Since the discovery of insulin, diabetes researchers have explored in ever greater depth how the condition affects people who are hit hardest by kidney disease, cardiovascular disease, nerve damage or changes in the brain. Now, some of these researchers are turning that per-spective on its head and looking for answers among those with the fewest diabetes complica-tions.
Early in September, Steno Diabetes Center Copenhagen hosted the symposium Longevity and Escapers from Diabetes Complications, where researchers discussed what we can learn from people who live well despite having type 1 or type 2 diabetes.
The invited researchers work with cohorts and biobanks to study people who have lived with diabetes for many years without serious complications. They compare them with other groups, including people who develop complications rapidly. This allows researchers to look for biological patterns and differences that may help explain this unusual resilience.
Early in the symposium, it became clear that researchers cannot yet explain this resilience with a simple formula. They are unlikely to find a single explanation, says Professor Jørgen Rungby, who studies diabetes and the brain and moderated the symposium.
“The picture among escapers is similar to what we see in research into complications: wher-ever you look, you find data that explain perhaps 5–10 per cent of the disease. The main in-sight is probably that there are many different protective mechanisms, and that they vary considerably between type 1 and type 2 diabetes.”
The escaper phenomenon from different perspectives
At the symposium, three researchers explored the escaper phenomenon from different per-spectives.
Professor Peter M. Nilsson of Lund University works with cohorts of people with type 1 diabe-tes, comparing those who have avoided serious complications with people who develop them rapidly. Daniel Gordin of the University of Helsinki and Joslin Diabetes Center investigates, among other things, what protects the brain, kidneys and blood vessels in people who have lived with diabetes for many years. Professor Valeriya Lyssenko of the University of Bergen and Steno Diabetes Center Copenhagen searches large biobanks for genetic and biological patterns that may help explain these differences.
These approaches all focus on people at opposite ends of the disease spectrum. This allows researchers to look for patterns in long-term blood glucose levels, proteins, genetics, cognition and medical history.
Valeriya Lyssenko’s analyses showed differences involving around 1,860 proteins between the groups. The findings also pointed to inflammation as a possible lead, although researchers cannot yet identify any one mechanism as the explanation. The large number of biological signals illustrates the complexity: researchers can identify many differences between the groups, but they still need to establish which signals play a protective role.
Protection may differ from organ to organ
Daniel Gordin’s research highlighted another important perspective at the symposium: protec-tion does not necessarily appear to be the same throughout the body. What protects the kid-neys may not be what protects the eyes or the brain.
In his research, he looks for specific biological clues – including proteins and metabolites – that might eventually be used to reproduce this natural protection in other people. Yet his data also showed how difficult it can be to establish who is truly protected. In a Finnish study of people with type 1 diabetes, Daniel Gordin and his colleagues found vascular changes in the brain in a quarter of the participants, even though they had no known neurological conditions and appeared to be living well with diabetes. Specifically, 24 per cent of the participants had signs of cerebral microbleeds, compared with 3.3 per cent of the control group.
Changes visible on a scan do not necessarily mean impaired function. This is why research-ers also use cognitive assessments alongside imaging, Jørgen Rungby emphasises.
“We can scan as many brains as we like, but if that does not tell us whether people are func-tioning less well, it is not enough. In our research, we have started looking much more closely at function. If the brain is working, we are not particularly interested in what it looks like,” says Jørgen Rungby.
Still looking for clues, with treatments some way off
Research into escapers is still some way from delivering new treatments. But Jørgen Rungby sees clear potential in following the existing cohorts over time and studying them and the bi-obanks using increasingly advanced methods.
“I am optimistic that, as researchers follow these cohorts and explore patterns in biobanks, they will eventually identify mechanisms against which new treatments can be tested. How-ever, currently they are still looking for clues.”
He highlights research into kidney complications, which Professor Peter Rossing, Head of Clinical and Translational Research at Steno Diabetes Center Copenhagen, has helped ad-vance. For many years, there was no progress, but recent years have brought breakthroughs. Patients receiving treatments such as SGLT2 inhibitors and finerenone for chronic kidney disease experience substantially fewer complications.
According to Jørgen Rungby, the long-term prospect for this research is not necessarily a single major breakthrough. Researchers may find one mechanism that gives some patients’ kidneys a little more protection. Another may reduce cardiovascular risk. A third may tell us something about the brain. Meanwhile, better blood glucose management and modern medi-cines that protect organs may further improve the outlook for patients. Together, these many small advances could make a decisive difference.
There is also a more personal perspective: living with a chronic condition is, to some extent, also about an individual’s attitude towards life.
“It was interesting that several of the researchers raised the possibility that the escaper phe-nomenon may not be solely about specific molecules and biological mechanisms. It may also be that some people have specific personal resources and have, in some way, decided that they want to live longer. I do not think we should forget that aspect,” says Jørgen Rungby.