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Research on insulin resistance in type 2 diabetes could lead to new treatment targets

A link between type 2 diabetes and high levels of certain amino acids could explain the cause of insulin resistance, American researchers suggest.
Insulin resistance is closely associated with type 2 diabetes, and occurs when the body can no longer effectively process sugar and becomes less sensitive to insulin. Because insulin doesn’t work properly in the body, blood glucose levels can become too high and this increases the likelihood of type 2 diabetes.
In this new study, researchers from the Perelman School of Medicine at the University of Pennsylvania used mouse and human muscle and blood samples to investigate the mechanisms that lead to insulin resistance.
They theorised that because excess fat inside skeletal muscle can be a cause of insulin resistance, reducing the fat in these muscles could prevent insulin resistance from developing.
Senior author Zoltan Arany, MD, PhD, explained: “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?”
Last week, University of Toronto researchers observed that high levels of branched-chain amino acids are linked to reduced insulin sensitivity. However, they could not prove that branched-chain amino acids caused insulin sensitivity, only that there was a correlation.
The Penn and Perelman researchers wanted to evaluate how branched-chain amino acids cause insulin resistance in type 2 diabetes, and how elevated blood glucose is related to these amino acids.
They found that a by-product compound is secreted from muscle cells when amino acids break down. The compound, called 3-HIB, activates cells in the vascular wall to transport more fat into skeletal muscle tissue.
When fat accumulation occurred in the mice, they developed insulin resistance. However, inhibiting the synthesis of 3-HIB in muscle cells prevented the uptake of fat.
“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 accumulatio, showing how increased amino acid flux can cause diabetes,” said Arany.
“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.”
Arany added that more research is required to fully examine how inhibiting 3-HIB in people with type 2 diabetes affects levels of insulin resistance.
The findings are published online in Nature Medicine.

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