Short Telomeres Compromise β-Cell Signaling and Survival
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{"title"=>"Short telomeres compromise β-cell signaling and survival", "type"=>"journal", "authors"=>[{"first_name"=>"Nini", "last_name"=>"Guo", "scopus_author_id"=>"7102597753"}, {"first_name"=>"Erin M.", "last_name"=>"Parry", "scopus_author_id"=>"22836512800"}, {"first_name"=>"Luo Sheng", "last_name"=>"Li", "scopus_author_id"=>"8127549200"}, {"first_name"=>"Frant", "last_name"=>"Kembou", "scopus_author_id"=>"37017246100"}, {"first_name"=>"Naudia", "last_name"=>"Lauder", "scopus_author_id"=>"23393245600"}, {"first_name"=>"Mehboob A.", "last_name"=>"Hussain", "scopus_author_id"=>"7401576403"}, {"first_name"=>"Per Olof", "last_name"=>"Berggren", "scopus_author_id"=>"7101706643"}, {"first_name"=>"Mary", "last_name"=>"Armanios", "scopus_author_id"=>"9940730700"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-79952500119", "doi"=>"10.1371/journal.pone.0017858", "sgr"=>"79952500119", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pmid"=>"21423765", "issn"=>"19326203", "pui"=>"361419324"}, "id"=>"1f149dab-1ed2-3317-8cd7-2e685076e377", "abstract"=>"The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis.", "link"=>"http://www.mendeley.com/research/short-telomeres-compromise-%CE%B2cell-signaling-survival", "reader_count"=>41, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>5, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>5, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Nursing and Health Professions"=>2, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>17, "Medicine and Dentistry"=>14, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>3, "Italy"=>1, "Switzerland"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/791690"], "description"=>"<p><b>A</b>. Dynamic insulin secretion in islets from mTR<sup>−/−</sup>G<sub>4</sub> mice compared with wild-type mice. Bars above the traces indicate the duration of stimulation. 3G, 11G, 16.7G+Arg and 25KCl indicate 3 mM and 11 mM glucose, 16.7 mM glucose plus 20 mM Arginine, and 25 mM KCl, respectively. CCh indicates carbachol. Insulin was measured every 2 minutes. Data are mean insulin level (ng/ng DNA). * Indicates P-value<0.05 and ** ≤0.01 (one-sided). <b>B</b>. Measurements of mitochondrial membrane potential in response to 11 mM glucose in islets from mTR<sup>−/−</sup>G<sub>4</sub> mice. The rhodamine 123 fluorescence decreases when the mitochondrial membrane polarizes. <b>C</b>. Data are means of decrease in % rhodamine 123 fluorescence normalized to carbonyl cyanide 4-(trifluoro-methoxy) phenylhydrazone (FCCP) depolarization. <b>D</b>. Decreased Δ peak [Ca<sup>2+</sup>]<sub>i</sub> values in islets from mTR<sup>−/−</sup>G<sub>4</sub> and control mice after stimulation with 11 mM glucose. (<b>E</b>) and (<b>F</b>) Fura-2 fluorescence ratio is shown. Bars above the traces indicate the duration of stimulation. 3G and 11G indicate 3 mM and 11 mM glucose, respectively. The traces are representatives of 12–13 experiments from four islet preparations. <b>G</b>. Glucose stimulated fast [Ca<sup>2+</sup>]<sub>i</sub> oscillation frequency in isolated islets from mTR<sup>−/−</sup>G<sub>4</sub> and control mice. <b>H</b>. Effects of adding 2.56 mM CaCl<sub>2</sub> in the perfusion chamber on changes in [Ca<sup>2+</sup>]<sub>i</sub>, indicating Ca<sup>2+</sup> influx over the plasma membrane. Example tracings of Fura-2 fluorescence ratio are shown. Bars above the traces indicate the duration of stimulation. 0 Ca<sup>2+</sup> and 2.56 Ca<sup>2+</sup> indicate 0 mM CaCl<sub>2</sub> plus 2 mM EGTA and 2.56 mM CaCl<sub>2</sub>, respectively. The traces are representatives of 10 experiments from four islet preparations. <b>I</b>. Means in Δfura-2 fluorescence ratio is shown for (<b>H</b>). Mice were 10 months old (wild-type n = 5, mTR<sup>−/−</sup>G<sub>4</sub> n = 6). Error bars represent SEM. For <b>B–I</b>, *, ** and *** indicate two-sided P-value<0.05, 0.01 and 0.001, respectively.</p>", "links"=>[], "tags"=>["insulin", "mitochondrial", "handling", "islets"], "article_id"=>462048, "categories"=>["Physiology", "Cell Biology", "Genetics", "Chemistry"], "users"=>["Nini Guo", "Erin M. Parry", "Luo-Sheng Li", "Frant Kembou", "Naudia Lauder", "Mehboob A. Hussain", "Per-Olof Berggren", "Mary Armanios"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017858.