Impaired immunity and recurring infections are common in type 1 and type 2 diabetes. Studies by researchers at Karolinska Institute, have now shown that the immune system of individuals with diabetes displays reduced levels of the antimicrobial peptide (AMP) psoriasin, which compromises the urinary bladder’s cell barrier, increasing the risk of urinary tract infection (UTI). The team also suggests that psoriasin may also represent a future therapeutic target.

“We found that high glucose concentrations reduce the levels of the antimicrobial peptide psoriasin, while insulin has no effect,” said research lead Annelie Brauner, PhD, professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institute. “People with diabetes have lower levels of psoriasin, which weakens the cells’ protective barrier function and increases the risk of bladder infection.”

Brauner and colleagues reported in Nature Communications on their collective studies in humans, mice, and cell lines. In their paper, titled “Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder,” the team concluded, “Taken together, our data suggest psoriasin as an important antimicrobial peptide in bacterial clearance of the urinary tract in diabetes and may in the future serve as a potential target for new therapeutic drugs.”

Diabetes results from a lack of, and/or decreased activity of insulin, the hormone that regulates glucose, and thus energy supply to cells. In type 1 diabetes (T1D) the body stops producing insulin, while in type 2 diabetes (T2D), cells have become less sensitive to insulin, which contributes to high blood glucose levels.

Diabetes may compromises the innate immune system, leaving many people with increased susceptibility to regular infections, such as urinary tract infections (UTIs) caused by E. coli bacteria. “The high prevalence of diabetes is a major global health challenge, often accompanied with increased risk of bacterial infections,” the authors wrote. “In particular, E. coli urinary tract infections (UTI) are common and more frequently associated with serious complications, such as urosepticemia.”

The Karolinska Institute researchers investigated whether glucose levels in people with diabetes (T1D, T2D, or prediabetes) are linked with levels of psoriasin, an endogenous antimicrobial peptide that is a part of the innate immune system. “The antimicrobial peptide psoriasin, encoded by S100A7 is a member of the S100 protein family and has been detected in the urinary tract,” the team further explained. “It is mainly known for its high antibacterial activity against E. coli, sequestering zinc which restricts the bacterial growth.” However, the team further pointed out, while the importance of psoriasin during E. coli infections is recognized, its possible activity in diabetes, and when glucose levels are high, isn’t known. “We here sought to investigate the impact of glucose on psoriasin and the pathogenesis of E. coli UTI, with emphasis on the uroepithelium and defense strategies in the urinary bladder during diabetes,” they stated.

Using urine, urinary bladder cells and blood serum samples from patients, the researchers analyzed levels of psoriasin and other peptides necessary for ensuring that the bladder mucosa remains intact and protects against infection. Their findings were verified in mice and urinary bladder cells with and without infection. “High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function together with altering cell membrane proteins and cytoskeletal elements, resulting in increasing bacterial burden,” they reported. “In line with our clinical findings from patients with diabetes, we also detected lower psoriasin levels in the urinary bladder of diabetic mice.”

Professor Brauner’s research group had previously shown that treatment with estrogen restores the protective function of bladder cells in humans and in mice, and thereby helps to regulate the immune response to a UTI. For their newly reported studies the researchers also tested how estrogen treatment impacted on infected cells exposed to high glucose concentrations. They found that estrogen treatment boosted levels of psoriasin and reduced bacterial populations, indicating that the treatment may have an effect also among patients with diabetes. “Estradiol treatment restores the cellular function with increasing psoriasin and bacterial killing in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia,” the investigators stated.

“We now plan to probe deeper into the underlying mechanisms of infections in individuals with diabetes,” said study lead author Soumitra Mohanty, PhD, researcher at the same department at Karolinska Institute. “The ultimate goal is to reduce the risk of infection in this growing patient group.”

The authors further concluded, “We here demonstrate that high glucose levels compromised the innate immune response and impaired epithelial integrity. These findings may offer an explanation of the clinical observation that patients with poorly controlled diabetes have higher recurrent UTI, acute pyelonephritis and urosepticemia.”

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