Patients with type 2 diabetes are unable to effectively control their blood sugar levels. The most commonly prescribed drug is called metformin, but if this doesn't work, or triggers side effects, patients are usually offered other drugs. These include a class of drugs called "incretin mimetics", which stimulate the release of insulin from specialized cells in the pancreas, called beta cells.
In the latest study, researchers focused on one of these compounds, a drug called exenatide, which patients inject twice-daily or weekly, depending on the formulation. The compound acts by binding to and activating a type of docking point - called GLP-1 receptors - found on the surface of beta cells, which stimulate the cells to release insulin.
In a paper, published in the journal Nature Communications, researchers explain how switching a few of the building blocks of exenatide could generate new compounds with slightly different properties, changing how they interact with the GLP-1 receptors and making the drugs more effective.
Normally, when GLP-1 receptors are activated - such as when a compound like exenatide binds to them - they move from the cell membrane to the inside of the cell, where they are either degraded, or recycled, i.e. they re-join the cell membrane ready to start the whole process again. This process, called receptor trafficking, can have a big impact on the effect of a drug and the degree of its side effects.
"Under normal conditions, we may not want cells to be continually activated, so these receptors are internalised and no longer accessible to naturally occurring GLP-1 outside of the cell," explained first author of the study. "However, when you have a disease where we can get benefit from continual stimulation of receptors, then avoiding this internalisation process could be an advantage.
The team found that one of their compounds, called "exendin-phe1", altered the GLP-1 receptor trafficking process. In trials with human beta cells in the lab they found that their compound reduced the degree to which the receptors left the membrane, leading to more receptors available on the cell surface to bind to the drug.
With the standard treatment, an estimated 90 per cent of GLP-1 receptors would move from the membrane into the cell, with only around 10 per cent being recycled. With the new compound, however, just 30 per cent of the receptors moved into the cell and the majority of those were recycled, returning to the cell membrane.
In mouse studies, the researchers found that while their new compound increased the amount of insulin being secreted from the animals' beta cells in the pancreas, it appeared to have no increased effect on GLP-1 receptors elsewhere in the body - namely GLP-1 receptors in the brain, which are associated with nausea.
"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," explained the first author. "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."
The Imperial team is now planning a small study with healthy human volunteers to further explore the mechanism of receptor trafficking and how it could be used, which is expected to begin within the coming months.
http://www.imperial.ac.uk/news/185856/hacking-drug-trafficking-network-could-make/
https://www.nature.com/articles/s41467-018-03941-2
Latest News
Mechanism of sugar signalin…
By newseditor
Posted 19 May
How does the brain turn wav…
By newseditor
Posted 19 May
A trial HIV vaccine trigger…
By newseditor
Posted 19 May
AI to predict DNA methylati…
By newseditor
Posted 19 May
Hyperactive platelets from…
By newseditor
Posted 19 May
Other Top Stories
Bacteria in tumors help cancer cells metastasize
Read more
Immunosuppression as a key factor leading to colorectal cancer deve…
Read more
Gene mutation that signals aggressive melanoma
Read more
New way to inhibit transcription factors
Read more
Synthetic receptors for programmed gene regulation in cell therapies
Read more
Protocols
Breast cancer-on-chip for p…
By newseditor
Posted 16 May
Methods for making and obse…
By newseditor
Posted 15 May
Mime-seq 2.0: a method to s…
By newseditor
Posted 13 May
Improved detection of DNA r…
By newseditor
Posted 09 May
Single-cell adhesive profil…
By newseditor
Posted 07 May
Publications
Identification of hypoxic m…
By newseditor
Posted 20 May
Molecular mechanism of treh…
By newseditor
Posted 19 May
Hue selectivity from recurr…
By newseditor
Posted 19 May
Vaccine induction of hetero…
By newseditor
Posted 19 May
Brain border-associated mac…
By newseditor
Posted 19 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar