,” Bertram said. “Type 2 diabetes is a very complicated disease. The way that we can beat it is by understanding how all these components work and that’s what we’re contributing to.  Scientific breakthroughs are often facilitated by mathematics.”


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