Diabetes Treatment: A novel ‘Flexible’ Approach discovered!

Subhajit Nan, Amity University, Kolkata

Through new research, scientists suggest that the conformational flexibility of peptides makes them more effective in the second type of diabetes treatment.

For those who are unversed, peptides refer to the short chunks of proteins. Many hormones are in-fact peptides, such as insulin and glucagon. These peptides provide important information to cells that affect metabolism, like regulating sugar levels in the blood.

Peptides constitute the most important components of the molecular signaling mechanism as they pass the information by binding to specialized receptor proteins on the exterior of a cell, thereby activating them and initiating the signaling pathway.

What is Type-2 diabetes?

The second type of diabetes is clinically known as Type-2 diabetes. It is described as a disorder pertaining to the glucose metabolism of the body. In the long term, this condition results in high levels of blood sugar. This, in turn, leads to nervous, circulatory, and immune systems malfunctioning.

The peptide used to promote insulin release, and therefore prevent Type-2 diabetes, is known as ‘GLP-1’. We had previously known that it adopted a rigidly helical, corkscrew shape. Scientists had hypothesized that the peptide followed a ‘lock-and-key’ relationship with the cellular receptor. This meant that the peptide would be required to possess a rigid and exact shape to function properly and effectively.

The new ‘flexible’ approach discovered for diabetes treatment:

In this new study, this conventional knowledge was contradicted. The scientists engineered a peptide with sudden ‘kink’, or constriction, near its end. When they compared this engineered peptide with a peptide locked with a rigid helical shape, they found that the engineered ‘flexible’ peptide was more effective in activating its cellular target receptor, which stimulates the release of the hormone insulin from the pancreas, which ultimately lowers the high sugar levels in the bloodstream.

When the research team conducted their experiments using these two different shapes, they found that the helical peptides bound strongly to the receptor but were not as effective in activating it. On the contrary, kinked peptides couldn’t bind very strongly, yet they activated the cellular receptor very effectively when eventually docked in.

These observations led the team to come up with a new model GLP-1’s structure in correlation with its function. Through their new model, they suggested that GLP-1 binds to its target and activates it as a helical structure, and fits perfectly, following the lock-and-key hypothesis. Then, GLP-1 switches to a new ‘conformation’, or shape, with a constricted end. The constriction, or kink, helps reorganize the GLP-1’s cellular receptor, preparing it to send a new molecular signal. The peptide then again reverts to its helical shape to anchor with its cellular receptor once again and the cycle repeats itself.

Consequently, the scientists concluded that GLP-1 peptide possesses a flexible conformation and is capable of switching ‘back-and-forth’ between these two forms, or configurations, to maximize its effectiveness in signal transduction. Their discoveries have the potential to improve the design for these diabetes therapeutic drugs and possibly other therapeutic peptides, and hence facilitate diabetes treatment in general.

Also read: Universal influenza vaccine under development

Reference:

1. Cary, Brian P., et al. ‘Structural and Functional Diversity among Agonist-Bound States of the GLP-1 Receptor’. Nature Chemical Biology, Dec. 2021, pp. 1–8. www.nature.com, https://doi.org/10.1038/s41589-021-00945-w.

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Author info:

Subhajit Nan is an aspiring biotechnologist, living in Kolkata. He is currently in his second year, pursuing a Bachelor of Science (Honours) in the field, from Amity University, Kolkata. He has completed his schooling at Calcutta Boys’ School in the Science stream. He has a keen interest in scientific research and writing. He likes debating, playing chess, and swimming in various competitions.

Other Publications of the Author: –

1. https://bioxone.in/news/worldnews/apples-give-info-on-co-evolution-of-host-and-microbiome/
2. https://bioxone.in/news/early-decrease-in-atmospheric-co2-concentration-caused-polar-ice-formation/
3. https://bioxone.in/news/worldnews/exploiting-plant-response-to-arsenic-contamination-in-soil-for-human-welfare/