A life without insulin injections? That is what diabetes patients would dream of, and researchers too. Erika Pinheiro Machado, Ph.D. student at the University of Groningen, investigates how insulin-producing cells could be transplanted directly under the patient’s skin. What ‘house’ do the cells need to survive? Here, Erica explains all about diabetes type 1 and how she works towards a cure! 

Constantly thirsty and, therefore, constantly urinating. Frequently hungry even when eating enough, but still losing weight. Tiredness, blurred vision, your wounds take so long to heal… The first known mention of symptoms associated with type 1 diabetes (T1DM) is dated from 1552 B.C.  In Greek, diabetes (diabainein) means "pass-through" – referring to the frequent urination –, and mellitus, "sweetened with honey" – referring to the sugar found in this urine. Sugar is the primary concern of a patient with T1DM, but living with this condition is nothing sweet.

We are talking about a disease that occurs because the body attacks and destroys one specific cell type: the insulin-producing cells (beta-cells). They are part of a structure in our pancreas called islets of Langerhans. The hormone insulin, produced only by these cells, is an essential molecule that has the primary function of regulating our blood sugar levels. These must be kept within a very narrow range to ensure the body's energy balance and, therefore, our survival.

You may be comparing between type 1 and type 2 diabetes (T2DM) now. T2DM is mostly associated with obesity, and it is suggested to occur when the body becomes resistant to insulin’s actions. It tends to be a lifestyle disease. Not always, but it tends to be more of a lifestyle-related condition. On the other hand, T1DM is an autoimmune disease occurring in predisposed individuals. It comes without warning, it can occur in children or adults, and it is a life-long condition. A century ago, a patient would barely have 3 to 5 extra years of life expectancy once diagnosed. That is an incredibly low life expectancy. But everything changed in 1921 when Dr. Frederick Banting, Charles Best, and John Macleod showed insulin injections were an effective way to control blood sugar levels. They received a Nobel Prize in 1923 for it, and insulin therapy was quickly transformed into the standard treatment for patients with T1DM. T1DM went from a life sentence disease to a chronic but treatable condition. 

Nowadays, men with the condition have an average life expectancy of 66 years old and women, 68. This is still, on average, more than a decade less than the average life expectancy of people without T1DM. Patients and caretakers even define the disease as fatal and, because it requires minute-to-minute regulation: "spending your life not dying." Patients have been long waiting for a cure. Technology and science can be the combo to tackle the issue, and fields such as regenerative medicine and tissue engineering have been making essential steps.

Could we deliver more? 

Insulin therapy seems to work fine. However, secondary complications (cardiovascular and kidney disease, nerve and eye damage, and others) still occur even in patients that carefully manage their blood sugar levels. It works, but it does not regulate blood sugar levels as good as healthy beta-cells or the islets would. Perhaps we could give patients new and healthy cells, right?

In the year 2000, 80 years after the insulin discovery, someone replied to this inquiry. Dr. James Shapiro, a brilliant Canadian scientist, and his team showed the world that pancreatic islet transplantation was a feasible way to treat T1DM. After isolating islets from human cadavers, they put these islets into the liver of T1DM patients. There, islets were shown to produce and secrete insulin, consequently transforming insulin-dependent patients into insulin-independent individuals for at least 5 years and a bit longer. The recipients were cured, but only temporarily.

Islet transplantation using the liver as a transplantation site was a breakthrough, but it has challenges. These include:      

1. the immune system reactions towards the new islets, 

2. the non-native pancreatic environment that these cells encounter (the liver structure is very different from the pancreas), and 

3. the lack of proper blood supply for blood sugar levels' sensing and oxygenation. 

Furthermore, the shortage of liver cells due to the shortage of donors remains a huge issue. The treatment’s price and the criteria to choose who can be a recipient as well. The ambitious goal of very motivated scientists (including me!) is to overcome these challenges. We aim to develop a treatment the closest to a cure and make it available to the largest number of patients possible.

Solving the “islet supply” limitation

To tackle the issue of “islet supply”, emerging technology can come to the rescue: the use of stem cells. These cells have a unique capacity to transform into any cell type in the body. They are considered immortal: they do not age and can proliferate indefinitely. 

What are we missing to have insulin-producing stem cells? The gaps we still need to fill are: 

1. which sources of stem cells we must use (there are many possibilities!); and 

2. which paths lead these cells to a safe and stable transformation? 

Scientists have been investigating different types of stem cells (embryonic, mesenchymal, and others). The approach has evolved enormously over the last years, and it holds great potential as a future therapy for T1DM.

Solving the “islet microenvironment” limitation

Having functional islets is crucial. However, it is only half of the challenge. We also need to develop ways to provide the new islets an optimal environment to reside in. The optimal environment includes the physical support and all complementary structures and neighborhoods. This is the research field I work with! 

The house: physical structure 

Different strategies to build up what we call scaffolds, structures used to physically support cells – like a house! – are being used. Scaffolds are made of polymers (biomaterials) compatible with the human body. These can be either man-made, such as the one I work with (PDLLC - Poly (D, L, -lactide-co-ε-caprolactone)), or natural polymers (alginate, decellularized extracellular matrix). Many types of scaffolds have been tested, and they show huge benefits in housing transplanted islets. 

The infrastructure: vascular network and extracellular matrix

A physical structure is not enough, right? Research shows that islets need an appropriate vascular network (blood supply!) in its surrounding to be fully functional. They also need what we call extracellular matrix (ECM), a 3D network of molecules that provide structural and biochemical support for cells. It was shown that the ECM plays a crucial role in the islets’ function. If we use a scaffold, how can we stimulate vascular network formation and reproduce the ECM? This is the core of my Ph.D.!

Stem cells have also been used to recreate the native pancreatic microenvironment providing proper infrastructure for transplanted islets in various approaches. A specific type of stem cells, the mesenchymal stem cells (MSC), were shown to act as supportive players if co-transplanted with islets, for example (yes, we can mix both cell types and transplant them at the same time!). MSC seems to protect islets from death, stimulate vascularization, and enhance islet functionality after transplantation. These therapeutic properties are suggested as a result of the actions from the MSC secreted factors. 

Cell-based strategies (using the cells as therapeutic agents) such as co-transplantation are exciting. Still, they can pose some important limitations, such as autoimmune reactions, where the body attacks itself. For this reason, at the Department of Pathology and Medical Biology in the UMCG, my research group and I have been working on an MSC cell-free strategy to enrich the scaffold we work with. If the MSC therapeutic potential comes from its secreted products, why don’t we use only them instead of the cells? We are working on providing the newly transplanted islets an optimal microenvironment (house + infrastructure) to reside in. 

The neighborhood: transplantation site  

House and infrastructure: check! But where should we build this up? If the liver does not seem to be the ideal site, should we implant this optimized scaffold? Many alternative sites have been proposed, and my Ph.D. project specifically investigates the skin as an ideal site. Islet transplantation using the subcutaneous space provides easy ways to follow up or remove the graft if needed. Moreover, it is reached through a minimally invasive procedure. Other research groups have also been working on this strategy's variants, and the topic is advancing fast.

In summary, what have we (scientists) been doing to provide patients with T1DM more than the standard treatment? We are working on a functional cure. We have been trying to deliver long-term functional treatment that can reach all patients. Instead of the multiple daily insulin injections, patients could be soon receiving a dose of insulin-producing stem cells within an optimized device (scaffold) placed under the skin that could last for many years. My wish is that my Ph.D. project and all science that has been done so far can provide the basis to offer patients a better quality of life in the future.