Study Reveals Obesity-Related Trigger that Can Lead to Diabetes

People with elevated levels of insulin also have defects in an enzyme important to the processing of a key fatty acid from the diet, according to research recently published in Cell Metabolism. The study may help explain how excess weight can contribute to diabetes and may provide researchers with a target to help prevent or delay diabetes in some of those at risk.

Researchers led by Clay F. Semenkovich, MD, director of the Division of Endocrinology, Metabolism & Lipid Research at the Washington University School of Medicine in St. Louis point out that when a person has too much body fat, it signals beta cells in the pancreas to secrete more insulin. When insulin levels become elevated and remain high, the body can become resistant to insulin, and eventually the beta cells that secrete insulin can fail, leading to diabetes.

Studying tissue samples, the researchers found that the overproduction of insulin involves palmitoylation, the process by which cells attach the fatty acid palmitate to proteins. Thousands of human proteins can be attached to palmitate, but the researchers found that when this fatty acid isn’t removed from proteins in beta cells, diabetes is the end result. Examining tissue samples from people who were thin or overweight, and with and without diabetes, the researchers found that the people with diabetes were deficient in an enzyme that removes palmitate from beta cells.

The research team also genetically engineered a mouse that was deficient in the enzyme called APT1, an enzyme responsible for palmitate removal from proteins. The engineered mice went on to develop diabetes. Because impaired APT1 function contributed to diabetes risk, the researchers worked with the university’s Center for Drug Discovery to screen and identify compounds that can increase the activity of the APT1 enzyme.

Although he said the new findings identifying APT1 as a target are an important step, Semenkovich says that APT1 is only one treatment target among many. “There are several ways that Type 2 diabetes may develop,” he says. “This enzyme is not the answer, but it’s an answer, and it appears we have some promising tools that might keep some people with prediabetes from developing diabetes.”