@article{slieker_identification_2023, title = {Identification of biomarkers for glycaemic deterioration in type 2 diabetes}, volume = {14}, issn = {2041-1723}, url = {https://www.nature.com/articles/s41467-023-38148-7}, doi = {10.1038/s41467-023-38148-7}, abstract = {Abstract We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of {\textasciitilde}1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.}, language = {en}, number = {1}, urldate = {2023-05-04}, journal = {Nature Communications}, author = {Slieker, Roderick C. and Donnelly, Louise A. and Akalestou, Elina and Lopez-Noriega, Livia and Melhem, Rana and Güneş, Ayşim and Abou Azar, Frederic and Efanov, Alexander and Georgiadou, Eleni and Muniangi-Muhitu, Hermine and Sheikh, Mahsa and Giordano, Giuseppe N. and Åkerlund, Mikael and Ahlqvist, Emma and Ali, Ashfaq and Banasik, Karina and Brunak, Søren and Barovic, Marko and Bouland, Gerard A. and Burdet, Frédéric and Canouil, Mickaël and Dragan, Iulian and Elders, Petra J. M. and Fernandez, Celine and Festa, Andreas and Fitipaldi, Hugo and Froguel, Phillippe and Gudmundsdottir, Valborg and Gudnason, Vilmundur and Gerl, Mathias J. and van der Heijden, Amber A. and Jennings, Lori L. and Hansen, Michael K. and Kim, Min and Leclerc, Isabelle and Klose, Christian and Kuznetsov, Dmitry and Mansour Aly, Dina and Mehl, Florence and Marek, Diana and Melander, Olle and Niknejad, Anne and Ottosson, Filip and Pavo, Imre and Duffin, Kevin and Syed, Samreen K. and Shaw, Janice L. and Cabrera, Over and Pullen, Timothy J. and Simons, Kai and Solimena, Michele and Suvitaival, Tommi and Wretlind, Asger and Rossing, Peter and Lyssenko, Valeriya and Legido Quigley, Cristina and Groop, Leif and Thorens, Bernard and Franks, Paul W. and Lim, Gareth E. and Estall, Jennifer and Ibberson, Mark and Beulens, Joline W. J. and ’t Hart, Leen M and Pearson, Ewan R. and Rutter, Guy A.}, month = may, year = {2023}, pages = {2533}, } @article{jones_vivo_2022, title = {In vivo and in vitro characterization of {GL0034}, a novel long-acting glucagon-like peptide-1 receptor agonist}, volume = {24}, issn = {1462-8902, 1463-1326}, shorttitle = {In vivo and in vitro characterization of {\textless}span style="font-variant}, url = {https://onlinelibrary.wiley.com/doi/10.1111/dom.14794}, doi = {10.1111/dom.14794}, language = {en}, number = {11}, urldate = {2022-10-05}, journal = {Diabetes, Obesity and Metabolism}, author = {Jones, Ben and Burade, Vinod and Akalestou, Elina and Manchanda, Yusman and Ramchunder, Zenouska and Carrat, Gaëlle and Nguyen‐Tu, Marie‐Sophie and Marchetti, Piero and Piemonti, Lorenzo and Leclerc, Isabelle and Thennati, Rajamannar and Vilsboll, Tina and Thorens, Bernard and Tomas, Alejandra and Rutter, Guy A.}, month = nov, year = {2022}, pages = {2090--2101}, } @article{cruciani-guglielmacci_homocysteine_2022, title = {Homocysteine {Metabolism} {Pathway} {Is} {Involved} in the {Control} of {Glucose} {Homeostasis}: {A} {Cystathionine} {Beta} {Synthase} {Deficiency} {Study} in {Mouse}}, volume = {11}, issn = {2073-4409}, shorttitle = {Homocysteine {Metabolism} {Pathway} {Is} {Involved} in the {Control} of {Glucose} {Homeostasis}}, url = {https://www.mdpi.com/2073-4409/11/11/1737}, doi = {10.3390/cells11111737}, abstract = {Cystathionine beta synthase (CBS) catalyzes the first step of the transsulfuration pathway from homocysteine to cystathionine, and its deficiency leads to hyperhomocysteinemia (HHcy) in humans and rodents. To date, scarce information is available about the HHcy effect on insulin secretion, and the link between CBS activity and the setting of type 2 diabetes is still unknown. We aimed to decipher the consequences of an inborn defect in CBS on glucose homeostasis in mice. We used a mouse model heterozygous for CBS (CBS+/−) that presented a mild HHcy. Other groups were supplemented with methionine in drinking water to increase the mild to intermediate HHcy, and were submitted to a high-fat diet (HFD). We measured the food intake, body weight gain, body composition, glucose homeostasis, plasma homocysteine level, and CBS activity. We evidenced a defect in the stimulated insulin secretion in CBS+/− mice with mild and intermediate HHcy, while mice with intermediate HHcy under HFD presented an improvement in insulin sensitivity that compensated for the decreased insulin secretion and permitted them to maintain a glucose tolerance similar to the CBS+/+ mice. Islets isolated from CBS+/− mice maintained their ability to respond to the elevated glucose levels, and we showed that a lower parasympathetic tone could, at least in part, be responsible for the insulin secretion defect. Our results emphasize the important role of Hcy metabolic enzymes in insulin secretion and overall glucose homeostasis.