Publications

@article{pmid31888393,

title = {Modulation of adiponectin receptors AdipoR1 and AdipoR2 by phage display-derived peptides in  and  models},

author = {Deborah Crombez and Sébastien Delcambre and Denis Nonclercq and Luce Vander Elst and Sophie Laurent and Miriam Cnop and Robert N Muller and Carmen Burtea},

doi = {10.1080/1061186X.2019.1710840},

issn = {1029-2330},

year  = {2020},

date = {2020-01-01},

journal = {J Drug Target},

volume = {28},

number = {7-8},

pages = {831--851},

abstract = {Type 2 diabetes (T2D) is often linked to metabolic syndrome, which assembles various risk factors related to obesity. Plasma levels of adiponectin are decreased in T2D and obese subjects. Aiming to develop a peptide able to bind adiponectin receptors and modulate their signalling pathways, a 12-amino acid sequence homologous in AdipoR1/R2 has been targeted by phage display with a linear 12-mer peptide library. The selected peptide P17 recognises AdipoR1/R2 expressed by skeletal muscle, liver and pancreatic islets. In HepaRG and C2C12 cells, P17 induced the activation of AMPK (AMPKα-pT172) and the expression of succinate dehydrogenase and glucokinase; no cytotoxic effects were observed on HepaRG cells. In db/db mice, P17 promoted body weight and glycaemia stabilisation, decreased plasma triglycerides to the range of healthy mice and increased adiponectin (in high fat-fed mice) and insulin (in chow-fed mice) levels. It restored to the range of healthy mice the tissue levels and subcellular distribution of AdipoR1/R2, AMPKα-pT172 and PPARα-pS12. In liver, P17 reduced steatosis and apoptosis. The docking of P17 to AdipoR is reminiscent of the binding mechanism of adiponectin. To conclude, we have developed an AdipoR1/AdipoR2-targeted peptide that modulates adiponectin signalling pathways and has therapeutic relevance for T2D and obesity associated pathologies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31877117,

title = {Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia},

author = {Mariana Igoillo-Esteve and Ana F Oliveira and Cristina Cosentino and Federica Fantuzzi and Céline Demarez and Sanna Toivonen and Amélie Hu and Satyan Chintawar and Miguel Lopes and Nathalie Pachera and Ying Cai and Baroj Abdulkarim and Myriam Rai and Lorella Marselli and Piero Marchetti and Mohammad Tariq and Jean-Christophe Jonas and Marina Boscolo and Massimo Pandolfo and Décio L Eizirik and Miriam Cnop},

doi = {10.1172/jci.insight.134221},

issn = {2379-3708},

year  = {2020},

date = {2020-01-01},

journal = {JCI Insight},

volume = {5},

number = {2},

abstract = {Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective, and frataxin-inducing effects of glucagon-like peptide-1 (GLP-1) analogs in in vivo and in vitro models and in patients with Friedreich ataxia. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β cells and brain and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress, and improved mitochondrial function in Friedreich ataxia patients' induced pluripotent stem cell-derived β cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30176740,

title = {Future Perspectives for the Treatment of Diabetes: Importance of a Regulatory Framework},

author = {Katsura Tsukamoto and Miriam Cnop and Daichi Mori and Shoen Kume and Takayuki Anazawa and Masako Doi and Kazuhiko Chikazawa and Naoki Matsumaru},

doi = {10.1177/2168479018795854},

issn = {2168-4804},

year  = {2019},

date = {2019-07-01},

journal = {Ther Innov Regul Sci},

volume = {53},

number = {4},

pages = {535--541},

abstract = {BACKGROUND: The number of diabetes patients is steadily increasing worldwide. Consequently, the social burden of diabetes is huge, requiring urgent countermeasures. We performed an intensive survey of antidiabetic drugs approved in Japan, the United States, and the European Union.



METHODS: Information about approved antidiabetic drugs was obtained by searching databases of regulatory authorities in the 3 regions. Other relevant information was also obtained from publicly available literature and documents.



