When Rob Sargis, an endocrinologist at the University of Chicago, talks about his research on metabolism, obesity, and diabetes, he makes it clear what he’s really trying to understand.
“Diabetes is the thing that matters. That’s what causes the amputations, the kidney failure, the blindness and the heart attacks,” he said. “Whether obesity is a part of that or not isn’t as important.”
Obesity is the popular explanation for the global epidemic of diabetes. Modern humans simply eat too much and don’t exercise enough, which leads to being overweight, becoming insulin resistant and eventually developing full-blown diabetes.
But the explanation of physical inactivity plus poor diet alone doesn’t account for the sheer scale and speed of the epidemic. In 2014, the International Diabetes Federation estimated that 387 million people had diabetes, and by 2035 that number will rise to 592 million—the vast majority of those type 2. Obesity also doesn’t account for the alarming increase in type 1 diabetes, an autoimmune condition that has nothing to do with body weight. A 2012 American Diabetes Association report showed a 23 percent rise in type 1 diabetes in American children from 2001 to 2009.
No one doubts that unhealthy lifestyles play a huge role in the diabetes epidemic, but Sargis’ work is part of a growing field of research into another factor, that exposure to chemicals in the environment disrupts the endocrine system in ways that can lead to diabetes and other metabolic diseases.
The idea that chemicals in the environment could affect human health entered into the public imagination in the 1960s, after Rachel Carson’s Silent Spring exposed the dangers of pesticides like DDT. Exposure to pesticides or industrial toxic waste is usually associated with cancer or neurological problems, not the metabolism, but in 1991 the first paper showing that chemical exposure could disrupt hormones was published. The first of these had to do with growth and reproduction, but later studies pointed to effects on hormones that regulate metabolism as well.
In the decades since, scientists have shown how exposure to specific endocrine disrupting chemicals (EDCs) can damage insulin-producing beta cells, disrupt the action of insulin itself, and alter the balance between glucose processing and fat storage in the body.
Sargis and the researchers in his lab have focused on how EDCs disrupt the glucocorticoid signaling pathway, a process that regulates genes controlling development, metabolism and immune response, all key factors in the development of diabetes. So far, four chemicals seem to cause trouble: bisphenol A (BPA) and dicyclohexyl phthalate, which are found in plastics, and two pesticides, endrin and tolylfluanid. When fed to mice, tolylfluanid caused weight gain, increased body fat, glucose intolerance and insulin resistance. But obesity and metabolic symptoms don’t always come together—in a mouse model of type 1 diabetes, mice that are exposed to phthalates in utero are more likely to develop diabetes later in life, independent of weight.
Making connections between chemicals and metabolic problems in a tightly controlled research model is one thing though—extrapolating it to humans living in the real world is quite another.
“People are exposed to thousands of chemicals in their lives, so each person’s cocktail is a little bit different,” Sargis said. “It’s hard to know [what contributes to disease] because most of these effects are small and summate over different exposures. There are a few chemicals that we know for sure, if you got exposed to that you will likely develop disease. But it’s a huge issue, because you often can’t specifically attribute someone’s disease to any one exposure in one instance.”
Add that messy cocktail of nearly infinite combinations of chemical exposures to the other lifestyle factors contributing to diabetes, and it may seem like a lost cause trying to pinpoint a specific culprit. But understanding the mechanism of how EDCs induce metabolic problems, like Sargis’ work on the glucocorticoid receptor, will also point scientists toward new treatments, or even ways to reverse the process.
This line of research also fits into a bigger picture of the spread of diabetes. Epidemiological studies can uncover patterns of exposure to EDCs that may be concentrated within certain populations, an overlooked dimension of the epidemic.
“Many of the chemicals that have been associated with metabolic dysfunction are not evenly distributed in the population, so you have racial and ethnic minorities, often those of lower economic means, who are more likely to be exposed,” Sargis said. “It creates this new form of health disparity that is wholly underappreciated.”
The final hurdle will be putting this knowledge into practice. Silent Spring led to a wholesale ban on DDT, but eliminating chemicals in plastics with more subtle health impacts may be more difficult. Sargis said that translation to the clinic starts with awareness, the point when physicians can ask patients at risk for diabetes about their homes and occupations along with standard health histories, to assess their risk of exposure to problematic chemicals.
“That’s not to deny the fact that diet and exercise and genetics are critically important as well,” he said. “It’s all important, but this opens up the possibility that we can think about this in multiple dimensions to understand how these exposures matter.”