}, language = {en}, number = {11}, urldate = {2022-06-22}, journal = {Cells}, author = {Cruciani-Guglielmacci, Céline and Meneyrol, Kelly and Denom, Jessica and Kassis, Nadim and Rachdi, Latif and Makaci, Fatna and Migrenne-Li, Stéphanie and Daubigney, Fabrice and Georgiadou, Eleni and Denis, Raphaël G. and Rodriguez Sanchez-Archidona, Ana and Paul, Jean-Louis and Thorens, Bernard and Rutter, Guy A. and Magnan, Christophe and Le Stunff, Hervé and Janel, Nathalie}, month = may, year = {2022}, pages = {1737}, } @article{raverdy_data-driven_2022, title = {Data-driven subgroups of type 2 diabetes, metabolic response, and renal risk profile after bariatric surgery: a retrospective cohort study}, volume = {10}, issn = {22138587}, shorttitle = {Data-driven subgroups of type 2 diabetes, metabolic response, and renal risk profile after bariatric surgery}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2213858722000055}, doi = {10.1016/S2213-8587(22)00005-5}, language = {en}, number = {3}, urldate = {2022-05-12}, journal = {The Lancet Diabetes \& Endocrinology}, author = {Raverdy, Violeta and Cohen, Ricardo V and Caiazzo, Robert and Verkindt, Helene and Petry, Tarissa Beatrice Zanata and Marciniak, Camille and Legendre, Benjamin and Bauvin, Pierre and Chatelain, Estelle and Duhamel, Alain and Drumez, Elodie and Oukhouya-Daoud, Naima and Chetboun, Mikael and Baud, Gregory and Ahlqvist, Emma and Wierup, Niels and Asplund, Olof and Laferrère, Blandine and Groop, Leif and Pattou, François}, month = mar, year = {2022}, keywords = {WP3, WP6}, pages = {167--176}, } @article{emamipour_transferability_2022, title = {The transferability and validity of a population-level simulation model for the economic evaluation of interventions in diabetes: the {MICADO} model}, issn = {1432-5233}, shorttitle = {The transferability and validity of a population-level simulation model for the economic evaluation of interventions in diabetes}, url = {https://link.springer.com/10.1007/s00592-022-01891-2}, doi = {10.1007/s00592-022-01891-2}, abstract = {Abstract Aims Valid health economic models are essential to inform the adoption and reimbursement of therapies for diabetes mellitus. Often existing health economic models are applied in other countries and settings than those where they were developed. This practice requires assessing the transferability of a model developed from one setting to another. We evaluate the transferability of the MICADO model, developed for the Dutch 2007 setting, in two different settings using a range of adjustment steps. MICADO predicts micro- and macrovascular events at the population level. Methods MICADO simulation results were compared to observed events in an Italian 2000–2015 cohort (Casale Monferrato Survey [CMS]) and in a Dutch 2008–2019 (Hoorn Diabetes Care Center [DCS]) cohort after adjusting the demographic characteristics. Additional adjustments were performed to: (1) risk factors prevalence at baseline, (2) prevalence of complications, and (3) all-cause mortality risks by age and sex. Model validity was assessed by mean average percentage error (MAPE) of cumulative incidences over 10 years of follow-up, where lower values mean better accuracy. Results For mortality, MAPE was lower for CMS compared to DCS (0.38 vs. 0.70 following demographic adjustment) and adjustment step 3 improved it to 0.20 in CMS, whereas step 2 showed best results in DCS (0.65). MAPE for heart failure and stroke in DCS were 0.11 and 0.22, respectively, while for CMS was 0.42 and 0.41. Conclusions The transferability of the MICADO model varied by event and per cohort. Additional adjustments improved prediction of events for MICADO. To ensure a valid model in a new setting it is imperative to assess the impact of adjustments in terms of model accuracy, even when this involves the same country, but a new time period.