Researchers discover cause of insulin resistance in type 2 diabetes

By John Murphy, MDLinx
Published March 8, 2016

Key Takeaways

Researchers have discovered a novel mechanism that explains how increased levels of branched-chain amino acids (BCAAs) lead to insulin resistance and cause type 2 diabetes, according to a study published online March 7, 2016 in the journal Nature Medicine. This finding suggests a new pathway that could potentially be targeted to treat diabetes.

Previous research has implicated BCAAs in the development of insulin resistance, but the underlying mechanisms haven’t been found. Researchers do know that insulin resistance in skeletal muscle stems from an excess accumulation of lipids. But what researchers don't know is how blood-borne lipids can traverse the blood vessel wall, and how that movement is regulated.

“This research sought to answer a few large questions: How does fat get into skeletal muscle? And how is the elevation of certain amino acids in people with diabetes related to insulin resistance?” said the study’s senior author Zoltan Arany, MD, PhD, Associate Professor of Cardiovascular Medicine at the University of Pennsylvania Perelman School of Medicine, in Philadelphia, PA.

“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,” Dr. Arany said. “However, we didn’t understand how this could cause insulin resistance and diabetes. How is elevated blood sugar related to these amino acids?”

To find out, the researchers used a transcriptional coactivator, which regulates all sorts of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a byproduct of BCAAs. In mouse experiments, they determined that 3-HIB is secreted from muscle cells and activates cells in the vascular wall to transport more fat into skeletal muscle tissue. This leads to fat accumulation in the muscle that, in turn, leads to insulin resistance in mice.

Conversely, when the researchers inhibited the synthesis of 3-HIB in muscle cells, it blocked the uptake of fat in muscle.

“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,” Dr. Arany said.

The team also found that 3-HIB is elevated in people with type 2 diabetes. In light of this finding, the researchers called for more studies to fully examine this mechanism in people with type 2 diabetes.

“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,” Dr. Arany said.

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