Obesity and overweight can lead to diabetes: Study | Health

Overweight and obese people are more likely to develop diabetes, but the exact mechanism is not well understood.

A new study at Washington University School of Medicine in St. Louis could help explain how being overweight can contribute to diabetes and could provide researchers with a target to help prevent or delay diabetes in some people at risk. The results suggest that many people with high levels of insulin – an early marker of diabetes risk – also have defects in an enzyme important for processing a key dietary fatty acid.

The research is published Jan. 11 in the journal Cell Metabolism.

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“Between 30 and 40 million people in the United States have type 2 diabetes, and another 90 to 100 million have risk factors that make them susceptible to developing Type 2 diabetes in the future,” said lead researcher Clay F. Semenkovich, MD, director of the division of endocrinology, metabolism, and lipid research at the School of Medicine. “Many people at risk for diabetes have high insulin levels, a hallmark of insulin resistance and a signal that means trouble may be brewing. If we could intervene before they actually develop diabetes, we might be able to prevent serious health issues, such as heart disease, chronic kidney disease, nerve damage, vision loss, and other problems — in a large number of people.”

When a person has too much body fat, it signals the beta cells in the pancreas to secrete more insulin. When insulin levels get high and stay high, the body can become insulin resistant and eventually the beta cells that secrete insulin can fail, leading to diabetes.

Studying human tissue samples, Semenkovich, Professor Irene E. and Michael M. Karl; first author Guifang Dong, PhD, senior scientist; Xiaochao Wei, PhD, associate professor of medicine; and other researchers at the University of Washington found that the overproduction of insulin involves a process called palmitoylation. It is the process by which cells attach the fatty acid palmitate to proteins.

Thousands of human proteins can be attached to palmitate, but researchers have found that when this fatty acid is not removed from beta cell proteins, diabetes is the end result. By examining tissue samples from thin or overweight people with and without diabetes, researchers found that people with diabetes lack an enzyme that removes palmitate from beta cells.

“They over-secret insulin because that process goes wrong and they can’t properly regulate insulin release from beta cells,” Semenkovich explained. “The regulation of insulin release is controlled in part by this palmitoylation process.”

With colleagues David W. Piston, PhD, Professor Edward W. Mallinckrodt Jr. and Head of the Department of Cell Biology and Physiology, Maria S. Remedi, PhD, Professor of Medicine and Cell Biology and Physiology, and Fumihiko Urano, MD , PhD, professor of medicine and pathology and immunology, the research team also genetically modified a mouse that was deficient in an enzyme called APT1, an enzyme responsible for removing palmitate from proteins. The modified mice then developed diabetes.

Since impaired APT1 function contributed to diabetes risk, the researchers worked with the university’s Center for Drug Discovery to screen and identify compounds that may increase the activity of the APT1 enzyme.

“We have found several drug candidates, and we are pursuing them,” Semenkovich said. “We believe that by increasing the activity of APT1, we could reverse this process and potentially prevent those at risk from progressing to diabetes.”

Although he said the new findings identifying APT1 as a target are a milestone, Semenkovich explained that APT1 is just one treatment target among many.

“Type 2 diabetes can develop in several ways,” he said. “This enzyme isn’t the answer, but it is, and it looks like we have some promising tools that could prevent some people with prediabetes from developing diabetes.”

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