Type 1 diabetes is an autoimmune disease in which the immune system destroys the insulin-producing beta cells in the pancreas. Currently, there is no cure for T1D. This means that patients must administer insulin for the rest of their lives. Even with insulin treatment, people with T1D remain at increased risk of complications such as eye disease, kidney damage, and cardiovascular problems.

According to Roep, it may not actually be the immune system that goes wrong — instead, the beta cells themselves may accidentally send out a distress signal. “Our immune system doesn’t normally attack healthy tissue,” Roep explains. “But in T1D, the beta cells are under extreme stress. In addition to insulin, they start producing a faulty protein called DRiP. The immune system recognizes DRiP as a threat and does exactly what it’s supposed to do — it removes it.” Unfortunately, in doing so, it also destroys the beta cells that produced DRiP in the first place. Roep’s team is exploring ways to create ‘stealth’ beta cells for people with T1D — cells that are invisible to the immune system. Several precise, patient-tailored strategies are being tested to achieve this.

Don’t worry, beta happy
Recent research from Roep’s group has shown that a milder form of T1D exists, linked to a small natural variation in the insulin gene. This genetic variant acts like an internal ‘steam valve’ that helps beta cells relieve stress, preventing the production of the faulty DRiP protein. As a result, these cells stay healthier, function better, and avoid immune attack.

“We want to better understand the insulin gene variant, the genetic predisposition for T1D, and the role of DRiP,” says Roep. “Why does it occur, does it have a function, what are the consequences — and most importantly, can we influence this process?” His team is studying these questions in the lab using beta cells grown from pluripotent stem cells (hiPSC). “In these stem cells, we can introduce the genetic variant responsible for the ‘steam valve’. The LUMC’s GMP facilities allow us to grow these hiPSC-derived beta cells under strictly controlled conditions. This opens the door to future transplants in which people with T1D receive beta cells equipped with a valve — cells that are more resilient to stress and less likely to be detected by the immune system.”

Smart delivery: the ‘backpack’ approach
Another pillar of Roep’s research focuses on targeted drug delivery to stressed beta cells using so-called bionics. These can be compared to tiny ‘backpacks’ carrying medication. The unique feature: these backpacks only open in stressed beta cells. Stressed beta cells activate a specific type of immune cell that produces an enzyme in large quantities — an enzyme that cuts open the backpack. This makes it possible to reduce stress in beta cells, restore their function, or even stimulate cell growth — precisely where it’s needed, without suppressing the entire immune system.

Who to treat, how, and when?
Roep’s research aims for the highest possible precision — care that targets the stressed beta cell itself. The insights gained also pave the way for personalized therapies. “The genetic variant that provides the ‘steam valve’ can help tailor therapies to individual patients. People with this variant often develop a milder form of T1D and still retain some beta cells. For them, we can explore inverse vaccination — a strategy that reprograms the immune system to leave their existing beta cells unharmed.”

“For patients with few or poorly functioning beta cells, another approach may be more suitable: transplantation of lab-grown beta cells derived from stem cells. In these cells, we can build in the valve, making them more resistant to stress and less vulnerable to immune attack.”

European Research Council
All these efforts come together in one clear and ambitious goal: a sustainable solution for type 1 diabetes that tackles both the cause and the consequences of the disease. From the fundamental discovery of DRiP as a distress signal, to engineering stress-resistant and invisible beta cells, and the precise delivery of therapies through bionics — Roep’s research combines scientific insight with technological ingenuity. Thanks to the ERC grant, this pioneering work has the opportunity to transform cutting-edge science into personalized care — with one ultimate mission: to fundamentally change the lives of people living with type 1 diabetes.