Cell Biology
Our section, based on the second floor of the Sir Alexander Fleming Building at the South Kensington Campus, was established in September 2006 and forms part of the Department’s and the College’s strategic thrust for researching the molecular basis of diabetes. Our focus is on the molecular and cellular mechanisms involved in the control of insulin release and hypothalamic activity in health and disease.
The section presently comprises three PIs.
β-cell physiology
My group is interested in the molecular mechanisms by which glucose regulates the secretion of insulin both acutely and in the longer term. We are using a combination of state of the art imaging approaches and transgenic models to address these problems. Particular interests include understanding the mechanics of the secretory event itself and how this may be affected in models of Type II diabetes.
Rapid confocal imaging of insulin secretion
Impact of Type II diabetes genes on insulin secretion
We are examining how genes identified in Genome Wide Association Studies as effecting the risk of Type II diabetes or impaired glucose homostasis act at the molecular level on the pancreatic β-cell. We use a combination of approaches including cell type specific deletion of the implicated genes, electrophysiology and imaging. (Nicolson et al, 2009; da Silva Xavier et al, 2009)
Role of nutrient regulated protein kinases in β-cell development and function
AMP-activated protein kinase (AMPK) is the founder member of a family of related and evolutionarily-conserved enzymes which sense nutrient concentrations and regulate cell growth and function. We have shown that these play an important role in the control of insulin and other islet hormone secretion and are currently dissecting the upstream and downstream signalling pathways involved. (da Silva Xavier et al, 2000, 2004; Sun et al 2010)
Role of 'disallowed' genes in β-cell function
We have identified a group of 38 genes whose expression is unusually low in the β-cell and which may be disregulated in Type II diabetes. We are examining the transcriptional and post-transcriptional (DNA methylation, microRNAs etc) mechanisms through which these genes are suppressed and the physiological consequences for regulated insulin secretion. (Pullen et al, 2010)
Ca2+ and Zn2+ signalling in the β-cell
We are examining the role of novel second messengers which control the free concentrations of these ions in single cells and developing novel probes to allow their imaging with subcellular resolution. (Vinkenborg et al, 2009; Rutter et al 2006)
Hypothalamic nutrient sensing
Subsets of neurons in the ventromedial hypothalamus respond to hormones, nutrients and other stimuli to control satiety and feeding. The activity of these neurons therefore provides the potential target for drugs to control over-eating and obesity. We are dissecting the intracellular signalling pathways through which regulatory stimuli control the firing of these cells.
Imaging insulin release by total internal reflection fluorescence (TIRF)
News
The Section welcomes new members of staff
Dr David Hodson joined the Section as Lecturer in February 2012 examining inter-islet communication in the intact pancreas.
Dr Shanna Tam has been awarded a one-year Fellowship from EFSD to examine the role of LKB1 in the control of beta cell growth and will join the laboratory in spring 2012.
Dr Gaelle Carrat joined the group in September 2011 as a post-doctoral Fellow examining the role of selected GWAS genes.
Awards and Prizes
In 2011 Professor Rutter was the receipient of a Royal Society Wolfson Research Merit Award.
http://www2.imperial.ac.uk/blog/reporter/2011/05/18/wolfson-awards/
Think zinc: molecular sensor could reveal zinc's role in diseases
Imperial College press release: http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_1-9-2009-16-5-1?newsid=72602
Rutter group publications
Selected publications
Pullen, T.J., Sylow, L, Sun, Halestrap, A.P., Richter, E.A., Rutter, G.A. Over-expression of monocarboxylate transporter-1 (slc16a1) in the pancreatic b cell leads to relative hyperinsulinism during exercise” Diabetes In press (2012)
Leclerc, I., Rutter, G.A., Meur, G., Noordeen, N.A Roles of Ca2+ ions in the Control of ChREBP Nuclear Translocation Journal of Endocrinology Epub Mar 8 (2012) http://dx.doi.org/10.1530/JOE-11-0480
