Fighting urban diabetes and obesity

Benzene, a major component of air pollution in urban manufacturing areas, may be an underlying cause of type 2 diabetes and obesity, according to Marianna Sadagurski, Ph.D., WSU assistant professor of biology. She and her research group are conducting animal studies to investigate the role of benzene and have found that chronic exposure to low levels causes inflammation of certain brain cells that set the stage for the development of type 2 diabetes and obesity.

In addition, the researchers have found that even maternal exposure during pregnancy is enough to cause brain inflammation in newborn mice, which similarly sets them on the path to developing type 2 diabetes later on.

All is not bad news, Sadagurski said. On a brighter note, her group has found that an anti-diabetes drug or potentially even a diet change may be able to counter the effects of benzene.

Tracking benzene

Benzene is a component of industrial emissions and motor-vehicle exhaust, as well as cigarette smoke and e-cigarette vapors, and has long been known as a carcinogen, but Sadagurski was more interested in its part in sensing and regulating glucose levels. She explained that exposure to benzene causes an inflammation in certain brain cells, called glial cells and glucose-sensing neurons.

Research over the past two decades has shown that these cells are involved in regulating appetite and metabolism (the process of converting food to usable energy), particularly through their combined ability to sense levels of glucose, as well as the hormones insulin and leptin, which work together to regulate metabolism. Insulin regulates glucose levels by delivering glucose to cells or storing it for future use, and leptin acts as an appetite monitor that tells an individual when to eat and when to stop eating. Benzene-associated inflammation can disrupt all of those functions, which can lead to type 2 diabetes and/or obesity, she explained.

To determine the impact of air pollution, Sadagurski began by putting her students to work. "The talented undergrads in the lab did a search through the epidemiological studies to try to see what was known about air pollution in urban areas," she said. Besides finding numerous studies reporting high levels of benzene in people who work in industrial factories, or who are regular tobacco smokers or e-cigarette users, the students also came across research publications showing lower but chronic benzene concentrations in children. In other words, simply living in the area was enough to introduce benzene to the system.

Sadagurski and her research group - led by a postdoctoral fellow in the lab, Lucas Debarba, in collaboration with the WSU biomedical engineering lab of Ulrike Klueh - then began controlled experiments with mice to "get a better understanding of whole-body metabolism, and what happens to the brain and neuroinflammatory signals with benzene exposure."

Since genetics and nutrition can alter metabolism (her group has done considerable work showing the nutrition-diabetes connection), they tested genetically similar mice that had been fed the same diet, so the only variable was benzene exposure. The mice were placed in a chamber, where they breathed air that contained defined concentrations and durations of benzene, and the researchers documented what happened.

"Humongous effect"

The results were stunning. "We didn't expect to see this, but even within a few hours of exposing animals to benzene in relatively low doses, it was enough to trigger a humongous inflammation of glial cells and trigger a neuroinflammatory response in their brains," Sadagurski said. "And after they were exposed to a few hours of benzene each day for five days a week and for four weeks, the glial cells developed massive inflammation, the glucose-sensing neurons had developed massive resistance to insulin and leptin, and they had diabetes. In just four weeks!"

In addition, Debarba together with a grad student in the lab, Lisa Koshko, exposed pregnant female mice to benzene to see whether that would have any impact on their future offspring. "Again we had a controlled system where we knew the food the mothers ate, the day they became pregnant, and the benzene exposure, which we ended on the day before birth, so the young were born in the clean air," she recounted. "What we found was huge effects in the offspring, especially in males." This included substantial inflammation of glial cells and neuroinflammatory responses in the brain at birth, followed by the diabetes symptoms of severe high blood glucose levels and severe insulin resistance by 9 months of age, which would be the equivalent of 30-40 years old in a human, she said.

"What we're seeing is not just that the offspring are sick at the beginning and it goes away; we're seeing this from birth to low middle age, and in mice that were never exposed to this pollutant except during gestation, and ate a normal diet," she reported. "This raises the question of whether predisposition in our children is due not only to nutrition but also to the pollution that we have in some particular areas?"

The good news

Sadagurski is the first to acknowledge that her group's findings are alarming. Short of waving a magic wand to eliminate benzene from the environment, or moving entire populations out of industrialized cities, does a solution exist? The answer, according to the group's newly published study, may be an anti-diabetes drug or possibly just a change in diet.

"Our study very strikingly showed that one of the clinically approved and very efficient anti-diabetes drugs, called acarbose, prevented any effects of metabolic imbalance in these animals, including glial inflammation, even among animals that had been exposed to benzene," she said. "Acarbose made the mice healthier, kept their insulin levels low, moderated glucose levels, and actually extended their lifespans."

In addition, the researchers noted that the drug's effects closely mimic those afforded by a low-glycemic-index diet, so by switching to that diet, "you're not far away from where you would be if you're exposed to benzene without using acarbose," she said. Likewise, she believes a low-glycemic-index diet - or some other diet that slows dietary carbohydrate digestion - during pregnancy could also counter the effects of benzene exposure on a child.

"This diet can potentially be a strategy for reducing any type of negative metabolic effects that we observe under gestational or chronic exposure to benzene, especially for people who are living or working in highly polluted urban areas. That's the take-away."

Back in the lab, Sadagurski's group is continuing their studies of predisposition to type 2 diabetes and obesity. One area of special interest stemmed from a finding that glial cells and glucose-sensing neurons could recover if benzene exposure only lasted for a couple of days. Debarba is embarking on a study to determine whether ending benzene exposure after longer periods could have similar effects. This project is now funded by the Center for Urban Responses to Environmental Stressors, or CURES.

"At this point, we don't know whether it will eventually resolve or it causes permanent damage," Sadagurski said, "but it is one more piece of the puzzle that we are very interested in."