Study Identifies an Obesity-related Risk factor for Diabetes

Study Identifies an Obesity-related Risk factor for Diabetes

Obesity is a major risk factor for the development of type 2 diabetes. New research has identified a specific obesity-related trigger that can lead to insulin resistance and ultimately diabetes. This trigger may involve changes in fat cell biology, inflammation, hormonal imbalances, and other mechanisms. The findings could lead to new treatments and strategies for preventing or managing diabetes in individuals who are overweight or obese. However, more research is needed to fully understand the underlying mechanisms and to develop effective interventions.

Researchers discovered that a defect in an enzyme called APT1 interferes with insulin secretion, contributing to the development of Type 2 diabetes in people who are overweight or obese. People who are overweight or obese have a significantly increased risk of developing diabetes, but the exact mechanism is unknown.

A new study at Washington University School of Medicine in St. Louis may help explain how obesity contributes to diabetes and may provide researchers with a target to help prevent or delay diabetes in some at-risk individuals. The findings suggest that many people with elevated insulin levels – an early indicator of diabetes risk – also have defects in an enzyme involved in the digestion of a key fatty acid from the diet.

The research is published in the journal Cell Metabolism.

We’ve identified several candidate drugs that we’re pursuing. We believe that increasing APT1 activity could reverse this process and potentially prevent people at risk from developing diabetes.

Clay F. Semenkovich

“In the United States, between 30 million and 40 million people have Type 2 diabetes, and another 90 million to 100 million have risk factors that make them more likely to develop Type 2 diabetes in the future,” said senior investigator Clay F. Semenkovich, MD, director of the School of Medicine’s Division of Endocrinology, Metabolism, and Lipid Research. “Many people at risk of diabetes have high insulin levels, which is a sign of insulin resistance and a warning sign that trouble is on the way. We may be able to prevent significant health problems such as heart disease, chronic kidney disease, nerve damage, vision loss, and other problems in a large number of people if we can intervene before they develop diabetes.”

When a person has too much body fat, beta cells in the pancreas secrete more insulin. When insulin levels rise and remain high, the body becomes insulin resistant, and the beta cells that secrete insulin eventually fail, resulting in diabetes.

Semenkovich, the Irene E. and Michael M. Karl Professor; first author Guifang Dong, Ph.D., a senior scientist; Xiaochao Wei, Ph.D., an associate professor of medicine; and other Washington University researchers discovered that insulin overproduction involves a process known as palmitoylation. This is the process by which cells attach the fatty acid palmitate to proteins.

Study reveals obesity-related trigger that can lead to diabetes
Study reveals obesity-related trigger that can lead to diabetes

Thousands of human proteins can be attached to palmitate, but the researchers discovered that diabetes occurs when this fatty acid is not removed from proteins in beta cells. The researchers discovered that people with diabetes were deficient in an enzyme that removes palmitate from beta cells when they examined tissue samples from people who were thin or overweight, and with and without diabetes.

“They hypersecrete insulin because this process goes wrong, and they can’t regulate the release of insulin from beta cells appropriately,” Semenkovich explained. “This palmitoylation process plays a role in insulin release regulation.”

With colleagues David W. Piston, Ph.D., the Edward W. Mallinckrodt Jr. Professor and head of the Department of Cell Biology & Physiology, Maria S. Remedi, Ph.D., a professor of medicine and of cell biology & physiology, and Fumihiko Urano, MD, Ph.D., a professor of medicine and of pathology & immunology, the research team also genetically engineered a mouse that was deficient in the enzyme called APT1, an enzyme responsible for palmitate removal from proteins. Diabetes developed in the engineered mice.

Because impaired APT1 function increased the risk of diabetes, the researchers collaborated with the university’s Center for Drug Discovery to screen and identify compounds that can increase APT1 enzyme activity.

“We’ve identified several candidate drugs that we’re pursuing,” Semenkovich said. “We believe that increasing APT1 activity could reverse this process and potentially prevent people at risk from developing diabetes.”

Although Semenkovich stated that the new findings identifying APT1 as a target are an important step, he added that APT1 is only one treatment target among many. “Type 2 diabetes can develop in a variety of ways,” he explained. “This enzyme is not the answer, but it is a step in the right direction, and it appears that we have some promising tools that could prevent some people with prediabetes from developing diabetes.”