Publications
61 results found
Martinez-Sanchez A, Pullen TJ, Nguyen-Tu MS, et al., 2015, Repression of acyl-CoA thioesterase 7 (Acot7) in beta cells is required for normal glucose tolerance and the potentiation of glucose-stimulated insulin secretion by fatty acids, DIABETIC MEDICINE, Vol: 32, Pages: 40-40, ISSN: 0742-3071
Kone M, Sun G, Ibberson M, et al., 2014, LKB1 and AMPK differentially regulate pancreatic beta-cell identity, Faseb Journal, Vol: 28, Pages: 4972-4985, ISSN: 1530-6860
Fully differentiated pancreatic b cellsare essential for normal glucose homeostasis in mammals.Dedifferentiation of these cells has been suggestedto occur in type 2 diabetes, impairing insulinproduction. Since chronic fuel excess (“glucotoxicity”)is implicated in this process, we sought here to identifythe potential roles in b-cell identity of the tumor suppressorliver kinase B1 (LKB1/STK11) and the downstreamfuel-sensitive kinase, AMP-activated proteinkinase (AMPK). Highly b-cell-restricted deletion ofeach kinase in mice, using an Ins1-controlled Cre, wastherefore followed by physiological, morphometric,and massive parallel sequencing analysis. Loss of LKB1strikingly (2.0–12-fold, E<0.01) increased the expressionof subsets of hepatic (Alb, Iyd, Elovl2) and neuronal(Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamatesignaling. These changes were partially recapitulatedby the loss of AMPK, which also up-regulated b-cell“disallowed” genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to3.4-fold (E<0.01). Correspondingly, targeted promoterswere enriched for neuronal (Zfp206; P51.3310233)and hypoxia-regulated (HIF1; P52.5310216) transcriptionfactors. In summary, LKB1 and AMPK, through onlypartly overlapping mechanisms, maintain b-cell identityby suppressing alternate pathways leading to neuronal,hepatic, and other characteristics. Selective targetingof these enzymes may provide a new approach tomaintaining b-cell function in some forms of diabetes.—Kone,M., Pullen, T. J., Sun, G., Ibberson, M.,Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S.,Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J.,Thorens, B., Reimann, F., Gribble, F., McGinty, J. A.,Chen, L., French, P. M., Birzele, F., Hildebrandt, T.,Uphues, I., Rutter, G. A. LKB1 and AMPK differentiallyregulate pancreatic b-cell identity.
Pullen TJ, Khan AM, Barton G, et al., 2014, Identification of genes selectively disallowed in the pancreatic islet, ISLETS, Vol: 2, Pages: 89-95, ISSN: 1938-2014
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- Citations: 117
Hodson DJ, Mitchell RK, Marselli L, et al., 2014, ADCY5 couples glucose to insulin secretion in human islets, Diabetes, Vol: 63, Pages: 3009-3021, ISSN: 0012-1797
Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar >8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action.
Carrat GRJ, Pullen TJ, Marselli L, et al., 2014, Roles of the type 2 diabetes- associated gene products Arap1 and StarD10 in the control of insulin secretion, DIABETOLOGIA, Vol: 57, Pages: S63-S64, ISSN: 0012-186X
Nguyen-Tu M-S, Kantor C, Sayers S, et al., 2014, LKB1 and AMPK regulate <i>Nptx2</i> expression and glutamate signalling in pancreatic beta cells, DIABETOLOGIA, Vol: 57, Pages: S48-S48, ISSN: 0012-186X
Pullen TJ, Rutter GA, 2014, Roles of IncRNAs in pancreatic beta cell identity and diabetes susceptibility, Frontiers in Genetics, Vol: 5, ISSN: 1664-8021
Type 2 diabetes usually ensues from the inability of pancreatic beta cells to compensate for incipient insulin resistance. The loss of beta cell mass, function, and potentially beta cell identity contribute to this dysfunction to extents which are debated. In recent years, long non-coding RNAs (lncRNAs) have emerged as potentially providing a novel level of gene regulation implicating critical cellular processes such as pluripotency and differentiation. With over 1000 lncRNAs now identified in beta cells, there is growing evidence for their involvement in the above processes in these cells. While functional evidence on individual islet lncRNAs is still scarce, we discuss how lncRNAs could contribute to type 2 diabetes susceptibility, particularly at loci identified through genome-wide association studies as affecting disease risk.
