Study provides new insights into biological mechanisms underpinning type 2 diabetes pathology

It has been estimated that the number of people with diabetes worldwide reached 422 million in 2014, boosting prevalence to 8.5% among adults over 18 years of age. This figure is expected to rise to 642 million people by 2040. A key pathological consequence of type 2 diabetes (T2D) is the progressive failure and depletion of β-cells in the pancreas, subsequently leading to defective glucose regulation. There is increasing evidence suggesting this depletion can result from the formation of pancreatic islet amyloid aggregates, which is toxic to β-cells. These aggregates are primarily composed by Islet Amyloid PolyPeptide (IAPP), a hormone co-secreted with insulin by β-cells. Whilst in healthy conditions, a lower amount of IAPP is produced than insulin, the rate of IAPP production rises dramatically during T2D development.

Despite some existing knowledge on T2D development, the precise biological mechanisms – in particular of how IAPP induces β-cell depletion – are still questioned. With the increasing prevalence of T2D, gaining a thorough understanding of the biology is crucial for imagining better drugs and improving current therapeutic approaches. A collaboration between Institut Laue-Langevin (ILL), the Institute for Molecular Engineering at the University of Chicago and Institut de Biologie Structurale at Grenoble Alpes University carried out a study, published in the Journal of the Americal Chemical Society, investigating the mechanisms of IAPP and its role in the pathology of T2D.

The overlap of amyloid aggregates with cell depletion has led to the hypothesis that the aggregates are the toxic species causing symptom onset. It is generally accepted that the mechanism of cell toxicity is the same for all amyloidoses – a group of diseases characterised by the presence of large insoluble protein fibre aggregates in organs – whereby damage to membranes induces cell death and disrupts the function of specific organs. However, the precise interactions of amyloid peptide and its target membrane remain unclear, with multiple different hypotheses existing today.

Researchers used a range of techniques including neutron scattering and reflectometry methods to investigate model membrane permeation and structural effects of IAPP. They observed that amyloid aggregation and membrane permeation are two independent processes. The two processes are in fact competitive, with aggregation inhibiting membrane permeation as a result. It has previously been hypothesised that IAPP amyloid aggregates cause membrane permeability, resulting in calcium leak, a signal triggering cell death. However, findings of this study favors a new hypothesis: amyloid aggregation is a defense mechanism employed by the human body, whereby encapsulating IAPP into aggregates ‘silences’ the cytotoxic peptides and blocks them from spreading, thus lowering the toxicity of IAPP to pancreatic β-cells, and delaying the onset of disease.

Anne Martel, scientist at ILL said:

Our observations of the interaction between IAPP and model membranes have brought a new and interesting hypothesis to the field, contradicting what was previously hypothesised regarding this interaction. Our results indicate the need to continue investigating the role of IAPP in the pathology of T2D to help with the development of drugs better tailored to tackle β-cell depletion in the pancreatic islets of Langerhans. With our new hypothesis suggesting that amyloid aggregates are a safety mechanism to reduce the spread of toxins, drug innovation could be re-directed towards those which promote rather than inhibit amyloid aggregation.

Preliminary tests of aggregation-promoting drugs are currently being carried out on artificial membranes. The next step of this research is to create a more biologically relevant artificial membrane that more accurately mimics the membrane of human cells, and to understand why IAPP targets this particular type of cells.

With diabetes predicted to reach epidemic proportions, furthering research into T2D is invaluable for the development of more effective strategies for prevention and treatment. The success of this interdisciplinary collaborative study is demonstrated by its novel findings, which enrich our understanding of the pathology of T2D.

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