The Role of Calcium, Lipid Membranes and Islet Amyloid Polypeptide in the Onset of Type 2 Diabetes: Innocent Bystanders or Partners in a Crime?

Milardi, Danilo; Sciacca, Michele F.M.; Randazzo, Loredana; Raudino, A.; Raudino, Antonio

doi:10.3389/fendo.2014.00216

Cited by 17 publications

(7 citation statements)

References 55 publications

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“…However, the role played by cholesterol in the development of amyloid disease is un-clear, as several studies reported conflicting results indicating that cholesterol may either protect membranes against amyloid-mediated permeabilization or affect the membrane integrity (90,91). In particular, although many evidences point to cholesterol as a causative agent of T2DM, its exact role in IAPP-evoked membrane damage and fibrillogenesis is still under debate (92). Previous experiments have demonstrated that IAPP aggregates in the presence of 1:2:1 DPPC/DOPC/Chol (model raft-containing membranes), but not in pure DOPC bilayers (93).…”

Section: Discussionmentioning

confidence: 99%

The Role of Cholesterol in Driving IAPP-Membrane Interactions

Sciacca

Lolicato

Mauro

et al. 2016

Biophysical Journal

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Our knowledge of the molecular events underlying type 2 diabetes mellitus-a protein conformational disease characterized by the aggregation of islet amyloid polypeptide (IAPP) in pancreatic β cells-is limited. However, amyloid-mediated membrane damage is known to play a key role in IAPP cytotoxicity, and therefore the effects of lipid composition on modulating IAPP-membrane interactions have been the focus of intense research. In particular, membrane cholesterol content varies with aging and consequently with adverse environmental factors such as diet and lifestyle, but its role in the development of the disease is controversial. In this study, we employ a combination of experimental techniques and in silico molecular simulations to shed light on the role of cholesterol in IAPP aggregation and the related membrane disruption. We show that if anionic POPC/POPS vesicles are used as model membranes, cholesterol has a negligible effect on the kinetics of IAPP fibril growth on the surface of the bilayer. In addition, cholesterol inhibits membrane damage by amyloid-induced poration on membranes, but enhances leakage through fiber growth on the membrane surface. Conversely, if 1:2 DOPC/DPPC raft-like model membranes are used, cholesterol accelerates fiber growth. Next, it enhances pore formation and suppresses fiber growth on the membrane surface, leading to leakage. Our results highlight a twofold effect of cholesterol on the amyloidogenicity of IAPP and help explain its debated role in type 2 diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

The Role of Cholesterol in Driving IAPP-Membrane Interactions

Sciacca

Lolicato

Mauro

et al. 2016

Biophysical Journal

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“…It has been observed that a genetic disease known as hypercalcemia linked to the reduction in the expression of the calcium receptor gene is implicated in the development of diabetes in people with this genetic disease. This observation supports the idea that calcium dyshomeostasis may be linked to the development of diabetes . From this observation, it has been suggested that high concentrations of calcium in the plasma may activate mechanisms involving hIAPP in the process of membrane destruction.…”

Section: Islet Amyloid Polypeptide and The “Amyloid Hypothesis” Of T2dmentioning

confidence: 99%

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

et al. 2021

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The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin and zinc on the mechanism of aggregation of hIAPP. weight reduction was observed. In a phase-1 clinical trial in which AM833 was combined with the GLP-1-agonist Semaglutid, 20 weeks of treatment, participants lost an average of 17.1 % body weight. Overweight and obesity are risk factors for T2D and cardiovascular disease and the presented weight loss exceed reductions observed for GLP-1 and metformin. It should be noted that an IAPP derivative, pramlintide (symlin) is used, in addition to insulin, in patients with insulindependent T1D and T2D that have been difficult to regulate with insulin by a single drug. 42 Cross-correlation with other diseasesEpidemiological studies link diabetes with neurodegenerative diseases, including Alzheimer's disease [43][44][45][46] and Parkinson's disease. [47][48][49] The link is unclear, but the three conditions are multifactorial and have protein aggregation in their pathophysiology in common. If protein aggregation constitutes the link between these diseases, however, still needs to be proven. The Rotterdam study 50 , published in 1999, showed that patients with T2D have an almost doubled risk of developing dementia and Alzheimer's disease (AD). Data from the ULSAM study (Uppsala Longitudinal study of adult men) showed that already a moderate disturbance in the first-phase insulin release at the age of 55 increased the risk of developing AD thirty years later. 51 This suggests that diabetes precedes AD. In fact, another type of diabetes has been proposed [52][53][54] , which is type 3 diabetes (T3DM) which is an AD associated insulin resistance, also described as "brain diabetes phenotype". A considerable number of biophysical studies have shown a close link between the amyloid-forming proteins IAPP and Aβ. [55][56][57][58] IAPP immunoreactivity is present in formic acid brain extracts from patients with AD 59 and exhibited pattern on the western blot ranges from dimers to 16 mers. 60 The laddering pattern suggests that IAPP is present in the Aβ amyloid deposit. Proximity ligation assay (PLA) using two primary antibodies can be applied to determine the co-deposition of proteins. The positive PLA signal obtained after the combination of anti-IAPP and anti-Aβ antibodies points to the co-deposition of IAPP and Aβ in vivo. To confirm that the peptides interact in vivo, hIAPP transgenic mice were injected with preformed fibrils of Aβ followed by high-fat feeding for ten months. 60 Mice injected with preformed Aβ fibrils developed amyloid in 15% of the islets, which is comparable to mice injected with preformed fibrils of proIAPP. In mice injected with preformed IAPP fibrils, IAPP amyloid was found in 24 % of the islets. Control mice injected with fib...

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“…The disruptive interaction with the membranes is a central event in the development of amyloidogenic diseases. Thus, inhibiting or preventing the membrane damage, together with the oligomerization and the fibril growth, might be one of the possible promising therapeutic strategies [130]. In this perspective, many studies aimed at investigating of the role of small molecules, as well as the interactions with physiologically relevant ions, which have been widely studied, such as calcium, copper or zinc [94,95,104,131,132], since the deep understanding of these mechanisms might be of fundamental importance.…”

Section: Interaction With Small Molecules and Ionsmentioning

confidence: 99%

Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes

Scollo

Raudino

2020

Life

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Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers.

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The Role of Calcium, Lipid Membranes and Islet Amyloid Polypeptide in the Onset of Type 2 Diabetes: Innocent Bystanders or Partners in a Crime?

Cited by 17 publications

References 55 publications

The Role of Cholesterol in Driving IAPP-Membrane Interactions

The Role of Cholesterol in Driving IAPP-Membrane Interactions

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes

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