}, language = {en}, urldate = {2022-05-11}, journal = {Acta Diabetologica}, author = {Emamipour, Sajad and Pagano, Eva and Di Cuonzo, Daniela and Konings, Stefan R. A. and van der Heijden, Amber A. and Elders, Petra and Beulens, Joline W. J. and Leal, Jose and Feenstra, Talitha L.}, month = apr, year = {2022}, keywords = {WP8}, } @article{leal_healthrelated_2022, title = {Health‐related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus: {Cross}‐sectional analysis of the {ADDITION}‐{PRO} study}, volume = {39}, issn = {0742-3071, 1464-5491}, shorttitle = {Health‐related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus}, url = {https://onlinelibrary.wiley.com/doi/10.1111/dme.14825}, doi = {10.1111/dme.14825}, language = {en}, number = {6}, urldate = {2022-05-12}, journal = {Diabetic Medicine}, author = {Leal, Jose and Becker, Frauke and Feenstra, Talitha and Pagano, Eva and Jensen, Troels Mygind and Vistisen, Dorte and Witte, Daniel R. and Jorgensen, Marit Eika}, month = jun, year = {2022}, keywords = {WP8}, } @article{hempel_impact_2022, title = {The {Impact} of {Pancreatic} {Head} {Resection} on {Blood} {Glucose} {Homeostasis} in {Patients} with {Chronic} {Pancreatitis}}, volume = {11}, issn = {2077-0383}, url = {https://www.mdpi.com/2077-0383/11/3/663}, doi = {10.3390/jcm11030663}, abstract = {Background: Chronic pancreatitis (CP) often leads to recurrent pain as well as exocrine and/or endocrine pancreatic insufficiency. This study aimed to investigate the effect of pancreatic head resections on glucose metabolism in patients with CP. Methods: Patients who underwent pylorus-preserving pancreaticoduodenectomy (PPPD), Whipple procedure (cPD), or duodenum-preserving pancreatic head resection (DPPHR) for CP between January 2011 and December 2020 were retrospectively analyzed with regard to markers of pancreatic endocrine function including steady-state beta cell function (\%B), insulin resistance (IR), and insulin sensitivity (\%S) according to the updated Homeostasis Model Assessment (HOMA2). Results: Out of 141 pancreatic resections for CP, 43 cases including 31 PPPD, 2 cPD and 10 DPPHR, met the inclusion criteria. Preoperatively, six patients (14\%) were normoglycemic (NG), 10 patients (23.2\%) had impaired glucose tolerance (IGT) and 27 patients (62.8\%) had diabetes mellitus (DM). In each subgroup, no significant changes were observed for HOMA2-\%B (NG: p = 0.57; IGT: p = 0.38; DM: p = 0.1), HOMA2-IR (NG: p = 0.41; IGT: p = 0.61; DM: p = 0.18) or HOMA2-\%S (NG: p = 0.44; IGT: p = 0.52; DM: p = 0.51) 3 and 12 months after surgery, respectively. Conclusion: Pancreatic head resections for CP, including DPPHR and pancreatoduodenectomies, do not significantly affect glucose metabolism within a follow-up period of 12 months.}, language = {en}, number = {3}, urldate = {2022-05-12}, journal = {Journal of Clinical Medicine}, author = {Hempel, Sebastian and Oehme, Florian and Ehehalt, Florian and Solimena, Michele and Kolbinger, Fiona and Bogner, Andreas and Welsch, Thilo and Weitz, Jürgen and Distler, Marius}, month = jan, year = {2022}, keywords = {WP5}, pages = {663}, } @article{akalestou_mechanisms_2021, title = {Mechanisms of {Weight} {Loss} {After} {Obesity} {Surgery}}, issn = {0163-769X, 1945-7189}, url = {https://academic.oup.com/edrv/advance-article/doi/10.1210/endrev/bnab022/6345381}, doi = {10.1210/endrev/bnab022}, abstract = {Abstract Obesity surgery remains the most effective treatment for obesity and its complications. Weight loss was initially attributed to decreased energy absorption from the gut but has since been linked to reduced appetitive behavior and potentially increased energy expenditure. Implicated mechanisms associating rearrangement of the gastrointestinal tract with these metabolic outcomes include central appetite control, release of gut peptides, change in microbiota, and bile acids. However, the exact combination and timing of signals remain largely unknown. In this review, we survey recent research investigating these mechanisms, and seek to provide insights on unanswered questions over how weight loss is achieved following bariatric surgery which may eventually lead to safer, nonsurgical weight-loss interventions or combinations of medications with surgery.