Publications

@article{pmid28951826,

title = {Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells},

author = {Miriam Cnop and Sanna Toivonen and Mariana Igoillo-Esteve and Paraskevi Salpea},

doi = {10.1016/j.molmet.2017.06.001},

issn = {2212-8778},

year  = {2017},

date = {2017-09-01},

journal = {Mol Metab},

volume = {6},

number = {9},

pages = {1024--1039},

abstract = {BACKGROUND: Pancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches.



SCOPE OF REVIEW: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells.



MAJOR CONCLUSIONS: Pancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28698383,

title = {Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF)},

author = {Daniel A Cunha and Monia Cito and Fabio Arturo Grieco and Cristina Cosentino and Tatiana Danilova and Laurence Ladrière and Maria Lindahl and Andrii Domanskyi and Marco Bugliani and Piero Marchetti and Décio L Eizirik and Miriam Cnop},

doi = {10.1074/jbc.M116.769877},

issn = {1083-351X},

year  = {2017},

date = {2017-09-01},

journal = {J Biol Chem},

volume = {292},

number = {36},

pages = {14977--14988},

abstract = {Cytokine-induced endoplasmic reticulum (ER) stress is one of the molecular mechanisms underlying pancreatic β-cell demise in type 1 diabetes. Thrombospondin 1 (THBS1) was recently shown to promote β-cell survival during lipotoxic stress. Here we show that ER-localized THBS1 is cytoprotective to rat, mouse, and human β-cells exposed to cytokines or thapsigargin-induced ER stress. THBS1 confers cytoprotection by maintaining expression of mesencephalic astrocyte-derived neutrotrophic factor (MANF) in β-cells and thereby prevents the BH3-only protein BIM (BCL2-interacting mediator of cell death)-dependent triggering of the mitochondrial pathway of apoptosis. Prolonged exposure of β-cells to cytokines or thapsigargin leads to THBS1 and MANF degradation and loss of this prosurvival mechanism. Approaches that sustain intracellular THBS1 and MANF expression in β-cells should be explored as a cytoprotective strategy in type 1 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28522407,

title = {High-throughput screening and bioinformatic analysis to ascertain compounds that prevent saturated fatty acid-induced β-cell apoptosis},

author = {Seung-Hee Lee and Daniel Cunha and Carlo Piermarocchi and Giovanni Paternostro and Anthony Pinkerton and Laurence Ladriere and Piero Marchetti and Decio L Eizirik and Miriam Cnop and Fred Levine},

doi = {10.1016/j.bcp.2017.05.007},

issn = {1873-2968},

year  = {2017},

date = {2017-08-01},

journal = {Biochem Pharmacol},

volume = {138},

pages = {140--149},

abstract = {Pancreatic β-cell lipotoxicity is a central feature of the pathogenesis of type 2 diabetes. To study the mechanism by which fatty acids cause β-cell death and develop novel approaches to prevent it, a high-throughput screen on the β-cell line INS1 was carried out. The cells were exposed to palmitate to induce cell death and compounds that reversed palmitate-induced cytotoxicity were ascertained. Hits from the screen were analyzed by an increasingly more stringent testing funnel, ending with studies on primary human islets treated with palmitate. MAP4K4 inhibitors, which were not part of the screening libraries but were ascertained by a bioinformatics analysis, and the endocannabinoid anandamide were effective at inhibiting palmitate-induced apoptosis in INS1 cells as well as primary rat and human islets. These targets could serve as the starting point for the development of therapeutics for type 2 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28323924,

title = {Guanabenz Sensitizes Pancreatic β Cells to Lipotoxic Endoplasmic Reticulum Stress and Apoptosis},

author = {Baroj Abdulkarim and Miriam Hernangomez and Mariana Igoillo-Esteve and Daniel A Cunha and Lorella Marselli and Piero Marchetti and Laurence Ladriere and Miriam Cnop},

doi = {10.1210/en.2016-1773},

issn = {1945-7170},

year  = {2017},

date = {2017-06-01},

journal = {Endocrinology},

volume = {158},

number = {6},

pages = {1659--1670},

abstract = {Deficient as well as excessive/prolonged endoplasmic reticulum (ER) stress signaling can lead to pancreatic β cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic β cells. One of the main ER stress response pathways is under the control of the protein kinase R-like endoplasmic reticulum kinase (PERK), leading to phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α). The antihypertensive drug guanabenz has been shown to inhibit eIF2α dephosphorylation and protect cells from ER stress. Here we examined whether guanabenz protects pancreatic β cells from lipotoxicity. Guanabenz induced β cell dysfunction in vitro and in vivo in rodents and led to impaired glucose tolerance. The drug significantly potentiated FFA-induced cell death in clonal rat β cells and in rat and human islets. Guanabenz enhanced FFA-induced eIF2α phosphorylation and expression of the downstream proapoptotic gene C/EBP homologous protein (CHOP), which mediated the sensitization to lipotoxicity. Thus, guanabenz does not protect β cells from ER stress; instead, it potentiates lipotoxic ER stress through PERK/eIF2α/CHOP signaling. These data demonstrate the crucial importance of the tight regulation of eIF2α phosphorylation for the normal function and survival of pancreatic β cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}