| 1. |
- Yusuf, D, et al.
(author)
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The transcription factor encyclopedia
- 2012
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906. ; 13:3, s. R24-
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Journal article (peer-reviewed)
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| 3. |
- Baekkeskov, S, et al.
(author)
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Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes
- 1987
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In: Journal of Clinical Investigation. - 0021-9738. ; 79:3, s. 34-926
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Journal article (peer-reviewed)abstract
- Antibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients are directed to a human islet cell protein of relative molecular mass (Mr) 64,000. Since IDDM seems to develop after a prodromal period of beta-cell autoimmunity, this study has examined whether 64,000 Mr antibodies could be detected in 14 individuals who subsequently developed IDDM and five first degree relatives who have indications of altered beta-cell function. Sera were screened by immunoprecipitation on total detergent lysates of human islets and positive sera retested on membrane protein preparations. Antibodies to the 64,000 Mr membrane protein were consistently detected in 11/14 IDDM patients, and in all 5 first degree relatives. 10 IDDM patients were already positive in the first samples, obtained 4-91 mo before the clinical onset of IDDM, whereas 1 patient progressed to a high 64,000 Mr immunoreactivity, at a time where a commencement of a decline in beta-cell function was detected. 64,000 Mr antibodies were detected before islet cell cytoplasmic antibodies (ICCA) in two patients. In the control groups of 21 healthy individuals, 36 patients with diseases of the thyroid and 5 SLE patients, the 64,000 Mr antibodies were detected in only one individual, who was a healthy sibling to an IDDM patient. These results suggest that antibodies against the Mr 64,000 human islet protein are an early marker of beta-cell autoimmunity and may be useful to predict a later development of IDDM.
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| 4. |
- Jacobsen, S. C., et al.
(author)
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Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men
- 2012
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55:12, s. 3341-3349
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Journal article (peer-reviewed)abstract
- Energy-dense diets that are high in fat are associated with a risk of metabolic diseases. The underlying molecular mechanisms could involve epigenetics, as recent data show altered DNA methylation of putative type 2 diabetes candidate genes in response to high-fat diets. We examined the effect of a short-term high-fat overfeeding (HFO) diet on genome-wide DNA methylation patterns in human skeletal muscle. Skeletal muscle biopsies were obtained from 21 healthy young men after ingestion of a short-term HFO diet and a control diet, in a randomised crossover setting. DNA methylation was measured in 27,578 CpG sites/14,475 genes using Illumina's Infinium Bead Array. Candidate gene expression was determined by quantitative real-time PCR. HFO introduced widespread DNA methylation changes affecting 6,508 genes (45%), with a maximum methylation change of 13.0 percentage points. The HFO-induced methylation changes were only partly and non-significantly reversed after 6-8 weeks. Alterations in DNA methylation levels primarily affected genes involved in inflammation, the reproductive system and cancer. Few gene expression changes were observed and these had poor correlation to DNA methylation. The genome-wide DNA methylation changes induced by the short-term HFO diet could have implications for our understanding of transient epigenetic regulation in humans and its contribution to the development of metabolic diseases. The slow reversibility suggests a methylation build-up with HFO, which over time may influence gene expression levels.
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| 5. |
- Khilji, M. S., et al.
(author)
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The inducible β5i proteasome subunit contributes to proinsulin degradation in GRP94-deficient β-cells and is overexpressed in type 2 diabetes pancreatic islets
- 2020
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In: American Journal of Physiology - Endocrinology and Metabolism. - 0193-1849. ; 318:6
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Journal article (peer-reviewed)abstract
- Proinsulin is a misfolding-prone protein, and its efficient breakdown is critical when β-cells are confronted with high-insulin biosynthetic demands, to prevent endoplasmic reticulum stress, a key trigger of secretory dysfunction and, if uncompensated, apoptosis. Proinsulin degradation is thought to be performed by the constitutively expressed standard proteasome, while the roles of other proteasomes are unknown. We recently demonstrated that deficiency of the proinsulin chaperone glucoseregulated protein 94 (GRP94) causes impaired proinsulin handling and defective insulin secretion associated with a compensated endoplasmic reticulum stress response. Taking advantage of this model of restricted folding capacity, we investigated the role of different proteasomes in proinsulin degradation, reasoning that insulin secretory dynamics require an inducible protein degradation system. We show that the expression of only one enzymatically active proteasome subunit, namely, the inducible β5i-subunit, was increased in GRP94 CRISPR/Cas9 knockout (KO) cells. Additionally, the level of β5i-containing intermediate proteasomes was significantly increased in these cells, as was β5i-related chymotrypsin-like activity. Moreover, proinsulin levels were restored in GRP94 KO upon β5i small interfering RNA-mediated knockdown. Finally, the fraction of β-cells expressing the β5i subunit is increased in human islets from type 2 diabetes patients. We conclude that β5i is an inducible proteasome subunit dedicated to the degradation of mishandled proinsulin. Copyright © 2020 the American Physiological Society.
