Study finds antimicrobial immune system peptide to be the link between diabetes and urinary tract infections

Impaired immunity and recurrent infections are common in type 1 and type 2 diabetes. Studies by researchers at the Karolinska Institute have now shown that the immune systems of people with diabetes show reduced levels of the antimicrobial peptide (AMP) psoriasin, which impairs the cellular barrier of the urinary bladder, increasing the risk of urinary tract infections (UTI). The team also suggests that psoriasin could also represent a future therapeutic target.

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

Brauner and colleagues reported Nature communications on their collective studies in humans, mice and cell lines. In their article, titled “Diabetes downregulates antimicrobial peptide psoriasin and increases E. coli load in the urinary bladder, “concluded the team,” 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 and / or decreased activity of insulin, the hormone that regulates glucose, and therefore from the supply of energy to cells. In type 1 diabetes (T1D) the body stops producing insulin, while in type 2 diabetes (T2D), the cells have become less sensitive to insulin, which contributes to high blood glucose levels.

Diabetes can compromise the innate immune system, leaving many people with a greater 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 by an increased risk of bacterial infections,” the authors write. “In particular, E. coli urinary tract infections (UTIs) are common and more frequently associated with serious complications, such as uroseptemia.

Researchers from the Karolinska Institute investigated whether glucose levels in people with diabetes (T1D, T2D, or prediabetes) are linked to levels of psoriasin, an endogenous antimicrobial peptide that is part of the innate immune system. ‘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 anti-bacterial activity E. coli, sequestrating the zinc which limits bacterial growth. However, the team further stressed while the importance of psoriasis during E. coli infections are recognized, its possible activity in diabetes and when glucose levels are high is not known. “We have tried here to study the impact of glucose on psoriasin and the pathogenesis of E. coli UTI, with an emphasis on uroepithelium and defense strategies in the urinary bladder during diabetes, “they said.

Using urine, urinary bladder cells and blood serum samples from patients, the researchers analyzed the levels of psoriasin and other peptides needed to ensure that the bladder mucosa remains intact and protects against infection. Their results were verified in mice and urinary bladder cells with and without infection. “High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function along with alteration of cell membrane proteins and cytoskeletal elements, resulting in increased bacterial load,” they reported. “In line with our clinical results in patients with diabetes, we also found lower psoriasin levels in the urinary bladder of diabetic mice.”

Professor Brauner’s research team had previously shown that estrogen treatment restores the protective function of bladder cells in humans and mice, and thus helps regulate the immune response to a urinary tract infection. For their recently reported studies, the researchers also tested the impact of estrogen treatment on infected cells exposed to high glucose concentrations. They found that estrogen treatment increases psoriasin levels and reduces bacterial populations, indicating that the treatment may have an effect even among patients with diabetes. “Treatment with estradiol restores cell function by increasing psoriasin and killing bacterial in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia,” the researchers said.

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

The authors further concluded: “Here we demonstrate that high glucose levels impaired the innate immune response and compromised epithelial integrity. These findings may offer an explanation for the clinical observation that patients with poorly controlled diabetes have urinary tract infections. recurrent higher levels, acute pyelonephritis and uroseptemia “.

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