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Study Reveals New Insights in Type 2 Diabetes Research, Potentially Leading to Novel Ways to Target Treatments

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Study Reveals New Insights in Type 2 Diabetes Research, Potentially Leading to Novel Ways to Target Treatments
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A research team at the Perelman School of Medicine at the University of Pennsylvania found a link between high levels of certain amino acids and type 2 diabetes. The team used mice and human blood and muscle samples to assess the mechanisms behind what is causing insulin resistance.

The study was published in the journal Nature Medicine, and is titled “A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.

There are more than 29 million people in the United States living with diabetes, most of whom suffer from type 2 diabetes. For these patients, insulin resistance — their bodies’ ability to effectively process sugar — means there are adequate levels of insulin in the body, but the body doesn’t recognize it effectively.

While people tend to connect insulin resistance to sugar levels in the bloodstream, diabetes is also related with excessive levels of fat, particularly inside skeletal muscle, leading to insulin resistance. The researchers hypothesized that if the level of fat in muscles could be decreased, then in theory, insulin resistance could be avoided.

“This research sought to answer a few large questions,” Zoltan Arany, M.D., Ph.D., associate professor of cardiovascular medicine and senior author of the study, said in a press release. “How does fat get into skeletal muscle? And how is the elevation of certain amino acids in people with diabetes related to insulin resistance? We have appreciated for over 10 years that diabetes is accompanied by elevations in the blood of branched-chain amino acids, which humans can only obtain in their diet. However, we didn’t understand how this could cause insulin resistance and diabetes. How is elevated blood sugar related to these amino acids?”

The research team discovered that muscle cells secrete 3-HIB, a byproduct compound of breakdown of these specific amino acids, and that, at the same time, 3-HIB activates cells in the vascular walls to transport fat into skeletal muscle tissue. This means that this process is leading to the accumulation of fat in the muscle, and, as a result, to insulin resistance, as observed in the mice used in the study. The team then thought that inhibiting 3-HIB synthesis in muscle cells could block the accumulation of fat in the muscle.

Arany and his colleagues conducted most of the study using mouse cells, but they also found that 3-HIB was abnormally elevated in type 2 diabetes patients, which led the team to conclude that further studies were needed to scrutinize the nature of this mechanism in people suffering from type 2 diabetes.

“In this study we showed a new mechanism to explain how 3-HIB, by regulating the transport of fatty acids in and out of muscle, links the breakdown of branched-chain amino acids with fatty acid accumulation, showing how increased amino acid flux can cause diabetes,” Arany said.

“The discovery of this novel pathway – the way the body breaks down these amino acids that drives more fat into the muscles – opens new avenues for future research on insulin resistance, and introduces a conceptually entirely new way to target treatment for diabetes,” he said.

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