}, language = {en}, urldate = {2021-11-30}, journal = {Endocrine Reviews}, author = {Akalestou, Elina and Miras, Alexander D and Rutter, Guy A and le Roux, Carel W}, month = aug, year = {2021}, keywords = {WP3, WP4}, pages = {bnab022}, } @article{so_paired_2021, title = {Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis}, volume = {13}, issn = {1946-6234, 1946-6242}, url = {https://spiral.imperial.ac.uk/handle/10044/1/91473}, doi = {10.1126/scitranslmed.abb1038}, language = {en}, number = {600}, urldate = {2021-10-14}, journal = {Science Translational Medicine}, author = {So, Wing Yan and Liu, Wai Nam and Teo, Adrian Kee Keong and Rutter, Guy A. and Han, Weiping}, month = jun, year = {2021}, keywords = {WP4}, pages = {eabb1038}, } @article{wigger_multi-omics_2021, title = {Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes}, volume = {3}, issn = {2522-5812}, url = {https://www.nature.com/articles/s42255-021-00420-9}, doi = {10.1038/s42255-021-00420-9}, language = {en}, number = {7}, urldate = {2021-09-07}, journal = {Nature Metabolism}, author = {Wigger, Leonore and Barovic, Marko and Brunner, Andreas-David and Marzetta, Flavia and Schöniger, Eyke and Mehl, Florence and Kipke, Nicole and Friedland, Daniela and Burdet, Frederic and Kessler, Camille and Lesche, Mathias and Thorens, Bernard and Bonifacio, Ezio and Legido-Quigley, Cristina and Barbier Saint Hilaire, Pierre and Delerive, Philippe and Dahl, Andreas and Klose, Christian and Gerl, Mathias J. and Simons, Kai and Aust, Daniela and Weitz, Jürgen and Distler, Marius and Schulte, Anke M. and Mann, Matthias and Ibberson, Mark and Solimena, Michele}, month = jul, year = {2021}, keywords = {WP4, WP5}, pages = {1017--1031}, } @article{clough_synthesis_2020, title = {Synthesis and in vivo behaviour of an exendin-4-based {MRI} probe capable of β-cell-dependent contrast enhancement in the pancreas}, volume = {49}, issn = {1477-9234}, url = {https://pubs.rsc.org/en/content/articlelanding/2020/dt/d0dt00332h}, doi = {10.1039/D0DT00332H}, abstract = {Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.}, language = {en}, number = {15}, urldate = {2020-04-17}, journal = {Dalton Transactions}, author = {Clough, Thomas J. and Baxan, Nicoleta and Coakley, Emma J. and Rivas, Charlotte and Zhao, Lan and Leclerc, Isabelle and Martinez-Sanchez, Aida and Rutter, Guy A. and Long, Nicholas J.}, month = apr, year = {2020}, note = {Publisher: The Royal Society of Chemistry}, keywords = {WP4, WP5}, pages = {4732--4740}, } @article{ahlqvist_novel_2018, title = {Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables}, volume = {6}, issn = {22138587}, shorttitle = {Novel subgroups of adult-onset diabetes and their association with outcomes}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2213858718300512}, doi = {10.1016/S2213-8587(18)30051-2}, language = {en}, number = {5}, urldate = {2018-11-26}, journal = {The Lancet Diabetes \& Endocrinology}, author = {Ahlqvist, Emma and Storm, Petter and Käräjämäki, Annemari and Martinell, Mats and Dorkhan, Mozhgan and Carlsson, Annelie and Vikman, Petter and Prasad, Rashmi B and Aly, Dina Mansour and Almgren, Peter and Wessman, Ylva and Shaat, Nael and Spégel, Peter and Mulder, Hindrik and Lindholm, Eero and Melander, Olle and Hansson, Ola and Malmqvist, Ulf and Lernmark, Åke and Lahti, Kaj and Forsén, Tom and Tuomi, Tiinamaija and Rosengren, Anders H and Groop, Leif}, month = may, year = {2018}, keywords = {WP3}, pages = {361--369}, } @article{eizirik_pancreatic_2020, title = {Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure}, volume = {16}, issn = {1759-5029, 1759-5037}, shorttitle = {Pancreatic β-cells in type 1 and type 2 diabetes mellitus}, url = {http://www.nature.com/articles/s41574-020-0355-7}, doi = {10.1038/s41574-020-0355-7}, language = {en}, number = {7}, urldate = {2021-09-07}, journal = {Nature Reviews Endocrinology}, author = {Eizirik, Décio L. and Pasquali, Lorenzo and Cnop, Miriam}, month = jul, year = {2020}, keywords = {WP5}, pages = {349--362}, } @article{lytrivi_inflammatory_2018, title = {Inflammatory stress in islet β-cells: therapeutic implications for type 2 diabetes?