Understanding the contribution of amyloid production to type 2 diabetes and other amyloid-related diseases raises the possibility of new treatments

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For the first time, scientists from the University of Leeds have uncovered the step-by-step changes that take place in a key molecule in the pancreas known as human islet amyloid polypeptide (hIAPP) as it changes into damaging amyloid. They have also discovered compounds that accelerate or delay this process.

Amyloid contributes to the development of type 2 diabetes, and is also implicated in a number of other diseases, including Alzheimer’s disease and Parkinson’s disease. 

The researchers said that their findings, which have been published in Nature Communications, raise the possibility of new treatments for type 2 diabetes and other amyloid-related diseases.

Unravelling the process of amyloid production 

The authors of the study explain that, in healthy people, hIAPP is secreted by pancreatic islet cells alongside insulin, and helps to regulate blood glucose levels and prevent gastric emptying. However, if hIAPP malfunctions, it self-assembles into clumps of amyloid fibrils. These fibrils are then deposited in insulin-producing islet cells, killing them. The formation and build-up of amyloid fibrils is seen in people with type 2 diabetes and other life-limiting illnesses, including Alzheimer’s disease and Parkinson’s disease, although the authors say that that the exact way in which it triggers disease is unknown.

Using chemical kinetics, the scientists studied the mechanisms underlying amyloid assembly from both wild-type hIAPP and a rare variant of hIAPP found in people with a genetic mutation known as S20G that puts them at greater risk of developing type 2 diabetes. They identified that hIAPP aggregation involves primary nucleation, secondary nucleation, and elongation as the hIAPP molecules transform into amyloid fibrils.

Professor Sheena Radford, Royal Society Research Professor and Professor of Biophysics at the Astbury Centre for Structural Molecular Biology in Leeds, who supervised the research, said: ‘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.’

Promising starting point for future treatments

Further findings were to emerge, as the scientists also discovered two new compounds—‘molecule modulators’—that are able to speed up or slow down the amyloid self-assembly process. 

Professor Radford said: ‘The compounds we have discovered are a first and important step towards small-molecule intervention in a disease that has foxed scientists for generations.’

These molecule modulators can be used as ‘chemical tools’, the authors said, to help scientists investigate the way that amyloid fibrils grow and how and why they become toxic. 

Their discoveries ‘may serve as promising starting points’ for the development of drugs that could halt or control amyloid fibril formation, and thereby help in the search to find new ways to treat type 2 diabetes and other amyloid-related diseases. 

Professor Radford added: ‘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.’

This article originally appeared on Medscape, part of the Medscape Professional Network.


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