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| 7. |
- Sondergaard, E., et al.
(author)
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ERG Controls B Cell Development by Promoting Igh V-to-DJ Recombination
- 2019
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 29:9
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Journal article (peer-reviewed)abstract
- B cell development depends on the coordinated expression and cooperation of several transcription factors. Here we show that the transcription factor ETS-related gene (ERG) is crucial for normal B cell development and that its deletion results in a substantial loss of bone marrow B cell progenitors and peripheral B cells, as well as a skewing of splenic B cell populations. We find that ERG-deficient B lineage cells exhibit an early developmental block at the pre-B cell stage and proliferate less. The cells fail to express the immunoglobulin heavy chain due to inefficient V-to-DJ recombination, and cells that undergo recombination display a strong bias against incorporation of distal V gene segments. Furthermore, antisense transcription at PAX5-activated intergenic repeat (PAIR) elements, located in the distal region of the Igh locus, depends on ERG. These findings show that ERG serves as a critical regulator of B cell development by ensuring efficient and balanced V-to-DJ recombination.
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| 10. |
- Khilji, M. S., et al.
(author)
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The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, low concentrations of interleukin 1 beta
- 2020
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:2
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Journal article (peer-reviewed)abstract
- A central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic beta cells, as this might facilitate autoantigen presentation by beta cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in beta cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes. We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the beta 5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by low concentrations of IL-1 beta stimulating proinsulin biosynthesis. These findings suggest that the beta cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.
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| 16. |
- Bugge, Anne, et al.
(author)
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A Novel Intronic Peroxisome Proliferator-activated Receptor gamma Enhancer in the Uncoupling Protein (UCP) 3 Gene as a Regulator of Both UCP2 and-3 Expression in Adipocytes
- 2010
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:23, s. 17310-17317
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Journal article (peer-reviewed)abstract
- Uncoupling Proteins (UCPs) are integral ion channels residing in the inner mitochondrial membrane. UCP2 is ubiquitously expressed, while UCP3 is found primarily in muscles and adipose tissue. Although the exact molecular mechanism of action is controversial, it is generally agreed that both homologues function to facilitate mitochondrial fatty acid oxidation. UCP2 and -3 expression is activated by the peroxisome proliferator-activated receptors (PPARs), but so far no PPAR response element has been reported in the vicinity of the Ucp2 and Ucp3 genes. Using genome-wide profiling of PPAR gamma occupancy in 3T3-L1 adipocytes we demonstrate that PPAR gamma associates with three chromosomal regions in the vicinity of the Ucp3 locus and weakly with a site in intron 1 of the Ucp2 gene. These sites are isolated from the nearest neighboring sites by >900 kb. The most prominent PPAR gamma binding site in the Ucp2 and Ucp3 loci is located in intron 1 of the Ucp3 gene and is the only site that facilitates PPAR gamma transactivation of a heterologous promoter. This site furthermore transactivates the endogenous Ucp3 promoter, and using chromatin conformation capture we show that it loops out to specifically interact with the Ucp2 promoter and intron 1. Our data indicate that PPAR gamma transactivation of both UCP2 and -3 is mediated through this novel enhancer in Ucp3 intron 1.
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| 19. |
- Ghiasi, S. M., et al.
(author)
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The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets
- 2020
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:12
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Journal article (peer-reviewed)abstract
- Background: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle cells by the prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects islet cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of diabetes. Methods: Apoptosis was measured in human islets shown to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1 beta + IFN gamma INS-1 cells shown to lack Cx43 were used to examine if RG protected human islet cells via Cx43 coupling. To study the mechanisms of action of Cx43-independent effects of RG, NO, IkB alpha degradation, mitochondrial activity, ROS, and insulin mRNA levels were determined. Results: RG reduced cytokine-induced apoptosis similar to 40% in human islets. In Cx43-deficient INS-1 cells, this protective effect was markedly blunted as expected, but unexpectedly, RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels, and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS expression, suggesting that RG blunts cytokine-induced NF-kappa B signaling in insulin-producing cells in a Cx43-independent manner. Conclusion: RG reduces cytokine-induced cell death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-kappa B signaling.
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| 20. |
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| 21. |
- Huang, Lam O., et al.
(author)
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Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities
- 2021
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In: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 3:2, s. 228-243
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Journal article (peer-reviewed)abstract
- Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.
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| 22. |
- Kahn, B, et al.
