Researchers for over thirty years have been trying to unravel the mystery of how a key biological molecule self assembles into a rogue protein-like substance—amyloid—which is thought to play a role in the development of type-2 diabetes (T2D), which reportedly affects 300 million people worldwide.

Now, a scientific team says it has been able to identify the step-by-step changes that take place in the molecule known as human islet amyloid polypeptide, or hIAPP, as it changes into amyloid. They have also discovered new compounds that are able to speed up or slow down the process.

In healthy people, hIAPP is secreted by islets in the pancreas alongside the hormone insulin and it helps to regulate blood glucose levels and the amount of food in the stomach. When hIAPP malfunctions, it forms clumps of a protein-like substance called amyloid fibrils that kill the insulin-producing islets in the pancreas. The build-up of amyloid fibrils is seen in people with type-2 diabetes although the exact mechanism of how it triggers disease is not known.

The research findings (“Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly”) are published Nature Communications.

The paper not only describes the complex molecular changes seen in hIAPP molecules as they transform into amyloid fibrils, but the scientists also announce that they have discovered two compounds, described as molecule modulators, which can control the process: one of the compounds delays it, the other accelerates it.

Molecule modulators as chemical tools

These molecule modulators can be used as “chemical tools” to help scientists investigate the way amyloid fibrils grow and how and why they become toxic. Significantly they offer “starting points” for the development of drugs that could halt or control amyloid fibril formation and help in the urgent search to find ways to treat type 2 diabetes.

“Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G,” write the investigators.

“We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations.

“Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase.

“These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D.”

According to Sheena Radford, PhD, Royal Society Research Professor and professor of biophysics at the Astbury Centre for Structural Molecular Biology at Leeds, who supervised the research, “This is an exciting and huge step forward in our quest to understand and treat amyloid disease and to tackle a major health issue that is growing at an alarming rate.

“The compounds we have discovered are a first and important step towards small molecule intervention in a disease that has foxed scientists for generations.”

The research team looked at hIAPP found commonly in the population and a rare variant found in people with a genetic mutation known as S20G which puts them at greater risk of developing type-2 diabetes.

Understanding amyloid fibril formation is a key area of health research. The formation of fibrils is believed to be a factor in a range of life-limiting illnesses including Alzheimer’s Disease and Parkinson’s Disease, as well as type-2 diabetes.

“The results are also hugely exciting as they open the door to using the same type of approaches to understanding other amyloid diseases, the vast majority of which currently lack any treatments,” added Radford.