}, volume = {43}, issn = {1471-4973}, shorttitle = {Inflammatory stress in islet β-cells}, doi = {10.1016/j.coph.2018.08.002}, 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.}, language = {eng}, journal = {Current Opinion in Pharmacology}, author = {Lytrivi, Maria and Igoillo-Esteve, Mariana and Cnop, Miriam}, month = dec, year = {2018}, pmid = {30142486}, keywords = {WP5}, pages = {40--45}, } @article{salem_leader_2019, title = {Leader β-cells coordinate {Ca} 2+ dynamics across pancreatic islets in vivo}, volume = {1}, copyright = {2019 The Author(s), under exclusive licence to Springer Nature Limited}, issn = {2522-5812}, url = {https://www.nature.com/articles/s42255-019-0075-2}, doi = {10.1038/s42255-019-0075-2}, abstract = {Pancreatic β-cells are highly connected, and this network is crucial for the pulsatile release of insulin. Here Salem and colleagues demonstrated the existence of leader β-cells that respond first to glucose and are more closely linked to the other β-cells. They also showed that glucose increases β-cell calcium dynamics and connectivity between the leader and non-leader β-cells.}, language = {En}, number = {6}, urldate = {2019-06-28}, journal = {Nature Metabolism}, author = {Salem, Victoria and Silva, Luis Delgadillo and Suba, Kinga and Georgiadou, Eleni and Gharavy, S. Neda Mousavy and Akhtar, Nadeem and Martin-Alonso, Aldara and Gaboriau, David C. A. and Rothery, Stephen M. and Stylianides, Theodoros and Carrat, Gaelle and Pullen, Timothy J. and Singh, Sumeet Pal and Hodson, David J. and Leclerc, Isabelle and Shapiro, A. M. James and Marchetti, Piero and Briant, Linford J. B. and Distaso, Walter and Ninov, Nikolay and Rutter, Guy A.}, month = jun, year = {2019}, keywords = {WP4, WP5}, pages = {615}, } @article{georgiadou_control_2020, title = {Control by {Ca2}+ of mitochondrial structure and function in pancreatic β-cells}, volume = {91}, issn = {01434160}, url = {https://linkinghub.elsevier.com/retrieve/pii/S014341602030124X}, doi = {10.1016/j.ceca.2020.102282}, language = {en}, urldate = {2020-12-04}, journal = {Cell Calcium}, author = {Georgiadou, Eleni and Rutter, Guy A.}, month = nov, year = {2020}, keywords = {WP4}, pages = {102282}, } @article{da_silva_xavier_metabolic_2020, title = {Metabolic and {Functional} {Heterogeneity} in {Pancreatic} β {Cells}}, volume = {432}, issn = {00222836}, url = {https://linkinghub.elsevier.com/retrieve/pii/S002228361930508X}, doi = {10.1016/j.jmb.2019.08.005}, language = {en}, number = {5}, urldate = {2021-12-03}, journal = {Journal of Molecular Biology}, author = {Da Silva Xavier, Gabriela and Rutter, Guy A.}, month = mar, year = {2020}, keywords = {WP4, WP5}, pages = {1395--1406}, } @article{diedisheim_modeling_2018, title = {Modeling human pancreatic beta cell dedifferentiation}, volume = {10}, issn = {22128778}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2212877818300085}, doi = {10.1016/j.molmet.2018.02.002}, language = {en}, urldate = {2018-11-26}, journal = {Molecular Metabolism}, author = {Diedisheim, Marc and Oshima, Masaya and Albagli, Olivier and Huldt, Charlotte Wennberg and Ahlstedt, Ingela and Clausen, Maryam and Menon, Suraj and Aivazidis, Alexander and Andreasson, Anne-Christine and Haynes, William G. and Marchetti, Piero and Marselli, Lorella and Armanet, Mathieu and Chimienti, Fabrice and Scharfmann, Raphael}, month = apr, year = {2018}, keywords = {WP5}, pages = {74--86}, } @article{cnop_endoplasmic_2017, title = {Endoplasmic reticulum stress and {eIF2α} phosphorylation: {The} {Achilles} heel of pancreatic β cells}, volume = {6}, issn = {22128778}, shorttitle = {Endoplasmic reticulum stress and {eIF2α} phosphorylation}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2212877817302636}, doi = {10.1016/j.molmet.2017.06.001}, language = {en}, number = {9}, urldate = {2018-11-26}, journal = {Molecular Metabolism}, author = {Cnop, Miriam and Toivonen, Sanna and Igoillo-Esteve, Mariana and Salpea, Paraskevi}, month = sep, year = {2017}, keywords = {WP5}, pages = {1024--1039}, } @article{dumayne_klf6_2020, title = {Klf6 protects β-cells against insulin resistance-induced dedifferentiation}, issn = {2212-8778}, url = {http://www.sciencedirect.com/science/article/pii/S2212877820300302}, doi = {10.1016/j.molmet.2020.02.001}, abstract = {Objectives In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic β-cell insulin secretion capacity and β-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of β-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The β-cell factors that normally protect against dedifferentiation remain poorly defined. Here, through a systems biology approach, we identify the transcription factor Klf6 as a regulator of β-cell adaptation to metabolic stress. Methods We use a β-cell specific Klf6 knockout mouse model to investigate whether Klf6 may be a potential regulator of β-cell adaptation to a metabolic stress. Results We show that inactivation of Klf6 in β-cells blunts their proliferation induced by the insulin resistance of pregnancy, high-fat high-sucrose feeding, and insulin receptor antagonism. Transcriptomic analysis showed that Klf6 controls the expression of β-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature β-cell identity and the induction of disallowed genes that impair insulin secretion; its expression also limits the transdifferentiation of β-cells into α-cells. Conclusion Our study identifies a new transcription factor that protects β-cells against dedifferentiation, and which may be targeted to prevent diabetes development.}, language = {en}, urldate = {2020-02-13}, journal = {Molecular Metabolism}, author = {Dumayne, Christopher and Tarussio, David and Sanchez-Archidona, Ana Rodriguez and Picard, Alexandre and Basco, Davide and Berney, Xavier Pascal and Ibberson, Mark and Thorens, Bernard}, month = feb, year = {2020}, keywords = {Type 2 diabetes, WP5, dedifferentiation, insulin resistance, transdifferentiation, β-cell proliferation}, } @article{thorens_use_2019, series = {Biomarkers of {Beta}-{Cell} {Health} and {Dysfunction}: {Towards} {Personalised} {Diabetes} {Care}}, title = {Use of preclinical models to identify markers of type 2 diabetes susceptibility and novel regulators of insulin secretion – {A} step towards precision medicine}, volume = {27}, issn = {2212-8778}, url = {http://www.sciencedirect.com/science/article/pii/S2212877819305691}, doi = {10.1016/j.molmet.2019.06.008}, abstract = {Background Progression from pre-diabetes to type 2 diabetes (T2D) and from T2D to insulin requirement proceeds at very heterogenous rates among patient populations, and the risk of developing different types of secondary complications is also different between patients. The diagnosis of pre-diabetes and T2D solely based on blood glucose measurements cannot capture this heterogeneity, thereby preventing proposition of therapeutic strategies adapted to individual needs and pathogenetic mechanisms. There is, thus, a need to identify novel means to stratify patient populations based on a molecular knowledge of the diverse underlying causes of the disease. Such knowledge would form the basis for a precision medicine approach to preventing and treating T2D according to the need of identified patient subgroups as well as allowing better follow up of pharmacological treatment. Scope of review Here, we review a systems biology approach that aims at identifying novel biomarkers for T2D susceptibility and identifying novel beta-cell and insulin target tissue genes that link the selected plasma biomarkers with insulin secretion and insulin action. This work was performed as part of two Innovative Medicine Initiative projects. The focus of the review will be on the use of preclinical models to find biomarker candidates for T2D prediction and novel regulators of beta-cell function. We will demonstrate that the study of mice with different genetic architecture and widely different adaptation to metabolic stress can be a powerful approach to identify biomarkers of T2D susceptibility in humans or for the identification of so far unrecognized genes controlling beta-cell function. Major conclusions The examples developed in this review will highlight the power of the systems biology approach, in particular as it allowed the discovery of dihydroceramide as a T2D biomarker candidate in mice and humans and the identification and characterization of novel regulators of beta-cell function.