(author)
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Women in metabolism: part I
- 2015
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In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 21:5, s. 654-657
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Journal article (peer-reviewed)
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| 23. |
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| 24. |
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| 25. |
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| 26. |
- Nolsoe, RL, et al.
(author)
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Association of a microsatellite in FASL to type II diabetes and of the FAS-670G > A genotype to insulin resistance
- 2006
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In: Genes and Immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 7:4, s. 316-321
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Journal article (peer-reviewed)abstract
- Type II diabetes is caused by a failure of the pancreatic beta-cells to compensate for insulin resistance leading to hyperglycaemia. There is evidence for an essential role of an increased beta-cell apoptosis in type II diabetes. High glucose concentrations induce IL-1 beta production in human beta-cells, Fas expression and concomitant apoptosis owing to a constitutive expression of FasL. FASL and FAS map to loci linked to type II diabetes and estimates of insulin resistance, respectively. We have tested two functional promoter polymorphisms, FAS-670 G > A and FASL-844C > T as well as a microsatellite in the 3' UTR of FASL for association to type II diabetes in 549 type II diabetic patients and 525 normal-glucose-tolerant (NGT) control subjects. Furthermore, we have tested these polymorphisms for association to estimates of beta-cell function and insulin resistance in NGT subjects. We found significant association to type II diabetes for the allele distribution of the FASL microsatellite (P-value 0.02, Bonferroni corrected). The FAS-670G > A was associated with homeostasis model assessment insulin resistance index and body mass index (P-values 0.02 and 0.02). We conclude that polymorphisms of FASL and FAS associate with type II diabetes and estimates of insulin resistance in Danish white subjects.
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| 27. |
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| 29. |
- Rønn, SG, et al.
(author)
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Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
- 2008
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:10, s. 1873-1882
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Journal article (peer-reviewed)abstract
- Aims/hypothesis The pro-inflammatory cytokines IL-1 and IFN gamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3 in primary rodent beta cells and diabetic animal models. Methods Using mice with beta cell-specific Socs3 expression and a Socs3-encoding adenovirus construct, we characterised the protective effect of SOCS3 in mouse and rat islets subjected to cytokine stimulation. In transplantation studies of NOD mice and alloxan-treated mice the survival of Socs3 transgenic islets was investigated. Results Socs3 transgenic islets showed significant resistance to cytokine-induced apoptosis and impaired insulin release. Neither glucose-stimulated insulin release, insulin content or glucose oxidation were affected by SOCS3. Rat islet cultures transduced with Socs3-adenovirus displayed reduced cytokine-induced nitric oxide and apoptosis associated with inhibition of the IL-1-induced nuclear factor-kappa B and mitogen-activated protein kinase (MAPK) pathways. Transplanted Socs3 transgenic islets were not protected in diabetic NOD mice, but showed a prolonged graft survival when transplanted into diabetic allogenic BALB/c mice. Conclusions/interpretation SOCS3 inhibits IL-1-induced signalling through the nuclear factor-kappa B and MAPK pathways and apoptosis induced by cytokines in primary beta cells. Moreover, Socs3 transgenic islets are protected in an allogenic transplantation model. SOCS3 may represent a target for pharmacological or genetic engineering in islet transplantation for treatment of type 1 diabetes mellitus.
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| 30. |
- Siersbaek, Majken S., et al.
(author)
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Genome-Wide Profiling of Peroxisome Proliferator-Activated Receptor gamma in Primary Epididymal, Inguinal, and Brown Adipocytes Reveals Depot-Selective Binding Correlated with Gene Expression
- 2012
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In: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 32:17, s. 3452-3463
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Journal article (peer-reviewed)abstract
- Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipocyte differentiation and function. We and others have previously mapped PPAR gamma binding at a genome-wide level in murine and human adipocyte cell lines and in primary human adipocytes. However, little is known about how binding patterns of PPAR gamma differ between brown and white adipocytes and among different types of white adipocytes. Here we have employed chromatin immunoprecipitation combined with deep sequencing to map and compare PPAR gamma binding in in vitro differentiated primary mouse adipocytes isolated from epididymal, inguinal, and brown adipose tissues. While these PPAR gamma binding profiles are overall similar, there are clear depot-selective binding sites. Most PPAR gamma binding sites previously mapped in 3T3-L1 adipocytes can also be detected in primary adipocytes, but there are a large number of PPAR gamma binding sites that are specific to the primary cells, and these tend to be located in closed chromatin regions in 3T3-L1 adipocytes. The depot-selective binding of PPAR gamma is associated with highly depot-specific gene expression. This indicates that PPAR gamma plays a role in the induction of genes characteristic of different adipocyte lineages and that preadipocytes from different depots are differentially preprogrammed to permit PPAR gamma lineage-specific recruitment even when differentiated in vitro.
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