Protein disulfide isomerase ameliorates β-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide

Montané, Joel; Pablo, Sara; Obach, Mercè; Cadavez, Lisa; Castaño, Carlos; Alcarraz-Vizán, Gema; Visa, Montserrat; Rodríguez‐Comas, Júlia; Parrizas, Marcelina; Servitja, Joan Marc; Novials, Anna

doi:10.1016/j.mce.2015.11.018

Cited by 21 publications

(14 citation statements)

References 49 publications

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“…The disulphide bridge in proIAPP (and proinsulin) is also formed at this stage by the enzyme protein disulphide isomerase (PDI) which allows correct folding of the peptides. However, it has been shown in hIAPP transgenic mouse islets that overexpression of this enzyme does not reduce hIAPP fibril assembly suggesting that cysteine bridge formation is unlikely to be a critical step for fibril assembly (Montane et al 2016). …”

Section: Proiapp In the Endoplasmic Reticulummentioning

confidence: 99%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

102

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Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in β-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of β-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro. These findings support a role for extracellular IAPP in β-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain.

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Section: Proiapp In the Endoplasmic Reticulummentioning

confidence: 99%

The β-cell assassin: IAPP cytotoxicity

Raleigh

Zhang

Hastoy

et al. 2017

Journal of Molecular Endocrinology

102

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“…IL-1 receptor antagonist (IL-1RA or anakinra; PeproTech, Rocky Hill, NJ, USA) was dissolved in water and used at 4 mg/ml. Adenoviral transduction for PDI overexpression was performed as previously described (13). For islet amyloid formation experiments, islets were incubated at 16.7 mM glucose for 7 d.…”

Section: Mouse Islet Isolation and Culturementioning

confidence: 99%

“…Furthermore, treatment with these chemical chaperones and with molecular chaperones such as binding immunoglobulin protein (BiP) and protein disulfide isomerase (PDI) ameliorates b-cell dysfunction associated with hIAPP overexpression in a rat pancreatic cell line (12). In this context, we have also demonstrated that PDI ameliorates b-cell dysfunction and cell apoptosis in hIAPP transgenic (hIAPP Tg) mouse islets (13). Likewise, a decrease in the aggregation of hIAPP can potentially reduce its damaging effects.…”

mentioning

confidence: 94%

Amyloid‐induced β‐cell dysfunction and islet inflammation are ameliorated by 4‐phenylbutyrate (PBA) treatment

et al. 2017

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Human islet amyloid polypeptide (hIAPP) aggregation is associated with β-cell dysfunction and death in type 2 diabetes (T2D). we aimed to determine whether treatment with chemical chaperone 4-phenylbutyrate (PBA) ameliorates hIAPP-induced β-cell dysfunction and islet amyloid formation. Oral administration of PBA in hIAPP transgenic (hIAPP Tg) mice expressing hIAPP in pancreatic β cells counteracted impaired glucose homeostasis and restored glucose-stimulated insulin secretion. Moreover, PBA treatment almost completely prevented the transcriptomic alterations observed in hIAPP Tg islets, including the induction of genes related to inflammation. PBA also increased β-cell viability and improved insulin secretion in hIAPP Tg islets cultured under glucolipotoxic conditions. Strikingly, PBA not only prevented but even reversed islet amyloid deposition, pointing to a direct effect of PBA on hIAPP. This was supported by calculations uncovering potential binding sites of PBA to monomeric, dimeric, and pentameric fibrillar structures, and by assays showing inhibition of hIAPP fibril formation by PBA. Collectively, these results uncover a novel beneficial effect of PBA on glucose homeostasis by restoring β-cell function and preventing amyloid formation in mice expressing hIAPP in β cells, highlighting the therapeutic potential of PBA for the treatment of T2D.-Montane, J., de Pablo, S., Castaño, C., Rodríguez-Comas, J., Cadavez, L., Obach, M., Visa, M., Alcarraz-Vizán, G., Sanchez-Martinez, M., Nonell-Canals, A., Parrizas, M., Servitja, J.-M., Novials, A. Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment.

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“…Recent studies have convincingly shown that PDI plays important roles in the physiology as well as pathophysiology of the disease states including diabetes [28] , cardiovascular diseases [66] , cancer [67] neurodegenerative conditions [68] and the entry of pathogens in infectious diseases [69] . However, the precise roles for PDI in each of these diseases have not yet been elucidated.…”

Section: Role Of Pdi In Diseases Statesmentioning

confidence: 99%

“…Further, protein disulfide isomerase ameliorates β-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide. Thus, it has protective role in Type II diabetes [28] . Recent studies have convincingly demonstrated that PDI also plays an important role in both the physiology and pathophysiology of disease states including diabetes [29] , cardiovascular diseases [30] .…”

Section: Introductionmentioning

confidence: 99%

Protein Disulfide Isomerase: Structure, Mechanism of Oxidative Protein Folding and Multiple Functional Roles

Khan

Siddiqui

Salahuddin

2016

Journal of Biochemistry and Molecular Biology Research

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Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily of redox proteins. Originally, PDI was identified in the lumen of the endoplasmic reticulum and subsequently detected abundantly in many other tissues and account for 0.8% of total cellular protein. PDI consists of four tandem thioredoxinlike domains a, b, b′, and a′ plus a C-terminal extension which are arranged into a U-shape structure. PDI has three catalytic activities including, thiol-disulfide oxidoreductase, disulfide isomerase and redox-dependent chaperone. Now the functions ascribed to PDI have evolved significantly because recent studies have shown that it has detrimental as well as protective effects in diseases states. Keeping the above views in mind, in this review we have discussed the structure of PDI, its catalytic and chaperone activity and its role in various diseases states.

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Protein disulfide isomerase ameliorates β-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide

Cited by 21 publications

References 49 publications

The β-cell assassin: IAPP cytotoxicity

The β-cell assassin: IAPP cytotoxicity

Amyloid‐induced β‐cell dysfunction and islet inflammation are ameliorated by 4‐phenylbutyrate (PBA) treatment

Protein Disulfide Isomerase: Structure, Mechanism of Oxidative Protein Folding and Multiple Functional Roles

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