}, language = {en}, urldate = {2020-04-21}, journal = {Molecular Metabolism}, author = {Thorens, Bernard and Rodriguez, Ana and Cruciani-Guglielmacci, Céline and Wigger, Leonore and Ibberson, Mark and Magnan, Christophe}, month = sep, year = {2019}, keywords = {Beta-cells, Biomarkers, Ceramides, Elongase, Insulin secretion, Pancreatic islets, Sphingolipids, Type 2 diabetes, WP4, WP5, WP6}, pages = {S147--S154}, } @article{marchetti_fostering_2019, title = {Fostering improved human islet research: a {European} perspective}, volume = {62}, issn = {1432-0428}, shorttitle = {Fostering improved human islet research}, url = {https://doi.org/10.1007/s00125-019-4911-4}, doi = {10.1007/s00125-019-4911-4}, language = {en}, number = {8}, urldate = {2020-04-21}, journal = {Diabetologia}, author = {Marchetti, Piero and Schulte, Anke M. and Marselli, Lorella and Schoniger, Eyke and Bugliani, Marco and Kramer, Werner and Overbergh, Lut and Ullrich, Susanne and Gloyn, Anna L. and Ibberson, Mark and Rutter, Guy and Froguel, Philippe and Groop, Leif and McCarthy, Mark I. and Dotta, Francesco and Scharfmann, Raphael and Magnan, Christophe and Eizirik, Decio L. and Mathieu, Chantal and Cnop, Miriam and Thorens, Bernard and Solimena, Michele}, month = aug, year = {2019}, keywords = {WP5}, pages = {1514--1516}, } @article{slieker_visit--visit_2019, title = {Visit-to-visit variability of glycemia and vascular complications: the {Hoorn} {Diabetes} {Care} {System} cohort}, volume = {18}, issn = {1475-2840}, shorttitle = {Visit-to-visit variability of glycemia and vascular complications}, url = {https://doi.org/10.1186/s12933-019-0975-1}, doi = {10.1186/s12933-019-0975-1}, abstract = {Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration.}, number = {1}, urldate = {2021-02-04}, journal = {Cardiovascular Diabetology}, author = {Slieker, Roderick C. and van der Heijden, Amber A. W. H. and Nijpels, Giel and Elders, Petra J. M. and ’t Hart, Leen M. and Beulens, Joline W. J.}, month = dec, year = {2019}, keywords = {Complications, Glycemia, Type 2 diabetes, Variability, WP3}, pages = {170}, } @article{nguyen-tu_adipocyte-specific_2021, title = {Adipocyte-specific deletion of {Tcf7l2} induces dysregulated lipid metabolism and impairs glucose tolerance in mice}, volume = {64}, issn = {1432-0428}, doi = {10.1007/s00125-020-05292-4}, abstract = {AIMS/HYPOTHESIS: Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/β-catenin signalling pathway implicated in type 2 diabetes risk through genome-wide association studies. Although its expression is critical for adipocyte development, the potential roles of changes in adipose tissue TCF7L2 levels in diabetes risk are poorly defined. Here, we investigated whether forced changes in Tcf7l2 expression in adipocytes affect whole body glucose or lipid metabolism and crosstalk between disease-relevant tissues. METHODS: Tcf7l2 was selectively ablated in mature adipocytes in C57BL/6J mice using Cre recombinase under Adipoq promoter control to recombine Tcf7l2 alleles floxed at exon 1 (referred to as aTCF7L2 mice). aTCF7L2 mice were fed normal chow or a high-fat diet for 12 weeks. Glucose and insulin sensitivity, as well as beta cell function, were assessed in vivo and in vitro. Levels of circulating NEFA, selected hormones and adipokines were measured using standard assays. RESULTS: Reduced TCF7L2 expression in adipocytes altered glucose tolerance and insulin secretion in male but not in female mice. Thus, on a normal chow diet, male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance at 16 weeks (p = 0.03) and increased fat mass (1.4 ± 0.1-fold, p = 0.007) but no changes in insulin secretion. In contrast, male homozygote knockout (aTCF7L2hom) mice displayed normal body weight but impaired oral glucose tolerance at 16 weeks (p = 0.0001). These changes were mechanistically associated with impaired in vitro glucose-stimulated insulin secretion (decreased 0.5 ± 0.1-fold vs control mice, p = 0.02) and decreased levels