RESULTS: No difference in the total number and types of approved drugs among the 3 regions was found ( = .173 by log-rank test). However, the numbers of approved dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in Japan were almost double of those in the other regions. The average sample size in clinical trials used for antidiabetic drug approval in Japan (1134 patients) was much smaller than that in the other regions ( < .001 by analysis of variance repeated measures test adjusted by the Holm method). Currently, 6 drugs with known modes of action are being developed for type 1 diabetes in Japan, whereas at the end of 2016, nearly 7-fold more products with novel modes of action were in clinical development in the United States.



CONCLUSION: Antidiabetic drug development in Japan costs less than that in the other regions, although novel development is less active because of regulatory differences. To achieve better pharmacotherapy for diabetes, the regulatory framework requires careful consideration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30907926,

title = {The tRNA Epitranscriptome and Diabetes: Emergence of tRNA Hypomodifications as a Cause of Pancreatic β-Cell Failure},

author = {Cristina Cosentino and Miriam Cnop and Mariana Igoillo-Esteve},

doi = {10.1210/en.2019-00098},

issn = {1945-7170},

year  = {2019},

date = {2019-05-01},

journal = {Endocrinology},

volume = {160},

number = {5},

pages = {1262--1274},

abstract = {tRNAs are crucial noncoding RNA molecules that serve as amino acid carriers during protein synthesis. The transcription of tRNA genes is a highly regulated process. The tRNA pool is tissue and cell specific, it varies during development, and it is modulated by the environment. tRNAs are highly posttranscriptionally modified by specific tRNA-modifying enzymes. The tRNA modification signature of a cell determines the tRNA epitranscriptome. Perturbations in the tRNA epitranscriptome, as a consequence of mutations in tRNAs and tRNA-modifying enzymes or environmental exposure, have been associated with human disease, including diabetes. tRNA fragmentation induced by impaired tRNA modifications or dietary factors has been linked to pancreatic β-cell demise and paternal inheritance of metabolic traits. Herein, we review recent findings that associate tRNA epitranscriptome perturbations with diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30656194,

title = {OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia},

author = {Anne-Sophie Azzi and Cristina Cosentino and Jésabelle Kibanda and Françoise Féry and Miriam Cnop},

doi = {10.1002/acn3.686},

issn = {2328-9503},

year  = {2019},

date = {2019-01-01},

journal = {Ann Clin Transl Neurol},

volume = {6},

number = {1},

pages = {161--166},

abstract = {Diabetes is a common complication of Friedreich ataxia, requiring sensitive diagnostic methods. Here, we compared the performance of different tests that assess glucose tolerance, insulin sensitivity, and -cell function in Friedreich ataxia patients, heterozygous  mutation carriers and controls. We find that diabetes is underdiagnosed with fasting glucose alone. The oral glucose tolerance test (OGTT) provides 1.2- to 3.5-fold more diagnoses of impaired glucose homeostasis and diabetes, and adequately measures insulin sensitivity, insulin secretion, and -cell function. Clinicians in charge of Friedreich ataxia patients and researchers should incorporate the OGTT as an accurate diagnostic and research tool.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30284016,

title = {Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer},

author = {Martin Gotthardt and Decio L Eizirik and Henk-Jan Aanstoot and Olle Korsgren and Dick Mul and Frank Martin and Marti Boss and Tom J P Jansen and Sanne A M van Lith and Mijke Buitinga and Olof Eriksson and Miriam Cnop and Maarten Brom},

doi = {10.1007/s00125-018-4745-5},

issn = {1432-0428},

year  = {2018},

date = {2018-12-01},

journal = {Diabetologia},

volume = {61},

number = {12},

pages = {2516--2519},

abstract = {In this issue of Diabetologia, Alavi and Werner ( https://doi.org/10.1007/s00125-018-4676-1 ) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as 'futile'. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a 'futile' effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30142486,

title = {Inflammatory stress in islet β-cells: therapeutic implications for type 2 diabetes?},

