Adjusting receptor trafficking of GLP-1R agonist improved insulin release

John Murphy, MDLinx | May 24, 2018

Researchers modified an existing diabetes drug so that it remained longer on the cell membrane, which extended insulin release without increasing the drug’s side effect of nausea, according to results of a study published recently in Nature Communications.

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Researchers modified the receptor trafficking of a GLP-1R agonist compound (green) to reduce internalization of receptors, leading to extended release of insulin (red). (Image: Jones B, et al; CC BY 4.0)

“We have harnessed a new mechanism based on receptor trafficking to develop a drug more effective for type 2 diabetes that doesn’t appear to carry an increased risk of side effects,” said first author Ben Jones, clinical research fellow, Investigative Medicine, Imperial College London, London, UK.

The researchers investigated whether they could modify receptor trafficking in compounds closely related to the diabetes drug exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist. Of the several compounds they developed, exendin-phe1 significantly altered the GLP-1 receptor trafficking process.

In trials with human beta cells, the researchers found that exendin-phe1 reduced internalization of receptors, leading to more receptors available on the cell surface to bind to the drug.

The compound also rapidly increased recycling of receptors to the cell membrane. With standard exenatide treatment, an estimated 90% of GLP-1 receptors internalize from the membrane into the cell, and only about 10% are recycled. But with exendin-phe1, just 30% of the receptors moved into the cell, and the majority of those were recycled, researchers found.

They also tested the compound in mice with induced type 2 diabetes, and confirmed that exendin-phe1 dramatically enhanced insulin secretion and lowered blood glucose. In addition, the compound appeared to have no increased effect on GLP-1 receptors in the brain, which are associated with nausea.

Between 30% and 50% of patients who take approved GLP-1R agonists experience nausea, the researchers noted. As the dose of these drugs increases, glycemia improves—but so do the rates of gastrointestinal adverse events.

“If this treatment were to make it to market, the advantage is that it could be more effective for treating diabetes compared to the existing treatment, and that extra effectiveness would not be accompanied by greater nausea and other side effects,” Dr. Jones said.

The researchers are now preparing a small clinical trial in healthy humans to further investigate the mechanism and utility of modifying receptor trafficking. The study is expected to begin in the coming months.

“We have found that making small changes to drug molecules can dramatically alter receptor trafficking. Ultimately, we’re interested in using these compounds as tools to try and understand receptor biology and generate even more effective drugs in the future,” said co-senior author Alejandra Tomas, PhD, lecturer, Cell Biology and Functional Genomics, Imperial College London. 

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