A food preservative called propionate – commonly used to make baked goods such as bread or cake, animal food and artificial flavorings – has been found to raise the risk of insulin resistance, diabetes and obesity in human and mouse studies, according to new research at Sheba Medical Center in Israel and Harvard University in Massachusetts.

The “groundbreaking” study, which combined data from a randomized placebo-controlled trial in humans as well as rodents in the lab, was published online in Science Translational Medicine under the title “A Metabolic Dysregulator in Hiding.”

The research at Sheba in Tel Hashomer, Israel, Tel Aviv University’s Sackler Faculty of Medicine and the Harvard Chan School of Public Health in collaboration with researchers from Brigham and Women’s Hospital indicated that propionate may act as a “metabolic disruptor.” They found that the naturally occurring short-chain fatty acid can trigger a cascade of metabolic events leading to insulin resistance and hyperinsulinemia – a condition marked by excessive levels of insulin. In mice, chronic exposure to propionate resulted in weight gain and insulin resistance.

More than 400 million people around the world suffer from diabetes, whose incidence is projected to rise 40% by 2040 despite extensive efforts to curb the disease. “The dramatic increase in the incidence of obesity and diabetes over the past 50 years suggests the involvement of contributing environmental and dietary factors,” said Associate Prof. of Medicine Amir Tirosh at Tel Aviv University’s Sackler School of Medicine, director of the division of endocrinology at Sheba and a research fellow at the Chan School.

“One such factor that warrants attention is the ingredients in common foods. We are exposed to hundreds of these chemicals on a daily basis, and most have not been tested in detail for their potential long-term metabolic effects,” he added.  

Understanding how ingredients in food affect the body’s metabolism at the molecular and cellular level could help us develop simple but effective measures to tackle the dual epidemics of obesity and diabetes,” said genetics and metabolism Prof. Gökhan Hotamisligil, who is director of the Sabri Ülker Center for Metabolic Research at the Chan School.

Researchers have suggested that dietary components including ingredients used for preparation or preservation of food may be a contributing factor, but there has been little research that evaluated these molecules.

For the study, the researchers focused on propionate, which helps prevent mold from forming on foods. When they fed it to mice, they found that it rapidly activated the sympathetic nervous system, which led to a surge in hormones, including glucagon, norepinephrine, and a newly discovered gluconeogenic hormone called fatty acid-binding protein 4 (FABP4).

This, in turn, set off a chain reaction, causing the mice to produce more glucose from their liver cells, leading to hyperglycemia – a defining trait of diabetes. Moreover, the researchers found that chronic treatment of mice with a dose of propionate that was equivalent to the amount typically consumed by humans led to significant weight gain in the mice, as well as insulin resistance.

To determine how the findings in mice may translate to humans, the researchers established a double-blinded placebo-controlled study that included 14 healthy participants. The participants were randomized into two groups: One group received a meal that contained one gram of propionate as an additive, while the other group was given a meal that contained a placebo. Blood samples were collected before the meal, within 15 minutes of eating the meal, and every half hour thereafter for four hours.

The researchers noted that while propionate is generally recognized as safe by the US Food and Drug Administration, these new findings require further investigation into propionate and potential alternatives that could be used in food preparation.