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    Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Cosentino Cristina,Toivonen Sanna,Diaz Villamil Esteban,Atta Mohamed,Ravanat Jean-Luc,Demine Stéphane,Schiavo Andrea Alex,Pachera Nathalie,Deglasse Jean-Philippe,Jonas Jean-Christophe,Balboa Diego,Otonkoski Timo,Pearson Ewan R,Marchetti Piero,Eizirik Décio L,Cnop Miriam,Igoillo-Esteve Mariana Nucleic acids research 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. 10.1093/nar/gky839
    MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Ardestani Amin,Paroni Federico,Azizi Zahra,Kaur Supreet,Khobragade Vrushali,Yuan Ting,Frogne Thomas,Tao Wufan,Oberholzer Jose,Pattou Francois,Conte Julie Kerr,Maedler Kathrin Nature medicine Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and strategies to prevent beta cell apoptosis and dysfunction are urgently needed. Here, we identified mammalian sterile 20-like kinase-1 (MST1) as a critical regulator of apoptotic beta cell death and function. Under diabetogenic conditions, MST1 was strongly activated in beta cells in human and mouse islets and specifically induced the mitochondrial-dependent pathway of apoptosis through upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. MST1 directly phosphorylated the beta cell transcription factor PDX1 at T11, resulting in the latter's ubiquitination and degradation and thus in impaired insulin secretion. MST1 deficiency completely restored normoglycemia, beta cell function and survival in vitro and in vivo. We show MST1 as a proapoptotic kinase and key mediator of apoptotic signaling and beta cell dysfunction and suggest that it may serve as target for the development of new therapies for diabetes. 10.1038/nm.3482
    Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist. Damond Nicolas,Thorel Fabrizio,Moyers Julie S,Charron Maureen J,Vuguin Patricia M,Powers Alvin C,Herrera Pedro L eLife Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgr(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing β-cells. Here, we show that diabetes prevention in STZ-treated Gcgr(-/-) animals requires remnant insulin action originating from spared residual β-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr(-/-) mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced β-cell loss, a situation of near-absolute insulin deficiency similar to type 1 diabetes. In addition, glucagon deficiency did not impair the natural capacity of α-cells to reprogram into insulin production after extreme β-cell loss. α-to-β-cell conversion was improved in Gcgr(-/-) mice as a consequence of α-cell hyperplasia. Collectively, these results indicate that glucagon antagonism could i) be a useful adjuvant therapy in diabetes only when residual insulin action persists, and ii) help devising future β-cell regeneration therapies relying upon α-cell reprogramming. 10.7554/eLife.13828
    Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development. Guay Claudiane,Kruit Janine K,Rome Sophie,Menoud Véronique,Mulder Niels L,Jurdzinski Angelika,Mancarella Francesca,Sebastiani Guido,Donda Alena,Gonzalez Bryan J,Jandus Camilla,Bouzakri Karim,Pinget Michel,Boitard Christian,Romero Pedro,Dotta Francesco,Regazzi Romano Cell metabolism Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the β cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to β cells favoring apoptosis. Inactivation of these miRNAs in recipient β cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in β cells. The induction of these genes may promote the recruitment of immune cells and exacerbate β cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells. 10.1016/j.cmet.2018.09.011
    Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. Nature Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells and somatostatin-producing δ-cells become insulin-expressing cells after the ablation of insulin-secreting β-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-β-cells, namely α-cells and pancreatic polypeptide (PPY)-producing γ-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing α-cells maintain expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases. 10.1038/s41586-019-0942-8
    Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis. Traub Shuyang,Meier Daniel T,Schulze Friederike,Dror Erez,Nordmann Thierry M,Goetz Nicole,Koch Norina,Dalmas Elise,Stawiski Marc,Makshana Valmir,Thorel Fabrizio,Herrera Pedro L,Böni-Schnetzler Marianne,Donath Marc Y Cell reports Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes. 10.1016/j.celrep.2017.03.005
    Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Pasquali Lorenzo,Gaulton Kyle J,Rodríguez-Seguí Santiago A,Mularoni Loris,Miguel-Escalada Irene,Akerman İldem,Tena Juan J,Morán Ignasi,Gómez-Marín Carlos,van de Bunt Martijn,Ponsa-Cobas Joan,Castro Natalia,Nammo Takao,Cebola Inês,García-Hurtado Javier,Maestro Miguel Angel,Pattou François,Piemonti Lorenzo,Berney Thierry,Gloyn Anna L,Ravassard Philippe,Skarmeta José Luis Gómez,Müller Ferenc,McCarthy Mark I,Ferrer Jorge Nature genetics Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes. 10.1038/ng.2870
    Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon α-cells. Cigliola Valentina,Ghila Luiza,Thorel Fabrizio,van Gurp Léon,Baronnier Delphine,Oropeza Daniel,Gupta Simone,Miyatsuka Takeshi,Kaneto Hideaki,Magnuson Mark A,Osipovich Anna B,Sander Maike,Wright Christopher E V,Thomas Melissa K,Furuyama Kenichiro,Chera Simona,Herrera Pedro L Nature cell biology The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change. 10.1038/s41556-018-0216-y
    β Cell-Specific Deletion of the IL-1 Receptor Antagonist Impairs β Cell Proliferation and Insulin Secretion. Böni-Schnetzler Marianne,Häuselmann Stéphanie P,Dalmas Elise,Meier Daniel T,Thienel Constanze,Traub Shuyang,Schulze Friederike,Steiger Laura,Dror Erez,Martin Praxedis,Herrera Pedro L,Gabay Cem,Donath Marc Y Cell reports Interleukin-1 receptor antagonist (IL-1Ra) is elevated in the circulation during obesity and type 2 diabetes (T2D) but is decreased in islets from patients with T2D. The protective role of local IL-1Ra was investigated in pancreatic islet β cell (βIL-1Ra)-specific versus myeloid-cell (myeloIL-1Ra)-specific IL-1Ra knockout (KO) mice. Deletion of IL-1Ra in β cells, but not in myeloid cells, resulted in diminished islet IL-1Ra expression. Myeloid cells were not the main source of circulating IL-1Ra in obesity. βIL-1Ra KO mice had impaired insulin secretion, reduced β cell proliferation, and decreased expression of islet proliferation genes, along with impaired glucose tolerance. The key cell-cycle regulator E2F1 partly reversed IL-1β-mediated inhibition of potassium channel Kir6.2 expression and rescued impaired insulin secretion in IL-1Ra knockout islets. Our findings provide evidence for the importance of β cell-derived IL-1Ra for the local defense of β cells to maintain normal function and proliferation. 10.1016/j.celrep.2018.01.063