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impaired_insulin_release_mitochondrial_function_and_Ca_2_handling_in_islets_with_short_telomeres_/462048", "title"=>"Impaired insulin release, mitochondrial function and Ca<sup>2+</sup> handling in islets with short telomeres.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-10 00:34:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/791818"], "description"=>"<p><b>A</b>. DNA damage foci in β-cells from mTR<sup>+/−</sup> late generation mice were detected by immunofluorescence against 53BP1 (green) in nuclei (blue). Analysis was limited to insulin positive cells and cells were deemed positive if they had at least one focus (n = 5 mice/group, 4 months old). <b>B</b>. Immunofluorescence images from wild-type and mTR<sup>+/−</sup> mice with short telomeres. Proliferating β-cells are positive for both insulin (green) and Ki-67 (red) (n = 5 mice/group, 50 islets/mouse, 6 weeks old). <b>C</b>. The percent of β-cells with incorporated EdU was lower in mTR<sup>−/−</sup>G<sub>4</sub> C57BL/6 mice after a 14 day pulse (n = 5/group, 50 islets/mouse, 6 months old). <b>D</b>. Relative expression of p16<i><sup>INK4a</sup></i> in islets shows a gradual increase with age in wild-type mice. mTR<sup>−/−</sup>G<sub>4</sub> mice have higher levels at the age groups shown. <b>E</b>. p16<i><sup>INK4a</sup></i> expression in islets was not increased in mTR<sup>−/−</sup>G1 mice. For <b>D</b> and <b>E</b>, n = 3–6 mice/timepoint. <b>F</b>. Heat map of mRNA microarray data shows differential expression profiles in wild-type compared with mTR<sup>−/−</sup>G<sub>4</sub> mice. The red color expresses genes that are up-regulated and green down-regulated genes. The fold-change based on color is shown in the key below <b>F</b>. Heat map is based on genes with 1.5-fold expression change (n = 3 mice/group, 15 months old). Values were normalized by subtracting the mean of all samples. Fold change indicated in the key is log<sub>2</sub>-based. <b>G</b>. β-cell relevant pathways that are altered in the gene ontology analysis plotted relative to the significance of the P-value. Only pathways with P-value<0.01 were analyzed. The number of genes altered relative to the total retrieved is shown to the right of the bar graph. <b>H</b>. qRT-PCR verification of Reg gene family expression shows significant increases in mTR<sup>−/−</sup>G<sub>4</sub> mice (n = 4 mice/group, 15 months old). Error bars represent SEM. * indicates two-sided P-value<0.05 and ** P-value<0.01.</p>", "links"=>[], "tags"=>["mice", "telomeres", "hallmarks"], "article_id"=>462184, "categories"=>["Physiology", "Cell Biology", "Genetics", "Chemistry"], "users"=>["Nini Guo", "Erin M. Parry", "Luo-Sheng Li", "Frant Kembou", "Naudia Lauder", "Mehboob A. Hussain", "Per-Olof Berggren", "Mary Armanios"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017858.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Islets_from_mice_with_short_telomeres_have_hallmarks_of_senescence_/462184", "title"=>"Islets from mice with short telomeres have hallmarks of senescence.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-10 00:36:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/791943"], "description"=>"<p><b>A</b>. Two hour glucose tolerance test of Ins2<sup>C96Y/WT</sup> mTR<sup>−/−</sup>iG<sub>4</sub> with short telomeres shows more severe impairments compared with Ins2<sup>C96Y/WT</sup> mice. <b>B</b>. Ins2<sup>C96Y/WT</sup>mTR<sup>−/−</sup>iG<sub>4</sub> mice have decreased β-cell mass compared with Ins2<sup>C96Y/WT</sup> mice. This decrease is associated with lower basal serum insulin levels (<b>C</b>). <b>D</b>. Representative images of TUNEL (red) co-staining with insulin (green) shows an increase in β-cell apoptosis as quantitated in the bar graph. Data shown are from 8 month old females (n = 5–10 mice/group). Error bars represent SEM. * indicates two-sided P-value<0.05.