Diabetes May Originate in the Intestines

By: Almas Eftekhari

While the role of the pancreas and the liver in the development of diabetes are well described, a recent study conducted by ADA-funded researchers at Washington University in St. Louis suggests that the digestive system may also play a surprising and important role in developing the disease.

Lead investigator Clay F. Semenkovich, MD is the main author on the February 16, 2012 Cell Host & Microbe publication, which links an insulin-regulated enzyme, called fatty acid synthase (FAS), to chronic inflammation in the gut – a known contributor to insulin resistance and type 2 diabetes. Dr. Semenkovich’s former postdoctoral fellow in an ADA mentorship grant, Xiaochao Wei, PhD, collaborated on the study and is first author on the paper.

While humans (and animals) depend on normal gut bacteria to aid with digestion and help produce vitamins, a protective mucus barrier prevents harmful pathogenic bacteria from invading the small intestines and colon. The scientists found that FAS, an enzyme which is critical in lipid and fat production, helps maintain this protective mucus membrane that lines the intestines. Since FAS is regulated by insulin, people with diabetes have lower levels of the enzyme and thus may be more vulnerable to inflammation in their digestive tract.

Dr. Semenkovich and Dr. Wei observed that mice with diabetes have weakened mucus barriers that allowed their intestines to become more permeable to inflammatory pathogens. By treating the animals with insulin, the researchers were able to increase FAS levels, restore the mucus layer, and decrease intestinal permeability.

"Diabetes may indeed start in your gut. 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," said Dr. Semenkovich. By identifying new mechanisms involved in the development of diabetes, these results could provide future avenues for developing therapeutics to combat the disease.

Dr. Semenkovich currently holds two active grants with the ADA and continues to mentor a new fellow, Mariko Johnson, MD, who is exploring related mechanisms. “These awards continue to make it possible for me to identify and nurture the careers of young scientists who hope to improve the quality of life for people afflicted with diabetes.”

(Wei X, Yang Z, Rey FE, Ridaura VK, Davidson, NO, Gordon JI, Semenkovich CS. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin2. Cell Host & Microbe, Feb. 16, 2012.)