title: Species-specific vesicular monoamine transporter 2 (VMAT2) expression in mammalian pancreatic beta cells: implications for optimising radioligand-based human beta cell mass (BCM) imaging in animal models.
abstract: OBJECTIVE
  Imaging of beta cell mass (BCM) is a major challenge in diabetes research. The vesicular monoamine transporter 2 (VMAT2) is abundantly expressed in human beta cells. Radiolabelled analogues of tetrabenazine (TBZ; a low-molecular-weight, cell-permeant VMAT2-selective ligand) have been employed for pancreatic islet imaging in humans. Since reports on TBZ-based VMAT2 imaging in rodent pancreas have been fraught with confusion, we compared VMAT2 gene expression patterns in the mouse, rat, pig and human pancreas, to identify appropriate animal models with which to further validate and optimise TBZ imaging in humans.
  
  
  METHODS
  We used a panel of highly sensitive VMAT2 antibodies developed against equivalently antigenic regions of the transporter from each species in combination with immunostaining for insulin and species-specific in situ hybridisation probes. Individual pancreatic islets were obtained by laser-capture microdissection and subjected to analysis of mRNA expression of VMAT2.
  
  
  RESULTS
  The VMAT2 protein was not expressed in beta cells in the adult pancreas of common mouse or rat laboratory strains, in contrast to its expression in beta cells (but not other pancreatic endocrine cell types) in the pancreas of pigs and humans. VMAT2- and tyrosine hydroxylase co-positive (catecholaminergic) innervation was less abundant in humans than in rodents. VMAT2-positive mast cells were identified in the pancreas of all species.
  
  
  CONCLUSIONS
  Primates and pigs are suitable models for TBZ imaging of beta cells. Rodents, because of a complete lack of VMAT2 expression in the endocrine pancreas, are a 'null' model for assessing interference with BCM measurements by VMAT2-positive mast cells and sympathetic innervation in the pancreas.
authors: Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Robert-Koch-Straße 8, 35037 Marburg, Germany. mkh.schafer@staff.uni-marburg.de
authors: M K-H
authors: MK
authors: Schäfer
authors: N R
authors: NR
authors: Hartwig
authors: N
authors: N
authors: Kalmbach
authors: M
authors: M
authors: Klietz
authors: M
authors: M
authors: Anlauf
authors: L E
authors: LE
authors: Eiden
authors: E
authors: E
authors: Weihe
mesh_terms: D000368:Aged; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009411:Nerve Endings / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000276:immunology / Q000294:innervation / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D013045:Species Specificity; D034421:Sus scrofa; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; C493452:SLC18A2 protein, human; C493453:Slc18a2 protein, mouse; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D013747:Tetrabenazine
references: FASEB J. 2000 Dec;14(15):2435-49
references: 11099461
references: J Mol Histol. 2008 Oct;39(5):543-51
references: 18791800
references: Endocrinology. 2004 Oct;145(10):4513-21
references: 15231694
references: J Nucl Med. 2012 Jun;53(6):908-16
references: 22573821
references: Cell Physiol Biochem. 2005;15(1-4):183-94
references: 15665528
references: J Nucl Med. 2010 Sep;51(9):1439-46
references: 20720057
references: J Neurosci. 2008 Sep 24;28(39):9850-6
references: 18815269
references: Nucl Med Biol. 2008 Nov;35(8):825-37
references: 19026944
references: J Histochem Cytochem. 2003 Aug;51(8):1027-40
references: 12871984
references: J Comp Neurol. 2005 Nov 21;492(3):370-9
references: 16217790
references: J Neurosci. 2006 Apr 26;26(17):4638-43
references: 16641244
references: Proc Natl Acad Sci U S A. 1996 May 14;93(10):5166-71
references: 8643547
references: J Nucl Med. 2010 Sep;51(9):1480-5
references: 20720042
references: Diabetes Obes Metab. 2008 Nov;10 Suppl 4:98-108
references: 18834437
references: Biochem Biophys Res Commun. 2011 Sep 2;412(3):413-8
references: 21820405
references: J Mol Med (Berl). 2008 Jan;86(1):5-16
references: 17665159
references: J Cereb Blood Flow Metab. 2006 Sep;26(9):1198-212
references: 16421508
references: Pflugers Arch. 2004 Feb;447(5):636-40
references: 12827358
references: J Clin Endocrinol Metab. 2008 Mar;93(3):1046-53
references: 18073315
references: Nucl Med Biol. 2010 Apr;37(3):357-63
references: 20346875
references: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10993-7
references: 1438304
references: FASEB J. 2000 Dec;14(15):2396-400
references: 11099457
references: FEBS Lett. 1994 Jan 24;338(1):16-22
references: 8307150
references: Ann N Y Acad Sci. 2011 Jan;1216:86-98
references: 21272013
references: Ann Neurol. 1996 Dec;40(6):873-84
references: 9007092
references: J Mol Neurosci. 1994 Fall;5(3):149-64
references: 7654518
references: FEBS Lett. 1993 Nov 29;335(1):27-32
references: 7902299
references: Nucl Med Biol. 2010 Nov;37(8):869-71
references: 21055616
references: Curr Med Chem. 2006;13(23):2761-73
references: 17073627
references: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20719-24
references: 22143775
references: Nucl Med Biol. 2006 Oct;33(7):855-64
references: 17045165
references: J Neurosci. 1995 Sep;15(9):6179-88
references: 7666200
references: J Nucl Med. 2010 Sep;51(9):1335-6
references: 20720043
references: J Nucl Med. 2010 Jul;51(7):1001-4
references: 20554742
references: Nucl Med Biol. 2007 Apr;34(3):233-7
references: 17383572