Protein that may predict future diabetes risk and death from cancer identified

New research, published in Diabetologia, suggests that people with elevated levels of the protein prostasin (mainly found in epithelial cells which line the surfaces and organs of the body) may be at higher risk of developing diabetes.

Importantly, the findings also indicate that individuals with elevated levels of both blood sugar and prostasin appear at significantly greater risk of death from cancer.

The results held true even after adjusting for a wide range of influential factors including age, $ex, waist circumference, smoking and drinking habits, LDL (bad) cholesterol, systolic blood pressure, and anti-hypertensive medication.

The study is the first to examine the association between prostasin blood levels and cancer mortality in the general population and analysed blood samples from over 4,000 middle-aged Swedish adults that were taken over a decade ago as part of the ongoing Malmö Diet and Cancer Study—a large population-based prospective study that has been running in Malmö, a city in southern Sweden since 1993.

“This is the most comprehensive analysis of its kind to date and sheds new light on the biological connection between diabetes and cancer,” says co-lead author Professor Gunnar Engström from Lund University in Malmö, Sweden. “Prostasin may be just an indicator that disease might occur, or could be causally relevant, which is exciting because it raises the possibility of targeting this protein with future treatments for both diabetes and cancer.”

Extensive evidence indicates that diabetes is linked with an increased risk of developing several types of cancer and death from cancer, and that medicines used to treat high blood sugar can alter this association. People with type 2 diabetes are around twice as likely to develop pancreatic, endometrial and liver cancer, have a 30% higher chance of developing bowel cancer and a 20% increased risk of breast cancer. However, the mechanisms that drive this predisposition are poorly understood.

Prostasin is a stimulator of epithelial sodium channels that regulate sodium balance, blood volume and blood pressure. Moreover, prostasin has been found to suppress hyperglycaemia (high blood sugar)-induced tumour growth and is associated with glucose metabolism. However, little is known about the link between prostasin, diabetes and cancer mortality.

To find out more, a team of Chinese and Swedish researchers conducted a cross-sectional analysis of the association between prostasin blood levels (categorised by quartiles) and diabetes in 4,658 adults (average age 58 years; 40% men) enrolled in the Malmö Diet and Cancer Study Cardiovascular Cohort between 1991 and 1994, of whom 361 (8%) had existing diabetes.

After adjusting for potential confounding factors including age, $ex and waist circumference, smoking and drinking habits, LDL-cholesterol, systolic blood pressure, and anti-hypertensive medication, elevated prostasin levels were found to be positively associated with the presence of diabetes, with those in the highest prostasin quartile almost twice as likely to have diabetes compared to the lowest.

Researchers then examined clinical data from the same cohort (excluding 361 participants with existing diabetes) until the end of 2019 to investigate associations with new cases of diabetes. Over an average 22-year follow-up, 702 participants developed diabetes. Longitudinal analyses identified a linear relationship between prostasin and incident diabetes, with participants with prostasin in the highest quartile 76% more likely to develop diabetes than those in the lowest quartile.

Interestingly, prostasin levels were found to be a better predictor of diabetes in younger participants, and those with lower blood glucose levels and better kidney function. The authors speculate that elevated prostasin levels may be a compensatory response to overly high blood sugar (hyperglycaemia) but may be insufficient to stop or reverse worsening glucose control. And because prostasin may be secreted into urine, normal kidney function may help to maintain optimal prostasin blood levels.

In further analyses examining whether prostasin has an effect on mortality (from any cause, cancer mortality, and cardiovascular mortality), researchers found that prostasin was significantly associated with both cancer mortality and all-cause mortality. During average follow-up of 24 years, 651 participants died from cancer. Participants with prostasin blood levels in the highest quartile were 43% more likely to die from cancer than those in the lowest quartile. For each doubling of prostasin concentration, risk of cancer mortality increased by 139% and 24%, respectively, among participants with and without elevated levels of blood glucose (impaired fasting glucose). No association was found for cardiovascular mortality.

“Prostasin is a new potential risk marker for the development of diabetes and for cancer mortality, especially in individuals with high blood glucose levels”, says first author Dr. Xue Bao from The Affiliated Hospital of Nanjing University Medical School in Nanjing, China. “It is easily accessible, which enhances its potential to serve as a warning marker in the future.”

Since prostasin has a role in regulating several diabetes-associated biological pathways that are also involved in the onset and promotion of some cancers, it may potentially mediate the process from high blood sugar to cancer, or at least may act as a marker for cancer susceptibility in participants with high blood sugar. To look at this in more detail, it will be useful for future studies to trace the exact origins of prostasin in blood, and to determine whether the association between prostasin and diabetes is causal.”

The authors note that the study is observational and point to several limitations, including that the study is limited by its use of one dataset from one Swedish city, therefore the findings might not be generalisable to other populations. They also note that prostasin levels were measured using frozen blood samples stored for more than a decade and their values may not be the same as measured in fresh samples. Furthermore, the study only measured prostasin levels at one time point and could not distinguish between diabetes types.