Unravelling the mysteries around type-2 diabetes

Date:
February 24, 2022
Source:
University of Leeds
Summary:
For more than 30 years, scientists have been trying to unravel
the mystery of how a key biological molecule self assembles
into a rogue protein-like substance known as amyloid, which is
thought to play a role in the development of type-2 diabetes -
a disease that affects 300 million people worldwide. A team of
scientists at the University of Leeds has, for the first time,
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.



FULL STORY ==========================================================================
For more than 30 years, scientists have been trying to unravel the
mystery of how a key biological molecule self assembles into a rogue protein-like substance known as amyloid, which is thought to play a
role in the development of type-2 diabetes -- a disease that affects
300 million people worldwide.


==========================================================================
A team of scientists at the University of Leeds has, for the first time,
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
today in the journalNature 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.



========================================================================== 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.

Sheena Radford, Royal Society Research Professor and Professor of
Biophysics at the Astbury Centre for Structural Molecular Biology at
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.

"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.

Amyloid fibril formation linked to disease 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.

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." ========================================================================== Story Source: Materials provided by University_of_Leeds. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Yong Xu, Roberto Maya-Martinez, Nicolas Guthertz, George R. Heath,
Iain
W. Manfield, Alexander L. Breeze, Frank Sobott, Richard Foster,
Sheena E.

Radford. Tuning the rate of aggregation of hIAPP into amyloid
using small-molecule modulators of assembly. Nature Communications,
2022; 13 (1) DOI: 10.1038/s41467-022-28660-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220224091148.htm

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