author = {Maria Lytrivi and Mariana Igoillo-Esteve and Miriam Cnop},

doi = {10.1016/j.coph.2018.08.002},

issn = {1471-4973},

year  = {2018},

date = {2018-12-01},

journal = {Curr Opin Pharmacol},

volume = {43},

pages = {40--45},

abstract = {Type 2 diabetes is a common complex disease. Relatively little is known about the underlying pathophysiology. Mild islet inflammation has been suggested to play a pathogenic role; here we review the available evidence. Mild islet inflammation is histologically detected in pancreas sections of type 2 diabetic patients. In experimental models, it can be triggered by excess nutrients, amyloid, lipopolysaccharide, and endoplasmic reticulum and oxidative stress. Transcriptome studies do not consistently identify pro-inflammatory gene expression signatures in type 2 diabetic islets, and genetic evidence calls into question the causality of inflammation. Several anti-inflammatory medications confer a modest glucose-lowering effect, supporting the role for inflammation in type 2 diabetes. Whether these anti-inflammatory therapies target inflammation in islets or in other metabolically relevant tissues remains unknown.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30247717,

title = {Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes},

author = {Cristina Cosentino and Sanna Toivonen and Esteban Diaz Villamil and Mohamed Atta and Jean-Luc Ravanat and Stéphane Demine and Andrea Alex Schiavo and Nathalie Pachera and Jean-Philippe Deglasse and Jean-Christophe Jonas and Diego Balboa and Timo Otonkoski and Ewan R Pearson and Piero Marchetti and Décio L Eizirik and Miriam Cnop and Mariana Igoillo-Esteve},

doi = {10.1093/nar/gky839},

issn = {1362-4962},

year  = {2018},

date = {2018-11-01},

journal = {Nucleic Acids Res},

volume = {46},

number = {19},

pages = {10302--10318},

abstract = {Transfer RNAs (tRNAs) are non-coding RNA molecules essential for protein synthesis. Post-transcriptionally they are heavily modified to improve their function, folding and stability. Intronic polymorphisms in CDKAL1, a tRNA methylthiotransferase, are associated with increased type 2 diabetes risk. Loss-of-function mutations in TRMT10A, a tRNA methyltransferase, are a monogenic cause of early onset diabetes and microcephaly. Here we confirm the role of TRMT10A as a guanosine 9 tRNA methyltransferase, and identify tRNAGln and tRNAiMeth as two of its targets. Using RNA interference and induced pluripotent stem cell-derived pancreatic β-like cells from healthy controls and TRMT10A-deficient patients we demonstrate that TRMT10A deficiency induces oxidative stress and triggers the intrinsic pathway of apoptosis in β-cells. We show that tRNA guanosine 9 hypomethylation leads to tRNAGln fragmentation and that 5'-tRNAGln fragments mediate TRMT10A deficiency-induced β-cell death. This study unmasks tRNA hypomethylation and fragmentation as a hitherto unknown mechanism of pancreatic β-cell demise relevant to monogenic and polygenic forms of diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30071851,

title = {Improving glycemic control in critically ill patients: personalized care to mimic the endocrine pancreas},

author = {J Geoffrey Chase and Thomas Desaive and Julien Bohe and Miriam Cnop and Christophe De Block and Jan Gunst and Roman Hovorka and Pierre Kalfon and James Krinsley and Eric Renard and Jean-Charles Preiser},

doi = {10.1186/s13054-018-2110-1},

issn = {1466-609X},

year  = {2018},

date = {2018-08-01},

journal = {Crit Care},

volume = {22},

number = {1},

pages = {182},

abstract = {There is considerable physiological and clinical evidence of harm and increased risk of death associated with dysglycemia in critical care. However, glycemic control (GC) currently leads to increased hypoglycemia, independently associated with a greater risk of death. Indeed, recent evidence suggests GC is difficult to safely and effectively achieve for all patients. In this review, leading experts in the field discuss this evidence and relevant data in diabetology, including the artificial pancreas, and suggest how safe, effective GC can be achieved in critically ill patients in ways seeking to mimic normal islet cell function. The review is structured around the specific clinical hurdles of: understanding the patient's metabolic state; designing GC to fit clinical practice, safety, efficacy, and workload; and the need for standardized metrics. These aspects are addressed by reviewing relevant recent advances in science and technology. Finally, we provide a set of concise recommendations to advance the safety, quality, consistency, and clinical uptake of GC in critical care. This review thus presents a roadmap toward better, more personalized metabolic care and improved patient outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29784605,

title = {CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability},

author = {Louise Montagne and Mehdi Derhourhi and Amélie Piton and Bénédicte Toussaint and Emmanuelle Durand and Emmanuel Vaillant and Dorothée Thuillier and Stefan Gaget and Franck De Graeve and Iandry Rabearivelo and Amélie Lansiaux and Bruno Lenne and Sylvie Sukno and Rachel Desailloud and Miriam Cnop and Ramona Nicolescu and Lior Cohen and Jean-François Zagury and Mélanie Amouyal and Jacques Weill and Jean Muller and Olivier Sand and Bruno Delobel and Philippe Froguel and Amélie Bonnefond},

doi = {10.1016/j.molmet.2018.05.005},

issn = {2212-8778},

year  = {2018},

date = {2018-07-01},

journal = {Mol Metab},

volume = {13},

pages = {1--9},

abstract = {OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step.



METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (n = 145).



RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations.



CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29133342,

title = {Exercise training protects human and rodent β cells against endoplasmic reticulum stress and apoptosis},

author = {Flavia M M Paula and Nayara C Leite and Patricia C Borck and Ricardo Freitas-Dias and Miriam Cnop and Mara P T Chacon-Mikahil and Claudia R Cavaglieri and Piero Marchetti and Antonio C Boschero and Claudio C Zoppi and Decio L Eizirik},

doi = {10.1096/fj.201700710R},

issn = {1530-6860},

year  = {2018},

date = {2018-03-01},

journal = {FASEB J},

volume = {32},

number = {3},

pages = {1524--1536},

abstract = {Prolonged exercise has positive metabolic effects in obese or diabetic individuals. These effects are usually ascribed to improvements in insulin sensitivity. We evaluated whether exercise also generates circulating signals that protect human and rodent β cells against endoplasmic reticulum (ER) stress and apoptosis. For this purpose, we obtained serum from humans or mice before and after an 8 wk training period. Exposure of human islets or mouse or rat β cells to human or rodent sera, respectively, obtained from trained individuals reduced cytokine (IL-1β+IFN-γ)- or chemical ER stressor-induced β-cell ER stress and apoptosis, at least in part via activation of the transcription factor STAT3. These findings indicate that exercise training improves human and rodent β-cell survival under diabetogenic conditions and support lifestyle interventions as a protective approach for both type 1 and 2 diabetes.-Paula, F. M. M., Leite, N. C., Borck, P. C., Freitas-Dias, R., Cnop, M., Chacon-Mikahil, M. P. T., Cavaglieri, C. R., Marchetti, P., Boschero, A. C., Zoppi, C. C., Eizirik, D. L. Exercise training protects human and rodent β cells against endoplasmic reticulum stress and apoptosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28911974,

title = {Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons},

author = {Sophie Calderari and Massimiliano Ria and Christelle Gérard and Tatiane C Nogueira and Olatz Villate and Stephan C Collins and Helen Neil and Nicolas Gervasi and Christophe Hue and Nicolas Suarez-Zamorano and Cécilia Prado and Miriam Cnop and Marie-Thérèse Bihoreau and Pamela J Kaisaki and Jean-Baptiste Cazier and Cécile Julier and Mark Lathrop and Michel Werner and Decio L Eizirik and Dominique Gauguier},

doi = {10.1016/j.ygeno.2017.09.001},

issn = {1089-8646},

year  = {2018},

date = {2018-03-01},

journal = {Genomics},

volume = {110},

number = {2},

pages = {98--111},

abstract = {The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q<0.05; enrichment range 1.40-9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting β-cells and neurons and underline the existence of trans‑nosology pathways in diabetes and its co-morbidities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29044173,

title = {Palmitate-induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets},

author = {Federica Ciregia and Marco Bugliani and Maurizio Ronci and Laura Giusti and Claudia Boldrini and Maria R Mazzoni and Sandra Mossuto and Francesca Grano and Miriam Cnop and Lorella Marselli and Gino Giannaccini and Andrea Urbani and Antonio Lucacchini and Piero Marchetti},