Locke, J.M., da Silva Xavier, G., Rutter, G.A.*, and Harries, L.W. An alternative polyadenylation in TCF7L2 generates isoforms which inhibit TCF-LEF-dependent target genes. Diabetologia, 54(12):3078-82 (2011) *Co-corresponding author http://dx.doi.org/10.1007/s00125-011-2290-6
Noordeen, N.A., Meur, G., Rutter, G.A.* and Leclerc, I. Glucose-induced nuclear shuttling of ChREBP is mediated by sorcin and Ca2+ ions. Diabetes 61(3):574-85 (2011) * Co-corresponding author http://dx.doi.org/10.2337/db10-1329
Semplici, F., Vaxillaire, M., Fogarty, S., Semach, M., Bonnefond, A., Fontes, G., Philippe, J., Meur, G., Diraison, F., Sessions, R.B., Rutter, J., Poitout, V., Froguel, P, and Rutter, G.A. Human mutation within the per-ARNT-sim (Pas) domain-containing protein kinase (PASK) causes basal insulin hypersecretion. J Biol Chem (2011) 286(51):44005-14 (2011) http://dx.doi.org/10.1074/jbc.M111.254995
Li, D., Chen, S., Bellomo, E.A., Tarasov, A.I., Kaut, C., Rutter, G.A. and Li, W.H. Imaging dynamic insulin release using a fluorescent zinc probe, ZIMIR. Proc Natl Acad Sci 108(52):21063-8 (2011) http://dx.doi.org/10.1073/pnas.1109773109
Pullen, T.J., da Silva Xavier, G., Kelsey, G., Rutter, G.A. miR-29a and miR-29b contribute to pancreatic beta-cell specific silencing of Monocarobxylate Transporter 1 (Mct1/slc16a1). Mol Cell Biol Epub Jun 6 (2011) PMID: 21646425 http://dx.doi.org/10.1128/MCB.01433-10
Bellomo, E.A., Meur, G., Rutter, G.A. Glucose regulates free cytosolic Zn2+ concentration, Slc39 (ZiP) and metallothionein gene expression in primary pancreatic islet beta-cells. J Biol Chem Epub May 25 (2011) PMID: 21613223 http://dx.doi.org/10.1074/jbc.M111.246082
Meur, G., Qian, Q., da Silva Xavier, G., Pullen, T.J., Tsuboi, T., McKinnon, C., Fletcher, L., Tavaré, J.M., Hughes, S., Johnson, P., Rutter, G.A. Nucleo-cytosolic shuttling of FOXO1 directly regulates mouse INS2 but not INS1 gene expression in pancreatic beta cells (min6). J Biol Chem Apr 15; 286(15):13647-56 Epub Feb 18 (2011) PMID: 21335550 http://dx.doi.org/10.1074/jbc.M110.204248
da Silva Xavier, G., Farhan H., Kim H., Caxaria S., Johnson P., Hughes S., Bugliani M., Marselli L., Marchetti P., Birzele F., Sun G., Scharfmann R., Rutter J., Siniakowicz K., Weir G., Parker H., Reimann F., Gribble F.M., Rutter G.A. Per-arnt-sim (PAS) domain containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion Diabetologia Apr; 54(4):819-27 2011 Epub Dec 23 (2010) PMID: 21181396 http://dx.doi.org/10.1007/s00125-010-2010-7
Dominguez, V., Raimondi, C., Somanath, S., Bugliani, M., Loder, M.K., Edling, C.E., Divecha, N., da Silva Xavier, G., Marselli, L., Persaud, S.J., Turner, M.D., Rutter, G.A., Marchetti, P., Falasca, M., Maffucci, T. Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells J Biol Chem Epub Dec 2 (2010) PMID: 21127054 http://dx.doi.org/10.1074/jbc.M110.200295
Leclerc, I., Sun, G., Morris, C., Fernandez-Millan, E., Nyerinda, M., Rutter, G.A. AMP-activated protein kinase regulates glucagon secretion from pancreatic alpha cells. Diabetologia Epub Oct 13 (2010) http://dx.doi.org/10.1007/s00125-010-1929-z
da Silva Xaiver, G., Sun, G., Qian, Q, Rutter, G.A. and Leclerc, I. ChREBP regulates Pdx-1 and other glucose-sensitive genes in pancreatic β-cells. Biochem Biophys Res Comm Epub Oct 11 (2010) http://dx.doi.org/10.1016/j.bbrc.2010.10.010
Lam CK, Chari, M., Rutter, G.A. and Lam TK. Hypothalamic nutrient sensing activates forebrain-hindbrain neuronal circuits to regulate glucose production in vivo. Diabetes Epub Sep 24 (2010) http://dx.doi.org/10.2337/db10-0994
Yang,C.S., Lam, C.K.L., Chari, M., Cheung, G.W.C., Kokorovic, A.K., Sun, G., Leclerc, I., Rutter, G.A., Lam, T.K. Hypothalamic AMPK regulates glucose production. Diabetes Suppl 1, A59-A59 (2010) http://dx.doi.org/10.2337/db10-0221
An R., da Silva Xavier G., Semplici F., Vakhshouri S., Hao H.X,. Rutter J., Pagano M.A., Meggio F., Pinna L.A., Rutter G.A. Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization Biochem Biophys Res Commun Epub Jul 15 (2010) PMID: 20637728 http://dx.doi.org/10.1016/j.bbrc.2010.07.035
MBaya, E., Oules, B., Caspersen, C., Tacine, R., Munnich, A., Rotig, A., Rizzuto, R., Rutter, G.A., Paterlini-Brechot, P., and Chami, M. Calcium signaling-dependent mitochondrial dysfunction and bioenergetic regulations in respiratory chain complex II deficiency. Cell Death Diff. Epub May 21 (2010) PMID: 20489732 http://dx.doi.org/10.1038/cdd.2010.51
Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter G.A., Wheeler MB. Beta cell-specific ZnT8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53(8):1656-68 Epub Apr 28 (2010) PMID: 20424817
Sun G, Tarasov AI, McGinty JA, French PM, McDonald A, Leclerc I, Rutter GA. LKB1 deletion with the RIP.Cre-transgene modifies pancreatic {beta}-cell morphology and enhances insulin secretion in vivo. Am J Physiol Endocrinol Metab, 298 (6): E1261-73 Epub Mar 30 (2010) PMID: 20354156
Sun, G., Tarasov, A.I., McGinty, J., McDonald, A., daSilvaXavier, G., Gorman, T., Marley, A., French, P.M., Parker, H., Gribble, F., Reimann, F., Viollet, B., Leclerc, I., Rutter, G.A. Ablation of AMPKα1 and α2 from pancreatic beta cells and RIP.Cre neurons suppresses insulin release in vivo. Diabetologia, 53 (5) 924-36 Epub Mar 11 (2010) PMID: 20221584 http://dx.doi.org/10.1007/s00125-010-1692-1
Pullen, T.J., Khan, AM., Barton, G., Sun., G., and Rutter, G.A. Identification of genes selectively disallowed in the pancreatic islet. Islets, 2(2), 89-95 (2010) PMID: 21099300 http://dx.doi.org/10.4161/isl.2.2.11025
Voronina, S.G., Barrow, S.L., Simpson, A.W., Gerasimenko, O.V., da Silva Xavier, G., Rutter, G.A. Petersen, O.H., and Tepikin, A.V. Dynamic changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells. Gastroenterology, 138(5):1976-87 Epub Jan 25 (2010) PMID: 20102715 http://dx.doi.org/10.1053/j.gastro.2010.01.037
Key publications prior to 2010
Vinkenborg, J.L., Nicolson, T.J., Bellomo, E.A., Koay, M.S., Rutter, G.A.* Merkx, M. Genetically encoded FRET sensors to monitor Zn2+ homeostasis. Nat Methods 6(10):737-40 (2009) * corresponding author http://dx.doi.org/10.1038/NMETH.1368
Nicolson, T.J. Bellomo, E.A., Wijesekara, N., Loder, M.K., Baldwin, J.M., Gyulkhandanyan, A.V., Koshkin, V., Tarasov, A.I., Carzaniga, R., Kronenberger, K., Taneja, T.K., da Silva Xavier, G., Libert, S., Froguel, P., Scharfmann, R., Stetsyuk, V., Ravassard, P., Parker, H., Gribble, F.M., Reimann, F., Sladek, R., Hughes, S.J., Johnson, P.R.V., Masseboeuf, M., Burcelin, R., Baldwin, S.A., Liu, M., Lara-Lemus, R., Arvan, P., Schuit, F.C., Wheeler, M.B., Chimienti, F., Rutter, G.A. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants Diabetes, 58(9):2070-83 (2009) http://dx.doi.org/10.2337/db09-0551
da Silva Xavier, G., Rutter, J., and Rutter G.A. Involvement of PAS kinase in the stimulation of preproinsulin and pancreatic duodenum homeobox-1 gene expression by glucose. Proc Natl Acad Sci 101(22), 8319-8324 (2004) http://dx.doi.org/10.1073/pnas.0307737101
Tsuboi, T., Lippiat, J.D., Ashcroft, F.M. and Rutter G.A. ATP-dependent interaction of the cytosolic domains of the inwardly rectifying K+ channel Kir6.2 revealed by fluorescence resonance energy transfer Proc Natl Acad. Sci 101, 76-81 (2004) http://dx.doi.org/10.1073/pnas.0306347101
Mitchell, K.J., Pinton, P., Varadi, A., Ainscow, E.K., Pozzan, T., Rizzuto, R., and Rutter, G.A. Dense core secretory vesicles revealed as a dynamic Ca2+ store in neuroendocrine cells with a VAMP2.aequorin chimaera J. Cell Biol. 155, 41-51 (2001) http://dx.doi.org/10.1083/jcb.200103145
Tsuboi, T., Zhao, C., Terakawa S. Rutter, G.A. Simultaneous evanescent wave imaging of the vesicle membrane and cargo during a single exocytotic event. Curr Biol. 10:1307-1310 (2000) http://dx.doi.org/10.1016/S0960-9822(00)00756-9
da Silva Xavier, G., Leclerc, I., Salt, I. Doiron, B., Hardie, D.G., Kahn, A., Rutter, G.A. Role of AMP-activated protein kinase in the regulation by glucose of islet beta-cell gene expression Proc. Natl. Acad. Sci 97: 4023-4028 (2000) http://dx.doi.org/10.1073/pnas.97.8.4023
Emmanouilidou, E., Teschemacher, A., Pouli, A.E., Nicholls, L.I., Seward, E.P. and Rutter, G.A. Imaging [Ca2+] changes at the secretory vesicle surface with a recombinant targeted cameleon Curr. Biol 9, 915-918 (1999) http://dx.doi.org/10.1016/S0960-9822(99)80398-4
Rutter, G.A., Burnett, P. Rizzuto, R., Brini, M., Pozzan, T., Tavaré, J.M. and Denton, R.M. Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted aequorin: Significance for the regulation of pyruvate dehydrogenase activity. Proc. Natl. Acad. Sci. 93, 5489-5494 (1996) http://dx.doi.org/10.1073/pnas.93.11.5489
