The endoplasmic reticulum is a labyrinth-like, tubular structure inside cells that, among other things, synthesizes many of the building blocks of glucose metabolism, such as lipids and proteins. Now, thanks to a new drug screening tool they developed, scientists have discovered a new compound that acts on a key pathway inside the endoplasmic reticulum to potentially target the cause of type 2 diabetes.
The drug-screening tool is the work of a team at the Harvard T.H. Chan School of Public Health in Boston, MA, and they call the potential antidiabetes compound azoramide.
In a paper published in Science Translational Medicine, the team describes how the screening technology might also be able to identify other molecules that target the key pathway in the endoplasmic reticulum, which is thought to be involved in several other diseases, including cystic fibrosis, retinitis pigmentosa, Huntington’s disease and Alzheimer’s disease.
Insulin resistance is a precursor of type 2 diabetes. It is a condition where, although the body is producing insulin – which cells need to convert glucose into energy – the cells do not respond to the hormone, resulting in high blood sugar and a range of cell malfunctions that can damage the heart and blood vessels.
Insulin resistance occurs when the endoplasmic reticulum is stressed.
This can happen, for instance, when a person becomes obese and the endoplasmic reticulum in their metabolic tissues, such as the pancreas, liver and fat tissue, can no longer keep up with the demand for protein and lipid production and become overwhelmed with nutrients.
Researchers have known for some time that endoplasmic reticulum stress is a key driver of diabetes and metabolic disease, but until this study, efforts to translate that into clinically useful methods have not been very successful, says senior author Gökhan S. Hotamisligil, a professor of genetics and metabolism.
In their paper, Prof. Hotamisligil and colleagues describe how they developed two complementary analytical procedures for monitoring the function of the endoplasmic reticulum in liver cells.
Using this screening tool, they could directly measure chaperones – molecules that “supervise” and promote key processes in the endoplasmic reticulum, such as correct folding of proteins in 3D. They could also measure how well the endoplasmic reticulum was folding the proteins.
When the endoplasmic reticulum is stressed, the chaperones cannot keep up with the demand for new proteins and lipids.
The team was able to show that under different types of endoplasmic reticulum stress, the compound azoramide protected cells from malfunctioning and death.
And they also found that azoramide greatly improved blood glucose levels in obese mice and mice with type 2 diabetes. They showed this improvement was the result of two things: better functioning of insulin-producing beta cells and greater insulin sensitivity in tissues.
They suggest one way that azoramide works is by increasing the number of chaperones in the endoplasmic reticulum.
The team now plans to test the compound, and others with a similar effect, in human clinical trials.
While obesity is one cause of endoplasmic reticulum stress, there are others. For example, there is a genetic mutation that can lead to vision loss through endoplasmic reticulum stress in retinal cells. The disease where this happens is called retinitis pigmentosa.
In a separate part of the study, the team showed azoramide could potentially protect retinal cells from this effect.
Prof. Hotamisligil concludes:
“These results show the broad potential for azoramide or drugs with similar functions targeted at the endoplasmic reticulum [ER]. ER dysfunction is implicated in many other disease processes such as cystic fibrosis, Huntington’s disease, and Alzheimer’s – which makes this novel screening strategy an exciting new tool that can be applied by multiple labs to discover new drug candidates for diseases that are linked to ER stress.”
The following short animation explains what happens when the endoplasmic reticulum becomes stressed, and the effect of azoramide.
MNT also recently learned that obesity can trigger type 2 diabetes via the microbiome – the diverse colonies of bacteria that inhabit our bodies.