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Poor Immune Response and High Glucose is Link to Diabetic Infections

According to new research by scientists at the University of Pittsburgh (Pitt) School of Medicine, the combination of immune failure and high levels of blood glucose in people with uncontrolled diabetes appears to provide an ideal environment for a common form of superbug to thrive unchecked and do its worst harm.

The researchers' studies showed that in glucose-rich diabetic environments, Staphylococcus aureus, a bacterium that is often immune to antibiotics, thrives, causing activation of some of its most virulent characteristics. The findings showed that in addition, a lack of insulin prevents the immune system from reacting to an infection. "This explains why a wound or cut in a diabetes patient really needs to be handled vigorously," said Anthony Richardson, PhD, associate professor in the microbiology & molecular genetics department of Pitt. "The immune system needs support to identify the infection and clear it before it can take root. The research titled "Lack of nutritional immunity in diabetic skin infections promotes Staphylococcus aureus virulence."

Around 11 percent of people in the United States are estimated to have diabetes, and more than a third of all adults have pre-diabetes. The global incidence of diabetes is also growing rapidly, and more than 590 million individuals are expected to be affected by 2035, the researchers wrote. Elevated blood glucose levels are a hallmark characteristic of diabetes, which occurs either when the body does not produce enough insulin, or when there is a weak reaction to the insulin that is released.

The researchers said that up to a third of individuals with diabetes would develop diabetic foot ulcers, which can lead to foot infection and amputation of the legs. "Skin and soft tissue infections (SSTIs) that often manifest as foot ulcers are one of the most common infections in people with diabetes. S. Aureus is the most common bacterium associated with these types of invasive infections, especially in people with poorly regulated diabetes mellitus and S. aureus  levels. Parallel infections of aureus and diabetes have emerged over the past three decades. "SSTIs are often polymicrobial in individuals with diabetes. The team added, "S.aureus is the most frequently isolated pathogen from diabetic SSTI."

Prior studies have shown that the severity of diabetic infections in both innate and adaptive immunity is correlated with defects. But while immune suppression was well reported in diabetic infections, the researchers noted, "to our knowledge, there have been few studies addressing how hyperglycemia affects the virulence capacity of bacterial pathogens in diabetic infections."

Previous analysis by lead author Lance Thurlow, PhD, who performed the newly published study at Pitt and is now at Chapel Hill University of North Carolina, has shown that two glucose transporters, glcA and glcC, were produced by S. aureus, which are in addition to the two that are already prevalent in most staphylococcal organisms. In diabetic conditions, S. aureus has an advantage over other bacteria in allowing use of excess blood sugar to proliferate.

In their new research, Richardson, Thurlow, and colleagues performed a series of experiments with diabetic and non-diabetic Streptozotocin (STZ) mice, using staphylococcus strains with and without extra transporters. They discovered a strain of S in diabetic mice. Biofilms and activated pathways which increased virulence were rapidly formed by aureus with four glucose transporters. Diabetic mice infected with staphylococcus strains that did not have extra glucose transporters, on the other hand, developed less invasive infections, although their immune systems were still slower than those of non-diabetic animals to respond. "In particular, we demonstrate that the recent acquisition of glcA and glcC by S. aureus. In hyperglycemic SSTIs, aureus is necessary for maximum toxin production and virulence potential,” they concluded

The findings confirmed that while non-diabetic animals' immune systems were typically capable of containing and battling they confirmed that S. aureus. The immune systems of the diabetic mice were especially slow to react to aureus infection, resulting in untreated infection and serious diabetic ulcers.

Their research showed that the diabetic mice showed a defective response to the immune system, with phagocytes of the immune system failing to express the requisite glucose transporters to take in enough glucose to fuel the mechanisms required to clear the infection. "We demonstrate that the absence of GLUT-1/-3 expression on STZ-treated, insulin-deficient animal infiltrating phagocytes correlates with their inability to mount an efficient oxidative burst and clear the infection," the team wrote.

This also suggested that for the S, aureus there was extra glucose. "The lack of glucose intake by these phagocytes coupled with total body hyperglycemia results in an atmosphere of infection that is full of excess glucose," they wrote, In order to achieve much higher densities in wounds, S. aureus bacteria Interestingly, diabetic mice given a drug that decreases blood sugar were just as capable of handling the infection as were the normal mice.

"The researchers proposed that their combined findings showed that "immune dysfunction mainly results in increased bacterial burdens in STZ-treated animals, whereas elevated tissue glucose is responsible for increase generation of the aureus virulence factor. The recent acquisition of the GlcA and GlcC glucose transporters significantly contributes to S. aureus virulence, especially in hyperglycemic tissue." we can now begin to understand why patients with diabetes suffer directly from S. aureus Infections.

Knowing the process, Richardson proposed that aureus uses severe infections in people with diabetes to induce therapies that prey on the bacteria's appetite for glucose, tricking it into eating a poisonous analogue. But we still can't lose sight of the need for diabetes prevention and management," he continued." "If we can prevent people from having diabetes and help regulate their blood sugar by helping people who have it, then S. aureus would have a much tougher time causing horrific infections like this.

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