The new study, in mice, may upend long-held theories about the causes of the disease. Because insulin is produced in the pancreas and sugar is stored in the liver, many scientists have looked to those organs for the underlying causes of diabetes.

In the new research, scientists studied mice that are unable to make fatty acid synthase (FAS) in the intestine. FAS, an enzyme crucial for the production of lipids, is regulated by insulin, and people with diabetes have defects in FAS. Mice without the enzyme in the intestines develop chronic inflammation in the gut, a powerful predictor of diabetes.

“Diabetes may indeed start in your gut,” says principal investigator Clay F. Semenkovich. “When people become resistant to insulin, as happens when they gain weight, FAS doesn’t work properly, which causes inflammation that, in turn, can lead to diabetes.”

“The first striking thing we saw was that the mice began losing weight,” says Wei, a research instructor in medicine. “They had diarrhea and other gastrointestinal symptoms, and when we looked closely at the tissue in the gut, we found a lot of inflammation.”

Initially, the researchers thought that the mice became sick because of changes to the mix of microbes that naturally live in the gut, where they help digest food and synthesize vitamins.

In collaboration with Jeffrey I. Gordon, director of the Center for Genome Sciences and Systems Biology at the School of Medicine, they looked more closely at gut microbes in the mice.

“The mice had substantial changes in their gut microbiome,” Semenkovich says. “But it wasn’t the composition of microbes in the gut that caused the problems.”

Instead, Wei says, the mice got sick because of a defect in fatty acid synthase. The mice without fatty acid synthase had lost the protective lining of mucus in the intestines that separates the microbes from direct exposure to cells. This allowed bacteria to penetrate otherwise healthy cells in the gut, making the mice sick.

“Fatty acid synthase is required to keep that mucosal layer intact,” Wei says. “Without it, bad bacteria invade cells in the colon and the small intestine, creating inflammation, and that, in turn, contributes to insulin resistance and diabetes.”

“Abdominal pain and diarrhea are some of the most common problems we see in people with diabetes,” he says. “We could only connect these ‘dots’ because other experts at the university could help us link what we observed in these mice to what occurs in patients with diabetes and inflammatory bowel disease,” Semenkovich says.

Semenkovich and Wei say much more study is needed, but they say that FAS and a key component of the intestinal mucosa called Muc2 may be potential targets for diabetes therapy. They now plan to study people with diabetes to see whether FAS is altered in a similar way, producing damage to the mucosal layer in the intestines.