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      GLIS3, a Susceptibility Gene for Type 1 and Type 2 Diabetes, Modulates Pancreatic Beta Cell Apoptosis via Regulation of a Splice Variant of the BH3-Only Protein Bim

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          Abstract

          Mutations in human Gli-similar (GLIS) 3 protein cause neonatal diabetes. The GLIS3 gene region has also been identified as a susceptibility risk locus for both type 1 and type 2 diabetes. GLIS3 plays a role in the generation of pancreatic beta cells and in insulin gene expression, but there is no information on the role of this gene on beta cell viability and/or susceptibility to immune- and metabolic-induced stress. GLIS3 knockdown (KD) in INS-1E cells, primary FACS-purified rat beta cells, and human islet cells decreased expression of MafA, Ins2, and Glut2 and inhibited glucose oxidation and insulin secretion, confirming the role of this transcription factor for the beta cell differentiated phenotype. GLIS3 KD increased beta cell apoptosis basally and sensitized the cells to death induced by pro-inflammatory cytokines (interleukin 1β + interferon-γ) or palmitate, agents that may contribute to beta cell loss in respectively type 1 and 2 diabetes. The increased cell death was due to activation of the intrinsic (mitochondrial) pathway of apoptosis, as indicated by cytochrome c release to the cytosol, Bax translocation to the mitochondria and activation of caspases 9 and 3. Analysis of the pathways implicated in beta cell apoptosis following GLIS3 KD indicated modulation of alternative splicing of the pro-apoptotic BH3-only protein Bim, favouring expression of the pro-death variant Bim S via inhibition of the splicing factor SRp55. KD of Bim abrogated the pro-apoptotic effect of GLIS3 loss of function alone or in combination with cytokines or palmitate. The present data suggest that altered expression of the candidate gene GLIS3 may contribute to both type 1 and 2 type diabetes by favouring beta cell apoptosis. This is mediated by alternative splicing of the pro-apoptotic protein Bim and exacerbated formation of the most pro-apoptotic variant Bim S.

          Author Summary

          Pancreatic beta cell dysfunction and death is a central event in the pathogenesis of diabetes. Genome-wide association studies have identified a large number of associations between specific loci and the two main forms of diabetes, namely type 1 and type 2 diabetes, but the mechanisms by which these candidate genes predispose to diabetes remain to be clarified. The GLIS3 gene region has been identified as a susceptibility risk locus for both type 1 and type 2 diabetes—it is actually the only locus showing association with both forms of diabetes and the regulation of blood glucose. We show that decreased expression of GLIS3 may contribute to diabetes by favouring beta cell apoptosis. This is mediated by the mitochondrial pathway of apoptosis, activated via alternative splicing (a process by which exons are joined in multiple ways, leading to the generation of several proteins by a single gene) of the pro-apoptotic protein Bim, which favours formation of the most pro-apoptotic variant. The present data provides the first evidence that a susceptibility gene for diabetes may contribute to disease via regulation of alternative splicing of a pro-apoptotic gene in pancreatic beta cells.

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          Most cited references 74

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          Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing.

          We carried out the first analysis of alternative splicing complexity in human tissues using mRNA-Seq data. New splice junctions were detected in approximately 20% of multiexon genes, many of which are tissue specific. By combining mRNA-Seq and EST-cDNA sequence data, we estimate that transcripts from approximately 95% of multiexon genes undergo alternative splicing and that there are approximately 100,000 intermediate- to high-abundance alternative splicing events in major human tissues. From a comparison with quantitative alternative splicing microarray profiling data, we also show that mRNA-Seq data provide reliable measurements for exon inclusion levels.
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            New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

            Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
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              Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

              To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                May 2013
                May 2013
                30 May 2013
                : 9
                : 5
                Affiliations
                [1 ]Laboratory of Experimental Medicine, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
                [2 ]Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
                [3 ]Division of Endocrinology, Erasmus Hospital, Brussels, Belgium
                [4 ]INSERM UMR-S 958, Faculté de Médecine Paris Diderot, Paris, France
                [5 ]University Paris 7 Denis–Diderot, Paris, France
                University of Oxford, United Kingdom
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TCN FMP OV MLC MC CJ DLE. Performed the experiments: TCN FMP OV MLC RFM DAC. Analyzed the data: TCN FMP OV CJ DLE. Contributed reagents/materials/analysis tools: LM PM MC CJ DLE. Wrote the paper: TCN FMP OV DLE.

                PGENETICS-D-12-02709
                10.1371/journal.pgen.1003532
                3667755
                23737756

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 17
                Funding
                This work was supported by grants from the Communaite Francaise de Belgique Actions de Recherche Concertes (ARC), Fonds National de la Recherche Scientifique (FNRS) Belgium, and the European Union (projects NAIMIT and BetaBat, in the Framework Programme 7 of the European Community). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Endocrine System
                Endocrine Physiology
                Insulin
                Genetics
                Molecular Genetics
                Gene Regulation
                Gene Expression
                Gene Splicing

                Genetics

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