Insulin regulates an antimicrobial peptide that is suppressed in patients with diabetes.
A recent study led by clinicians and researchers at Nationwide Children’s Hospital reports a potential explanation for why urinary tract infections (UTIs) are so common in patients with diabetes – insulin regulates an antimicrobial peptide (AMP) that is suppressed in those patients.
Patients with diabetes mellitus are ten times more likely to suffer from UTIs than the general population, and more likely to experience kidney injury as a result. Recent studies have identified a particular AMP known as Ribonuclease 7 (RNase 7) as playing an important role in shielding the urinary tract from infection. RNase 7 is one of the most abundant AMPs in human urine, and when researchers experimentally block its antimicrobial activity in human urine, bacteria grows more abundantly.
Those two pieces of information led John David Spencer, MD, a pediatric nephrologist and principal investigator in the Center for Clinical and Translational Research in The Research Institute at Nationwide Children’s, to believe that RNase 7 is an essential AMP in urine that prevents infection. In the recent study, published in Kidney International, Dr. Spencer and colleagues hypothesize that diabetic patients’ increased likelihood of UTIs is due to suppressed RNase 7 production. Because diabetes is associated with deficient insulin production, the researchers also propose that insulin regulates the production of RNase 7.
The researchers measured RNase 7 concentrations in urine samples from healthy children and children with newly-diagnosed type I diabetes. The children with diabetes had significantly lower concentrations of the AMP in their urine, but these levels increased approximately two- to three-fold after the children began insulin therapy. These results suggest that insulin regulates RNase 7.
The researchers then conducted a series of cell culture experiments using human kidney and bladder cells to determine how insulin stimulates the production of RNase 7.
“Insulin has been shown to affect specific signaling pathways and one of them is the PI3 kinase pathway,” says Dr. Spencer, who is also an assistant professor of Pediatrics at The Ohio State University College of Medicine. “It’s one of the major downstream targets of insulin. We show that if we block that pathway, despite treating cells with insulin, RNase 7 production does not increase. This shows that insulin needs that pathway to produce RNase 7.”
Dr. Spencer and colleagues also demonstrated that boosting RNase 7 levels with insulin kills infectious E. coli. The results indicate that by increasing RNase 7 production with insulin, one protects the bladder and kidney cells from infection.
Together, the experiments identify a unique mechanism that could explain why patients with diabetes are at an increased risk of UTIs: insulin contributes to urinary tract sterility by boosting the production of RNase 7 through the PI3 kinase pathway.
Dr. Spencer and his colleagues hope their results will provide a foundation for future studies looking at ways of preventing and treating UTIs.
“Maybe there will be ways to design therapeutics for patients that work through this PI3 kinase signaling pathway,” says Dr. Spencer, “or ways to augment a diabetic patient’s insulin regimen to prevent infection.”
Dr. Spencer’s team is continuing to investigate the role of insulin in infection protection.
“This work is focused on UTIs, but it may also be applicable to other infections like pneumonia or skin infections, to which patients with diabetes are also more susceptible,” says Dr. Spencer. “Our long-term goal is to determine if it applies to other populations with abnormal insulin sensitivity or signaling, such as people with chronic kidney disease or metabolic syndromes.”
Eichler TE, Becknell B, Easterling RS, Ingraham SE, Cohen DM, Schwaderer AL, Hains DS, Li B, Cohen A, Metheny J, Tridandapani S, Spencer JD. Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract. Kidney International. 2016 Sep;90(3):568-79.
Photo credit: Nationwide Children’s