title: Aged insulin granules display reduced microtubule-dependent mobility and are disposed within actin-positive multigranular bodies.
abstract: Insulin secretion is key for glucose homeostasis. Insulin secretory granules (SGs) exist in different functional pools, with young SGs being more mobile and preferentially secreted. However, the principles governing the mobility of age-distinct SGs remain undefined. Using the time-reporter insulin-SNAP to track age-distinct SGs we now show that their dynamics can be classified into three components: highly dynamic, restricted, and nearly immobile. Young SGs display all three components, whereas old SGs are either restricted or nearly immobile. Both glucose stimulation and F-actin depolymerization recruit a fraction of nearly immobile young, but not old, SGs for highly dynamic, microtubule-dependent transport. Moreover, F-actin marks multigranular bodies/lysosomes containing aged SGs. These data demonstrate that SGs lose their responsiveness to glucose stimulation and competence for microtubule-mediated transport over time while changing their relationship with F-actin.
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany;
authors: Peter
authors: P
authors: Hoboth
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany;
authors: Andreas
authors: A
authors: Müller
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany;
authors: Anna
authors: A
authors: Ivanova
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany;
authors: Hassan
authors: H
authors: Mziaut
authors: Department of Systems Immunology and Braunshweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors: Jaber
authors: J
authors: Dehghany
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany;
authors: Anke
authors: A
authors: Sönmez
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany;
authors: Martina
authors: M
authors: Lachnit
authors: Department of Systems Immunology and Braunshweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany;
authors: Michael
authors: M
authors: Meyer-Hermann
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; and Faculty of Bioengineering and Bioinformatics, Moscow State University, 119234 Moscow, Russia.
authors: Yannis
authors: Y
authors: Kalaidzidis
authors: Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, and German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; and michele.solimena@tu-dresden.de.
authors: Michele
authors: M
authors: Solimena
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D007328:Insulin / Q000502:physiology*; D018613:Microscopy, Confocal; D008870:Microtubules / Q000502:physiology*; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D000199:Actins; D007328:Insulin
keywords: Bayesian probability theory; diabetes; islets; processivity; secretion
references: Eur J Clin Invest. 2002 Jun;32 Suppl 3:3-13
references: 12028370
references: J Cell Sci. 1998 Feb;111 ( Pt 3):303-12
references: 9427679
references: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):9955-9
references: 15226507
references: Diabetes. 2013 Nov;62(11):3687-96
references: 23929935
references: Science. 1972 Mar 10;175(4026):1128-30
references: 4551150
references: Endocrinology. 1992 Jan;130(1):167-78
references: 1370150
references: Cell Metab. 2010 Aug 4;12(2):117-29
references: 20674857
references: Traffic. 2004 Oct;5(10):750-62
references: 15355511
references: J Cell Biol. 1984 Jan;98(1):222-8
references: 6368567
references: Cell. 2005 Sep 9;122(5):735-49
references: 16143105
references: Diabetes. 1975 Oct;24(10):892-901
references: 1100458
references: Diabetologia. 1991 Nov;34(11):767-78
references: 1769434
references: Nature. 2003 Mar 13;422(6928):176-80
references: 12634788
references: Diabetes. 2002 Feb;51 Suppl 1:S60-7
references: 11815460
references: Biotechniques. 2006 Aug;41(2):167-70, 172, 174-5
references: 16925018
references: J Cell Biol. 1982 Apr;93(1):164-74
references: 7040413
references: Eur J Clin Invest. 1975 Nov 21;5(6):477-85
references: 811472
references: Mol Biol Cell. 2013 Feb;24(3):319-30
references: 23223571
references: Diabetologia. 2013 Feb;56(2):359-69
references: 23132338
references: Science. 1976 Jan 9;191(4222):88-90
references: 1108194
references: Histochem J. 1980 Jul;12(4):381-403
references: 7440248
references: Annu Rev Physiol. 1990;52:625-45
references: 2184771
references: Chem Biol. 2003 Apr;10(4):313-7
references: 12725859
references: Endocrinology. 1982 Apr;110(4):1183-8
references: 6174318
references: J Clin Invest. 1969 Dec;48(12):2309-19
references: 5355342
references: Curr Biol. 2007 Jun 19;17(12):R478-86
references: 17580082
references: Diabetes. 2002 Feb;51 Suppl 1:S74-82
references: 11815462
references: J Cell Sci. 2006 May 15;119(Pt 10):2156-67
references: 16638805
references: Traffic. 2008 Jul;9(7):1191-203
references: 18397364
references: Diabetologia. 2012 Oct;55(10):2693-702
references: 22814762
references: Mol Biol Cell. 1994 Nov;5(11):1199-213
references: 7865885
references: J Cell Biol. 2007 May 21;177(4):695-705
references: 17502420
references: J Clin Invest. 2011 Jun;121(6):2118-25
references: 21633180
references: Nat Methods. 2012 Jul;9(7):676-82
references: 22743772
references: J Clin Invest. 1973 May;52(5):1041-51
references: 4573352
references: EMBO J. 2003 Aug 1;22(15):3844-54
references: 12881419
references: Nat Methods. 2008 Jul;5(7):605-7
references: 18536722
references: PLoS One. 2010;5(9):e12870
references: 20877725
references: Diabetologia. 1987 May;30(5):348-53
references: 3301485
references: News Physiol Sci. 2000 Apr;15:72-77
references: 11390882
references: Int J Biol Macromol. 2006 Aug 15;39(1-3):66-76
references: 16503347
references: Mol Cell Endocrinol. 1981 Jan;21(1):75-84
references: 7202836
references: Biochem J. 2004 Jul 1;381(Pt 1):13-8
references: 15128287
references: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8704-9
references: 15939893
references: J Cell Biol. 2005 Oct 10;171(1):99-109
references: 16216924
references: Proc Natl Acad Sci U S A. 1977 Feb;74(2):628-32
references: 191819
references: J Biol Chem. 1980 Jul 10;255(13):6003-6
references: 6993463
references: Ann N Y Acad Sci. 1986;466:813-31
references: 3524374
references: J Cell Sci. 2002 Nov 1;115(Pt 21):4177-89
references: 12356920
references: Science. 1982 Oct 1;218(4567):56-8
references: 6181562
references: Diabetes. 1972;21(2 Suppl):594-604
references: 4559921
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19333-8
references: 18040047
references: Biochem Biophys Res Commun. 2003 Nov 14;311(2):272-82
references: 14592410
references: Biochem J. 1998 Jun 15;332 ( Pt 3):593-610
references: 9620860
references: Endocrinology. 1968 Sep;83(3):572-84
references: 4877098
references: PLoS One. 2010;5(10):e13290
references: 20948964
references: Mol Biol Cell. 2005 Jun;16(6):2670-80
references: 15788565
references: Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15929-34
references: 17893335
references: Methods. 2004 Apr;32(4):437-44
references: 15003606
references: Diabetologia. 2012 Apr;55(4):1013-23
references: 22252472
references: J Clin Endocrinol Metab. 2001 Dec;86(12):5824-9
references: 11739446
references: Acta Endocrinol (Copenh). 1967 Jun;55(2):278-304
references: 5338206
references: Diabetes. 1972 Oct;21(10):987-98
references: 4561331
references: Mol Biol Cell. 2010 Jan 1;21(1):87-94
references: 19889833
references: Endocrinology. 1975 Jul;97(1):178-88
references: 1140167
references: J Cell Sci. 2005 Dec 15;118(Pt 24):5873-84
references: 16317050
references: J Biol Chem. 2013 Sep 6;288(36):25851-64
references: 23867458