Martinez-Sanchez A, Pullen TJ, Rutter GA, 2014, Repression of Acot7 in β-Cells Is Required for the Potentiation of GSIS by Fatty Acids, Publisher: AMER DIABETES ASSOC, Pages: A552-A552, ISSN: 0012-1797
Mitchell RK, Marselli L, Pullen TJ, et al., 2014, ADCY5 couples glucose to insulin secretion in human islets, DIABETIC MEDICINE, Vol: 31, Pages: 5-5, ISSN: 0742-3071
Martinez-Sanchez A, Pullen TJ, Rutter GA, 2014, Acyl-CoA thioesterase 7 (Acot7) silencing in beta cells: underlying mechanisms and function, DIABETIC MEDICINE, Vol: 31, Pages: 30-30, ISSN: 0742-3071
Rutter GA, Sun G, Pullen TJ, et al., 2013, LKB1 and AMPK differentially regulate pancreatic beta cell fate, 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S95-S95, ISSN: 0012-186X
Pullen TJ, Rutter GA, 2013, Could IncRNAs contribute to β-cell identity and its loss in Type 2 diabetes?, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 41, Pages: 797-801, ISSN: 0300-5127
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- Citations: 13
Pullen TJ, Rutter GA, 2013, When less is more: the forbidden fruits of gene repression in the adult β-cell, DIABETES OBESITY & METABOLISM, Vol: 15, Pages: 503-512, ISSN: 1462-8902
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- Citations: 80
Rutter GA, Pullen TJ, 2012, Comment on: Schuit et al. β-Cell-specific gene repression: a mechanism to protect against inappropriate or maladjusted insulin secretion? Diabetes 2012;61:969-975., Diabetes, Vol: 61
Pullen TJ, Rutter GA, 2012, An islet-specific long non-coding RNA (lncRNA) expressed from the Pdx1 locus regulates Pdx1 activity, DIABETOLOGIA, Vol: 55, Pages: S94-S94, ISSN: 0012-186X
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- Citations: 2
Tarasov AI, Semplici F, Ravier MA, et al., 2012, The mitochondrial Ca<SUP>2+</SUP> uniporter MCU is essential for glucose and sulfonylurea sensing by mouse pancreatic beta cells, DIABETOLOGIA, Vol: 55, Pages: S47-S47, ISSN: 0012-186X
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- Citations: 1
Tarasov AI, Semplici F, Ravier MA, et al., 2012, The mitochondrial Ca2+ uniporter MCU Is essential for glucose-induced ATP increases in pancreatic beta-cells, PLOS One, Vol: 7, ISSN: 1932-6203
Glucose induces insulin release from pancreatic β-cells by stimulating ATP synthesis, membrane depolarisation and Ca2+ influx. As well as activating ATP-consuming processes, cytosolic Ca2+ increases may also potentiate mitochondrial ATP synthesis. Until recently, the ability to study the role of mitochondrial Ca2+ transport in glucose-stimulated insulin secretion has been hindered by the absence of suitable approaches either to suppress Ca2+ uptake into these organelles, or to examine the impact on β-cell excitability. Here, we have combined patch-clamp electrophysiology with simultaneous real-time imaging of compartmentalised changes in Ca2+ and ATP/ADP ratio in single primary mouse β-cells, using recombinant targeted (Pericam or Perceval, respectively) as well as entrapped intracellular (Fura-Red), probes. Through shRNA-mediated silencing we show that the recently-identified mitochondrial Ca2+ uniporter, MCU, is required for depolarisation-induced mitochondrial Ca2+ increases, and for a sustained increase in cytosolic ATP/ADP ratio. By contrast, silencing of the mitochondrial Na+-Ca2+ exchanger NCLX affected the kinetics of glucose-induced changes in, but not steady state values of, cytosolic ATP/ADP. Exposure to gluco-lipotoxic conditions delayed both mitochondrial Ca2+ uptake and cytosolic ATP/ADP ratio increases without affecting the expression of either gene. Mitochondrial Ca2+ accumulation, mediated by MCU and modulated by NCLX, is thus required for normal glucose sensing by pancreatic β-cells, and becomes defective in conditions mimicking the diabetic milieu.
