Insulin Resistance Appears to Disrupt Natural Defense Against Urinary Tract Infections

Insulin receptor signaling provides a possible target to boost protection for patients with diabetes and prediabetes.

People with diabetes or prediabetes suffer more and harsher urinary tract infections than the general population. The medical community has long attributed the problem to excess amounts of the sugar glucose in the urine.

But Nationwide Children’s researchers have found that when they mimic insulin resistance, a hallmark of type 2 diabetes (the more common of the two types) and prediabetes, infection susceptibility increases with and without excess sugar present.

Looking further, the investigators found that insulin receptor signaling in certain kidney cells appears to regulate production of two antimicrobial peptides (AMPs) that defend the urinary tract against infections. 

The research “suggests that infections may not be solely due to abnormal glucose levels but insulin resistance itself,” says John David Spencer, MD, a nephrologist and principal investigator in the Center for Clinical and Translational Research.

The work, published in The Journal of Clinical Investigation, could have global impact. The International Diabetes Federation estimates 415 million people worldwide have diabetes and that the number is growing. The U.S. Centers for Disease Control and Prevention estimates that nearly half of the country’s adult population has prediabetes or diabetes.

Dr. Spencer and a team of investigators mimicked insulin resistance by deleting insulin receptors in mouse models. They found that by deleting insulin receptors in the kidney’s collecting duct and intercalated cells, production of the protective AMPs lipocalin 2 (Lcn 2) and ribonuclease 4 (RNase 4)  was subdued and infection susceptibility increased.

And, in tissue cultures of mouse and human renal epithelial cells, production Lcn 2 and RNase 4 was induced in the presence of insulin. But when researchers suppressed the signaling channel that insulin works through to regulate the AMPs, Lcn 2 and RNase 4 production was suppressed.

“We’ve potentially identified new therapeutic targets to help prevent patients with diabetes from getting infections,” says Dr. Spencer, who is also an assistant professor of Pediatrics at The Ohio State University College of Medicine.

“Historically, people use antibiotics to treat infections,” he says. “This work could help generate non-antibiotic solutions. With the growing resistance of pathogens to antibiotics, that could have a large impact on patient care.”

After their series of experiments using mouse models and tissue cultures, the researchers wanted to see if insulin resistance had an impact on human urinary AMP expression. They analyzed the urine of children and teens with type 2 diabetes and found they had lower levels of Lcn 2 and RNase 4 compared to healthy controls.

Dr. Spencer and his colleagues are now trying to find ways to boost the insulin-signaling pathway, to try to protect against infection. The team is also investigating whether there are biomarkers in the urine or genetic material that can help predict which people with or without diabetes are likely to have infections.

Citation: Murtha MJ, Eichler T, Bender K, Metheny J, Li B, Schwaderer AL, Mosquera C, James C, Schwartz L, Becknell B, Spencer JD. Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses. The Journal of Clinical Investigation.  2018 Nov 12. pii: 98595.