Abstract
The current diabetes epidemic is associated with a diverse set of risk factors including obesity and exposure to plastics. Notably, significant elevations of negatively charged amphiphilic molecules are observed in obesity (e.g. free fatty acids and phosphatidic acid) and plastics exposure (monophthalate esters). It remains unclear whether these factors share pathogenic mechanisms and whether links exist with islet amyloid polypeptide (IAPP) misfolding, a process central to β-cell dysfunction and death. Using a combination of fluorescence, circular dichroism and electron microscopy, we show that phosphatidic acid, oleic acid, and the phthalate metabolite MBzP partition into neutral membranes and enhance IAPP misfolding. The elevation of negative charge density caused by the presence of the risk factor molecules stabilizes a common membrane-bound α-helical intermediate that, in turn, facilitates IAPP misfolding. This shared mechanism points to a critical role for the membrane-bound intermediate in disease pathogenesis, making it a potential target for therapeutic intervention.
Highlights
The misfolding and aggregation of the 37-amino acid peptide, islet amyloid polypeptide (IAPP), is thought to be one of the main factors responsible for the β-cell defect that drives the pathogenesis of type 2 diabetes mellitus (T2DM)
Using circular dichroism (CD), fluorescence spectroscopy and transmission electron microscopy (EM) we found that physiologically relevant amounts of phosphatidic acid (PA), oleic acid (OA) and monobenzyl ester phthalate (MBzP) potently promote IAPP misfolding via a membrane-bound α-helical intermediate
The current T2DM epidemic is fueled by a number of risk factors, making it important to understand how these risk factors contribute to disease pathogenesis
Summary
The misfolding and aggregation of the 37-amino acid peptide, islet amyloid polypeptide (IAPP), is thought to be one of the main factors responsible for the β-cell defect that drives the pathogenesis of type 2 diabetes mellitus (T2DM). Whether metabolic or phthalate-based risk factors act independently of IAPP or exert their effects by affecting IAPP misfolding is unknown Both plasticizer exposure and metabolic syndrome lead to significant elevations of negatively charged amphiphilic lipid or lipid-like molecules (Fig. S1). The central question addressed in the present study is whether the aforementioned, negatively charged lipids or lipid-like molecules promote IAPP misfolding If so, this would indicate that metabolic and phthalate-based risk factors could contribute to T2DM pathogenesis by enhancing IAPP toxicity. Using circular dichroism (CD), fluorescence spectroscopy and transmission electron microscopy (EM) we found that physiologically relevant amounts of PA, OA and MBzP potently promote IAPP misfolding via a membrane-bound α-helical intermediate These data directly link T2DM risk factors to IAPP misfolding via a common catalytic pathway
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
