Lower immunity and recurrent infections are common in type 1 and type 2 diabetes. Researchers at the Karolinska Institute in Sweden now show that the immune systems of people with diabetes have lower levels of the antimicrobial peptide psoriasin, which compromises the cellular barrier of the urinary bladder, which increases the risk of urinary tract infection. The study is published in Nature Communications .
Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli load in the urinary bladder Summary Diabetes is known to increase susceptibility to infections, in part due to altered granulocyte function and changes in innate immunity. Here, we investigated the effect of diabetes and high glucose on the expression of the antimicrobial peptide, psoriasin, and the putative consequences for E. coli urinary tract infection. Exfoliated cells from patients’ blood, urine, and urine are studied . The influence of glucose and insulin is examined during hyperglycemic clamps in individuals with prediabetes and in euglycemic hyperinsulinemic clamp patients with type 1 diabetes. Important findings are confirmed in vivo in type 2 diabetic mice and verified in human uroepithelial cell lines . High glucose concentrations induce lower levels of psoriasin and alter epithelial barrier function along with alteration of cell membrane proteins and cytoskeletal elements, resulting in increased bacterial load. Estradiol treatment restores cellular function with increased psoriasin and bacterial death in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia. In conclusion , our findings present the effects and underlying mechanisms of high glucose compromising innate immunity. |
Schematic representation of altered uroepithelial immune responses in high glucose. The impact of high glucose on uroepithelial cells and the effects of psoriasin, IL-1β, IL-6, and estradiol on the background of uroepithelial cells exposed to high glucose are demonstrated in the current study. Immunological changes that occur due to high glucose compared to a low glucose condition. b High glucose significantly downregulates psoriasin, IL-1β, IL-6, occludin, SOCS3 and RhoB without altering the level of pSTAT-3, but upregulates the expression of AHR, caveolin 1 with increased YAP /TAZ nuclear and cortical actin leading to increased bacterial activity. burden. E. coli infection further increases MRC1 expression in high glucose-treated cells. c High glucose-treated cells supplemented with IL-1β increase IL-6 and psoriasin. IL-6 supplementation increases psoriasin, SOCS3 and results in reduced nuclear YAP/TAZ. d Psoriasin peptide supplementation increases occludin and decreases caveolin 1 in cells treated with high glucose. Estradiol reverses the effect of high glucose and increases IL-6, psoriasin, and cortical actin with reduced nuclear YAP/TAZ, leading to increased killing of intracellular bacteria even in cells treated with high glucose.
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Diabetes is the result of a lack of insulin and/or decreased insulin action. Insulin is a hormone that regulates glucose (sugar) and therefore energy to cells. In type 1 diabetes, the body stops producing insulin, while in type 2 diabetes, cells become less sensitive to insulin, contributing to high blood glucose levels. Diabetes is a common disease that affects health in many ways.
One effect is that it compromises the innate immune system, leaving many people with increased susceptibility to regular infections, such as urinary tract infections (UTIs) caused by the E. coli bacteria. In people with diabetes, this is more likely to cause general blood poisoning, sepsis, originating in the urinary tract.
An endogenous antibiotic
Researchers at Karolinska Institutet have now investigated whether glucose levels in people with diabetes (type 1, type 2 or prediabetes) are related to psoriasin, an endogenous antibiotic that is part of the innate immune system.
Using urine, urinary bladder cells and blood serum samples from patients, the researchers analyzed the levels of psoriasin and other peptides necessary to ensure that the bladder mucosa remains intact and protects against infection. The findings were then verified in mice and urinary bladder cells with and without infection.
"We found that high concentrations of glucose reduce the levels of the antimicrobial peptide psoriasin, while insulin has no effect," says Annelie Brauner, professor at the Department of Microbiology, Tumor and Cell Biology at the Karolinska Institutet, who led the study.
“People with diabetes have lower levels of psoriasin, which weakens the protective barrier function of cells and increases the risk of bladder infection.”
Estrogen therapy reduced bacterial population
Professor Brauner’s research group has previously shown that estrogen treatment restores the protective function of bladder cells in humans and mice and therefore helps regulate the immune response to a urinary tract infection. Therefore, the researchers tested how estrogen treatment affects infected cells exposed to high concentrations of glucose. They found that the treatment increased psoriasin levels and reduced bacterial populations, indicating that the treatment may also have an effect among patients with diabetes.
“We now plan to delve deeper into the underlying mechanisms of infections in people with diabetes,” says the study’s lead author, Soumitra Mohanty, a researcher in the same department at Karolinska Institutet. “The ultimate goal is to reduce the risk of infection in this growing group of patients.”
The study was carried out in collaboration with Karolinska University Hospital, Stockholm Region, Capio and Uppsala University in Sweden and Universitätsklinikum Schleswig-Holstein in Germany. It was largely funded by the Olle Engkvist Foundation, Stockholm Region (ALF funding), the KI Research Foundation, the Swedish Society of Medicine, the Swedish Society for Medical Research (SSMF), the Clas Groschinsky Memorial Foundation, the Åke Foundation Wiberg and the Magnus Bergvall Foundation. There are no conflicts of interest reported.