of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (0.6 ± 0.1-fold and 0.4 ± 0.1-fold vs control mice, p = 0.04 and p {\textless} 0.0001, respectively). Circulating levels of plasma NEFA and fatty acid binding protein 4 were increased by 1.3 ± 0.1-fold and 1.8 ± 0.3-fold vs control mice (p = 0.03 and p = 0.05, respectively). Following exposure to a high-fat diet for 12 weeks, male aTCF7L2hom mice exhibited reduced in vivo glucose-stimulated insulin secretion (0.5 ± 0.1-fold vs control mice, p = 0.02). CONCLUSIONS/INTERPRETATION: Loss of Tcf7l2 gene expression selectively in adipocytes leads to a sexually dimorphic phenotype, with impairments not only in adipocytes, but also in pancreatic islet and enteroendocrine cells in male mice only. Our findings suggest novel roles for adipokines and incretins in the effects of diabetes-associated variants in TCF7L2, and further illuminate the roles of TCF7L2 in glucose homeostasis and diabetes risk. Graphical abstract.}, language = {eng}, number = {1}, journal = {Diabetologia}, author = {Nguyen-Tu, Marie-Sophie and Martinez-Sanchez, Aida and Leclerc, Isabelle and Rutter, Guy A. and da Silva Xavier, Gabriela}, month = jan, year = {2021}, pmid = {33068125}, pmcid = {PMC7567653}, keywords = {Adipocyte, Beta cell, Fatty acid, Incretin, Insulin, Mouse, TCF7L2, Type 2 diabetes, WP4, WP6}, pages = {129--141}, } @article{le_stunff_deciphering_2019, title = {Deciphering the {Link} {Between} {Hyperhomocysteinemia} and {Ceramide} {Metabolism} in {Alzheimer}-{Type} {Neurodegeneration}}, volume = {10}, issn = {1664-2295}, url = {https://www.frontiersin.org/articles/10.3389/fneur.2019.00807/full}, doi = {10.3389/fneur.2019.00807}, abstract = {While aging is clearly the strongest risk factor for Alzheimer’s disease (AD), emerging data suggest that dyslipidemic states can either contribute to or serve as co-factors in its pathogenesis. AD could be regarded as a metabolic disease mediated by peripheral insulin resistance disorders. Insulin resistance is associated with dyslipidemia, which results in increased hepatic ceramide generation. Progressive hepatic steatosis incites inflammation and pro-inflammatory cytokine activation, which is mediated by the increased ceramides production. Ceramides accumulate in cells due to disturbances in sphingolipid metabolism and upregulated expression of enzymes involved in ceramide synthesis. Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation following injury or cell death caused by local liver inflammation, and due to their lipid soluble nature, cross the blood-brain barrier and exert neurotoxic effects by impairing insulin signaling and activating pro-inflammatory cytokines. These abnormalities establish or help propagate a cascade of neurodegeneration associated with oxidative stress and ceramide generation, which exacerbate brain insulin resistance, cell death, myelin degeneration, and neuro-inflammation. Therefore, toxic lipids generated in liver can cause neurodegeneration. Elevated homocysteine level is a risk factor for AD pathology and is closely associated with metabolic diseases and non-alcoholic fatty liver disease. Results suggest the existence of a homocysteine/ceramides signaling pathway which suggest that homocysteine toxicity may be at least partly mediated by intracellular ceramide accumulation via a direct consequence of stimulation of ceramide synthase. In this article, we briefly examined the role of homocysteine and ceramide metabolism linking metabolic diseases and non-alcoholic fatty liver disease to AD. We therefore analyzed the expression of mainly enzymes implicated in ceramide and sphingolipid metabolism and demonstrated deregulation of de novo ceramide synthesis and S1P metabolism in liver and brain of hyperhomocysteinemic mice.}, language = {English}, urldate = {2021-02-05}, journal = {Frontiers in Neurology}, author = {Le Stunff, Hervé and Véret, Julien and Kassis, Nadim and Denom, Jessica and Meneyrol, Kelly and Paul, Jean-Louis and Cruciani-Guglielmacci, Céline and Magnan, Christophe and Janel, Nathalie}, year = {2019}, note = {Publisher: Frontiers}, keywords = {Alzheimer's disease, Ceramides, Hyperhomocystienemia, NAFLD, Sphingolipid metabolism, WP6}, }