Elevated Levels of a Certain Protein Increase Risk of Diabetes and Cancer Death

Deadly Cancer Cells Rendering

The protein could potentially predict future cancer death and diabetes risk.

A Swedish investigation of nearly 4,000 individuals over 22 years found that those with prostasin blood levels in the top quartile were 76% more likely to acquire diabetes and 43% more likely to die from cancer.

According to recent research, those who have elevated levels of the protein prostasin—which is primarily found in the epithelial cells that line the body’s surfaces and organs—may be more likely to develop diabetes. This research was recently published in Diabetologia, the journal of the European Association for the Study of Diabetes (EASD).

Importantly, the results also suggest that those with high blood sugar and prostasin levels seem to have a much higher chance of dying from cancer.

Even after accounting for a variety of important variables, such as age, sex, waist circumference, drinking and smoking patterns, LDL (bad) cholesterol, systolic blood pressure, and anti-hypertensive medication, the findings remained consistent.

The Malmö Diet and Cancer Study, a sizable population-based prospective study that has been ongoing in Malmö, a city in southern Sweden, since 1993, was the source of blood samples for the study, which is the first to examine the relationship between prostasin blood levels and cancer mortality in the general population.

“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.”

Numerous studies have shown a connection between diabetes and a higher chance of getting various cancers as well as a higher mortality rate from cancer. Diabetes medications can also change this correlation. In addition to having a 30% greater risk of bowel cancer and a 20% increased risk of breast cancer, those with type 2 diabetes are about twice as likely to acquire pancreatic, endometrial, and liver cancer. However, little is known about the mechanisms behind this predisposition.

Prostasin is a stimulator of epithelial sodium channels that regulate sodium balance, blood volume, and blood pressure. Moreover, prostasin has been found to suppress hyperglycemia (high blood sugar)-induced tumor 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 (categorized 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, sex 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 (hyperglycemia) 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 an 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, the 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 generalizable 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.

Reference: “Plasma prostasin: a novel risk marker for incidence of diabetes and cancer mortality” by Xue Bao, Biao Xu, Iram Faqir Muhammad, Peter M. Nilsson, Jan Nilsson and Gunnar Engström, 4 August 2022, Diabetologia.
DOI: 10.1007/s00125-022-05771-w

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