The impact of the immune system on diabetes
6 October 2022
Diabetes is the world’s fastest growing public health disease. Today, a total of about 465 million people live with diabetes. Modern medicines have led to better health and longer life expectancy, but there are still many challenges for research.
At Uppsala University, diabetes research is underway to increase our understanding of the immune system and its function early in life to find out what influences the risk of developing diabetes later in life.
The idea for the new study arose unexpectedly, like many of the biggest discoveries. Together with her research team, Mia Phillipson, Professor of Physiology at the Department of Medical Cell Biology, has had several successful research projects over the years. They study what the cells of the immune system do in different tissues, both healthy and diseased, and have discovered new functions for the cells. One discovery is that a particular type of immune cell, called macrophages, is important for wound healing, which is currently being tested clinically in patients with diabetic foot ulcers.
“Basic research involves a lot of random discoveries, and these need to be nurtured and allowed to germinate in a creative and permissive research environment. In our mouse models of stained macrophages, used in completely different projects, we found a very high accumulation of these cells in other healthy tissues, such as the pancreas,” says Mia Phillipson.
“We found that these macrophages have completely different functions than they do later in life and that they are important for the insulin-producing islets of the pancreas to mature and become functional after birth. We now want to investigate how these macrophages are involved in the risk of developing diabetes later in life.”
Infections may affect the development of diabetes
The research involves discovering new functions of immune cells, and then developing drugs that use these functions to heal damaged tissue and treat inflammatory bowel disease, diabetes or cancer.
“We now want to understand, for example, whether infections in the first year of life affect pancreatic macrophages, leading to a higher risk of developing diabetes later in life, and how we can counteract this. Knowing more about why we have different levels of risk of diabetes will make it possible in the long term to tailor advice and treatments for different subgroups, so that we stay healthy,” says Mia Phillipson.
“I’m driven by exciting research topics and always learning new things in different contexts. It gives me energy. My long-term hope is that we will understand the full repertoire of functions of the immune cells, and be able to use these to develop immunotherapies, drugs, not only to treat the complications that diabetes can cause, but also the underlying disease itself.”
Key collaborations with clinics and other researchers
“The vast majority of ambitious projects are collaborations that rely on many different skills, techniques and approaches. I am very happy to work at Uppsala University with its proximity to the clinic at the University Hospital, the Diabetes Centre and microbiologists at the SLU. As a preclinician, without direct patient contact, it is important to have the expertise of others and feedback on our data so that the results ultimately have clinical relevance with practical significance for healthcare," concludes Mia Phillipson.
New strategies to detect and stop diabetes
Diabetes, both type 1 and type 2, are chronic diseases and there is currently no cure. Current research is dominated both by finding strategies to stop the progression of the disease in affected patients, and by finding ways to detect at an early stage those at risk of developing diabetes to stop the progression before the disease breaks out.
“Research is now underway in studies using mesenchymal stem cells to prevent the progression of type 1 diabetes. Through treatment, it is hoped that the remaining insulin-producing cells, which are about 25–50% at the onset of diabetes, can be preserved, allowing the patient to survive on very low insulin doses,” says Per-Ola Carlsson, Senior Physician and Professor of Medical Cell Biology, who works both experimentally and clinically with diabetes research. “After treatment in the studies, patients have on average the same or slightly better ability to produce insulin when glucose rises compared to when they first became ill.”
Reduced risk of complications
Ultimately, this has the potential to reduce the risk of complications, provide better living conditions and increase longevity.
“In the future, it may be possible to identify individuals who are beginning to show signs of immune activity against insulin-producing cells and treat them to stop the destruction of the cells before so many are lost that high blood sugar levels are reached. One approach is to screen for antibodies to the insulin-producing cells in people at risk of type 1 diabetes, such as those who have close relatives with type 1 diabetes. The antibodies can often be detected in the blood several years before the onset of diabetes," says Per-Ola Carlsson.”
Another area of research is the transplantation of stem cell-derived insulin-producing cells. This treatment is aimed at type 1 diabetes patients who have already lost their insulin-producing cells.
“From stem cells, infinite amounts of insulin-producing cells can be generated,” continues Per-Ola Carlsson, “but what is currently preventing their use in patients is the risk that the cells may be rejected by the patient if immunosuppressive drugs are not used. These drugs can cause side effects such as infections, kidney failure and an increased risk of cancer. Therefore, the aim is to develop strategies for transplantation without immunosuppressive drugs.”
Increase in type 2 diabetes in the younger population
Problems such as increased weight and obesity have led to an increase in type 2 diabetes in society, particularly at younger ages. Treatment is mainly diet and exercise. Many new medicines are effective and reduce the risk of secondary diseases, but no medicines can currently stop the progressive course of type 2 diabetes.
“There is, of course, a hope to develop drugs that target the disease mechanism itself, that is, that stop the progression of the disease. These could be drugs that affect free radical stress on insulin-producing cells. It would be extremely valuable if we could intervene in the disease process”, concludes Per-Ola Carlsson.
Different forms of diabetes
The two most common forms are type 1 and type 2 diabetes and have different disease courses.
- In type 1 diabetes, the body's own immune system attacks the insulin-producing cells in the pancreas, resulting in insulin deficiency. The body completely stops producing insulin, and the patient needs to administer it via an insulin pump or through injections for the rest of their lives.
- In type 2 diabetes, there is an insensitivity to insulin in the body tissues coupled with an inadequate ability to increase insulin production. The effect is an incomplete uptake of sugar into the body's tissues with high blood sugar as a result. Type 2 diabetes often occurs along with high blood pressure, high blood fats and obesity.
The two types of diabetes need to be treated differently.