Pullen TJ, Sylow L, Sun G, et al., 2012, Overexpression of Monocarboxylate Transporter-1 (<i>Slc16a1</i>) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise, DIABETES, Vol: 61, Pages: 1719-1725, ISSN: 0012-1797
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- Citations: 75
Pullen TJ, Xavier GDS, Kelsey G, et al., 2011, miR-29a and miR-29b Contribute to Pancreatic β-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1), MOLECULAR AND CELLULAR BIOLOGY, Vol: 31, Pages: 3182-3194, ISSN: 0270-7306
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- Citations: 215
Meur G, Qian Q, Xavier GDS, et al., 2011, Nucleo-cytosolic Shuttling of FoxO1 Directly Regulates Mouse <i>Ins2</i> but Not <i>Ins1</i> Gene Expression in Pancreatic Beta Cells (MIN6), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 13647-13656, ISSN: 0021-9258
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- Citations: 25
Rutter GA, Pullen TJ, 2010, miR-29a, miR-29b and miR-124 contribute to pancreatic beta cell specific silencing of monocarboxylate transporter 1 (<i>Mct1</i>/<i>Slc16a1</i>), 46th Annual Meeting of the European-Association-for-the- Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S35-S36, ISSN: 0012-186X
Pullen TJ, Rutter GA, 2010, Inducible expression of Monocarboxylate Transporter 1 (Mct1/Slc16a1) in the beta cell of transgenic mice: a model of exercise induced hyperinsulinism, 46th Annual Meeting of the European-Association-for-the- Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S36-S36, ISSN: 0012-186X
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- Citations: 1
Noordeen NA, Khera TK, Sun G, et al., 2010, Carbohydrate-Responsive Element-Binding Protein (ChREBP) Is a Negative Regulator of ARNT/HIF-1β Gene Expression in Pancreatic Islet β-Cells, DIABETES, Vol: 59, Pages: 153-160, ISSN: 0012-1797
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- Citations: 55
Pullen TJ, Xavier GD, Kelsey G, et al., 2008, Beta cell specific silencing of the plasma membrane monocarboxylate transporter MCT1 (SLC16A1) is not effected through methylation of its promoter, 44th Annual Meeting of the European-Association-for-the-Study-of-Diabetes, Pages: S195-S195
Pullen TJ, Xavier GDS, Kelsey G, et al., 2008, Beta cell specific silencing of the plasma membrane monocarboxylate transporter <i>MCT1</i> (<i>SLC16A1</i>) is not effected through methylation of its promoter, DIABETOLOGIA, Vol: 51, Pages: S195-S195, ISSN: 0012-186X
Michaux G, Pullen TJ, Haberichter SL, et al., 2006, P-selectin binds to the D′-D3 domains of von Willebrand factor in Weibel-Palade bodies, BLOOD, Vol: 107, Pages: 3922-3924, ISSN: 0006-4971
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- Citations: 48
Ginger ML, Ngazoa ES, Pereira CA, et al., 2005, Intracellular positioning of isoforms explains an unusually large adenylate kinase gene family in the parasite <i>Trypanosoma brucei</i>, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 280, Pages: 11781-11789, ISSN: 0021-9258
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- Citations: 44
Pullen TJ, Ginger ML, Gaskell SJ, et al., 2004, Protein targeting of an unusual, evolutionarily conserved adenylate kinase to a eukaryotic flagellum, MOLECULAR BIOLOGY OF THE CELL, Vol: 15, Pages: 3257-3265, ISSN: 1059-1524
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- Citations: 58
Bastin P, Pullen TJ, Moreira-Leite FF, et al., 2000, Inside and outside of the trypanosome flagellum: a multifunctional organelle, MICROBES AND INFECTION, Vol: 2, Pages: 1865-1874, ISSN: 1286-4579
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- Citations: 50
Bastin P, Pullen TJ, Sherwin T, et al., 1999, Protein transport and flagellum assembly dynamics revealed by analysis of the paralysed trypanosome mutant <i>snl</i>-1, JOURNAL OF CELL SCIENCE, Vol: 112, Pages: 3769-3777, ISSN: 0021-9533
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- Citations: 78
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