doi = {10.1038/s41598-017-13908-w},

issn = {2045-2322},

year  = {2017},

date = {2017-10-01},

journal = {Sci Rep},

volume = {7},

number = {1},

pages = {13445},

abstract = {Type 2 diabetes is characterized by progressive β cell dysfunction, with lipotoxicity playing a possible pathogenetic role. Palmitate is often used to examine the direct effects of lipotoxicity and it may cause mitochondrial alterations by activating protein acetylation. However, it is unknown whether palmitate influences protein acetylation in β cells. We investigated lysine acetylation in mitochondrial proteins from INS-1E β cells (INS-1E) and in proteins from human pancreatic islets (HPI) after 24 h palmitate exposure. First, we confirmed that palmitate damages β cells and demonstrated that chemical inhibition of deacetylation also impairs INS-1E function and survival. Then, by 2-D gel electrophoresis, Western Blot and Liquid Chromatography-Mass Spectrometry we evaluated the effects of palmitate on protein acetylation. In mitochondrial preparations from palmitate-treated INS-1E, 32 acetylated spots were detected, with 13 proteins resulting over-acetylated. In HPI, 136 acetylated proteins were found, of which 11 were over-acetylated upon culture with palmitate. Interestingly, three proteins, glutamate dehydrogenase, mitochondrial superoxide dismutase, and SREBP-1, were over-acetylated in both INS-1E and HPI. Therefore, prolonged exposure to palmitate induces changes in β cell protein lysine acetylation and this modification could play a role in causing β cell damage. Dysregulated acetylation may be a target to counteract palmitate-induced β cell lipotoxicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29026101,

title = {Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance},

author = {Kashyap A Patel and Jarno Kettunen and Markku Laakso and Alena Stančáková and Thomas W Laver and Kevin Colclough and Matthew B Johnson and Marc Abramowicz and Leif Groop and Päivi J Miettinen and Maggie H Shepherd and Sarah E Flanagan and Sian Ellard and Nobuya Inagaki and Andrew T Hattersley and Tiinamaija Tuomi and Miriam Cnop and Michael N Weedon},

doi = {10.1038/s41467-017-00895-9},

issn = {2041-1723},

year  = {2017},

date = {2017-10-01},

journal = {Nat Commun},

volume = {8},

number = {1},

pages = {888},

abstract = {Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10) and Finnish (n = 80, odds ratio = 22, P = 1 × 10) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28892713,

title = {Stearic acid at physiologic concentrations induces in vitro lipotoxicity in circulating angiogenic cells},

author = {Valentina Spigoni and Federica Fantuzzi and Alessia Fontana and Monia Cito and Eleonora Derlindati and Ivana Zavaroni and Miriam Cnop and Riccardo C Bonadonna and Alessandra Dei Cas},

doi = {10.1016/j.atherosclerosis.2017.09.004},

issn = {1879-1484},

year  = {2017},

date = {2017-10-01},

journal = {Atherosclerosis},

volume = {265},

pages = {162--171},

abstract = {BACKGROUND AND AIMS: Saturated free fatty acids (SFAs) can induce lipotoxicity in different cells. No studies have investigated the effects of SFA in circulating angiogenic cells (CACs), which play a key role in endothelial repair processes. The aim of the study was to assess the effects of SFAs, specifically stearic acid (SA), on viability and function of CACs and to investigate potential underlying molecular mechanisms.



METHODS: CACs were isolated from healthy subjects by established methods. CACs were incubated with BSA-complexed stearate (100 μM) to assess the time course (from 8 to 24 h exposure) of the effects on viability and apoptosis (activation of caspases 3/7), angiogenic function (tube formation assay), pro-inflammatory cytokine (IL-1β, IL-6, IL-8, MCP-1 and TNFα) gene expression (qPCR) and secretion (ELISA), activation of MAPK (JNK, p38 and Erk1/2) by Western blot and endoplasmic reticulum (ER) stress marker (CHOP, BIP, ATF4, XBP-1 and sXBP-1) gene expression by qPCR.



RESULTS: Stearic acid activates effector caspases in CACs in a dose- and time-dependent manner. SA also impairs CAC function and increases pro-inflammatory molecule (IL-1β, IL-6, IL-8, MCP-1 and TNFα) gene expression and secretion in CACs starting from 3 h of incubation. The activation of JNK by SA mediates pro-inflammatory response, but it may be not necessary for apoptosis. Moreover, SA induces the expression of ER stress markers across the three branches of the ER stress response.



CONCLUSIONS: In humans, both function and viability of CACs are exquisitely vulnerable to physiologic concentrations of stearate; lipotoxic impairment of endothelial repair processes may be implicated in vascular damage caused by SFAs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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}

}