Human islet amyloid polypeptide (hIAPP) aggregation in type 2 diabetes: Correlation between intrinsic physicochemical properties of hIAPP aggregates and their cytotoxicity.

08:00 EDT 10th June 2019 | BioPortfolio

Summary of "Human islet amyloid polypeptide (hIAPP) aggregation in type 2 diabetes: Correlation between intrinsic physicochemical properties of hIAPP aggregates and their cytotoxicity."

A large number of pathological diseases are known now to be associated with the misfolding and the aberrant oligomerization and deposition of peptides and proteins into various aggregates. One of these peptides is islet amyloid polypeptide (IAPP), which is responsible for amyloid formation in type 2 diabetes. The mechanism of IAPP amyloid formation in vivo and in vitro is not well understood and the factors behind the peptide aggregates toxicity are not fully defined. Therefore, the precise nature of toxic agents still remains to be elucidated. In this context, first we used a complementary biophysical approach to undertake a systematic study of the hIAPP aggregation process with focus on the lag phase, followed by the study of their degrees of toxicity when added to the extracellular medium of pancreatic cells. The structural properties of hIAPP aggregates are characterized by evaluating their size with DLS, their surface hydrophobicity with ANS, and the interactions between monomers through the intrinsic fluorescence of aromatic residues or by the quenching of these residues mainly the tyrosine in position 37. Our results indicate that despite the method used to study hIAPP aggregation, the obtained curve is easily well fitted in a sigmoidal curve but with some differences. In fact, the analysis of the kinetic parameters gives different information about the hIAPP aggregation process such as lag time and growth rate. Moreover, a high surface hydrophobicity and small size of the aggregates, mainly for the species formed during the lag time, shows strong correlation with the cytotoxicity. These findings provide new insights into the structural changes during hIAPP aggregation and are consistent with a model in which the exposure of hydrophobic surfaces and the small size of aggregates formed during the early stage of the process are crucial for their cytotoxicity.


Journal Details

This article was published in the following journal.

Name: International journal of biological macromolecules
ISSN: 1879-0003


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Medical and Biotech [MESH] Definitions

A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.

G-protein coupled receptors that are formed through the dimerization of the CALCITONIN RECEPTOR with a RECEPTOR ACTIVITY-MODIFYING PROTEIN. Their affinity for ISLET AMYLOID POLYPEPTIDE is dependent upon which of several receptor activity-modifying protein subtypes they are bound to.

Compounds that stimulate the activity of AMYMIN RECEPTORS. Included under this heading is the endogenous form of ISLET AMYLOID POLYPEPTIDE and synthetic compounds that mimic its effect.

A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.

The time period before the development of symptomatic diabetes. For example, certain risk factors can be observed in subjects who subsequently develop INSULIN RESISTANCE as in type 2 diabetes (DIABETES MELLITUS, TYPE 2).

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