</p>", "links"=>[], "tags"=>["telomeres", "worsen", "severity", "akita", "mice"], "article_id"=>462294, "categories"=>["Physiology", "Cell Biology", "Genetics", "Chemistry"], "users"=>["Nini Guo", "Erin M. Parry", "Luo-Sheng Li", "Frant Kembou", "Naudia Lauder", "Mehboob A. Hussain", "Per-Olof Berggren", "Mary Armanios"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017858.g004", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Short_telomeres_worsen_diabetes_severity_in_Akita_mice_and_cause_946_cell_loss_/462294", "title"=>"Short telomeres worsen diabetes severity in Akita mice and cause β-cell loss.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-10 00:38:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/396441", "https://ndownloader.figshare.com/files/396486", "https://ndownloader.figshare.com/files/396519", "https://ndownloader.figshare.com/files/396543", "https://ndownloader.figshare.com/files/396574", "https://ndownloader.figshare.com/files/396601", "https://ndownloader.figshare.com/files/396641"], "description"=>"<div><p>The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In <em>ex vivo</em> studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca<sup>2+</sup> influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16<em><sup>INK4a</sup></em>. Specifically, we identified gene expression changes in pathways which are essential for Ca<sup>2+</sup>-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis.</p> </div>", "links"=>[], "tags"=>["telomeres", "signaling"], "article_id"=>138315, "categories"=>["Physiology", "Cell Biology", "Genetics", "Chemistry"], "users"=>["Nini Guo", "Erin M. Parry", "Luo-Sheng Li", "Frant Kembou", "Naudia Lauder", "Mehboob A. Hussain", "Per-Olof Berggren", "Mary Armanios"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017858.s001", "https://dx.doi.org/10.1371/journal.pone.0017858.s002", "https://dx.doi.org/10.1371/journal.pone.0017858.s003", "https://dx.doi.org/10.1371/journal.pone.0017858.s004", "https://dx.doi.org/10.1371/journal.pone.0017858.s005", "https://dx.doi.org/10.1371/journal.pone.0017858.s006", "https://dx.doi.org/10.1371/journal.pone.0017858.s007"], "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Short_Telomeres_Compromise_Cell_Signaling_and_Survival/138315", "title"=>"Short Telomeres Compromise β-Cell Signaling and Survival", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-03-10 02:18:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/791594"], "description"=>"<p><b>A</b>. mTR<sup>+/−</sup> with short telomeres have fasting hyperglycemia compared with wild-type mice (n = 25/group). <b>B</b>. Higher mean serum glucose during an intraperitoneal 2 hour glucose tolerance test in mice with short telomeres (n = 25/group). <b>C</b>. mTR<sup>+/−</sup> mice with short telomeres have lower fasting insulin levels. <b>D</b>. The fasting insulin is lower even when corrected for serum glucose. <b>E</b>. When challenged with glucose, mTR<sup>+/−</sup> with short telomeres have lower insulin levels. <b>F</b>. Insulin tolerance test shows mTR<sup>+/−</sup> mice with short telomeres have intact peripheral insulin sensitivity. Serum glucose was measured after insulin injection at the timepoints shown. Mice were 3–4 months of age. For <b>C–F</b>, n = 10–14/group. Error bars represent SEM. * indicates two-sided P-value<0.05.</p>", "links"=>[], "tags"=>["telomeres", "defective", "insulin"], "article_id"=>461956, "categories"=>["Physiology", "Cell Biology", "Genetics", "Chemistry"], "users"=>["Nini Guo", "Erin M. Parry", "Luo-Sheng Li", "Frant Kembou", "Naudia Lauder", "Mehboob A. Hussain", "Per-Olof Berggren", "Mary Armanios"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017858.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mice_with_short_telomeres_have_defective_insulin_secretion_/461956", "title"=>"Mice with short telomeres have defective insulin secretion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-10 00:32:36"}

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Relative Metric

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Net::HTTPTooManyRequests

Source
Scopus
Time
2019-08-27 18:06:04 UTC
Target URL
https://api.elsevier.com/content/search/index:SCOPUS?query=DOI(10.1371%2Fjournal.pone.0017858)
Trace

/app/models/concerns/networkable.rb:21:in `get_result'
/app/models/source.rb:165:in `get_data'
/app/models/retrieval_status.rb:47:in `perform_get_data'
/app/jobs/source_job.rb:52:in `block (2 levels) in perform'
/app/jobs/source_job.rb:51:in `block in perform'
/app/jobs/source_job.rb:35:in `each'
/app/jobs/source_job.rb:35:in `perform'