title: The impact of type 1 diabetes mellitus on corneal epithelial nerve morphology and the corneal epithelium.
abstract: Diabetic corneal neuropathy can result in chronic, sight-threatening corneal pathology. Although the exact etiology is unknown, it is believed that a reduction in corneal sensitivity and loss of neurotrophic support contributes to corneal disease. Information regarding the relationship between nerve loss and effects on the corneal epithelium is limited. We investigated changes in the corneal epithelium and nerve morphology using three-dimensional imaging in vivo and in situ in a streptozotocin-induced diabetic mouse model. Streptozotocin-treated mice showed increased levels of serum glucose and growth retardation consistent with a severe diabetic state. A reduction in the length of the subbasal nerve plexus was evident after 6 weeks of disease. Loss of the subbasal nerve plexus was associated with corneal epithelial thinning and a reduction in basal epithelial cell density. In contrast, loss of the terminal epithelial nerves was associated with animal age. Importantly, this is the first rodent model of type 1 diabetes that shows characteristics of corneal epithelial thinning and a reduction in basal epithelial cell density, both previously have been documented in humans with diabetic corneal neuropathy. These findings indicate that in type 1 diabetes, nerve fiber damage is evident in the subbasal nerve plexus before terminal epithelial nerve loss and that neurotrophic support from both the subbasal nerve plexus and terminal epithelial nerves is essential for the maintenance of corneal epithelial homeostasis.
authors.affiliation: Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cai
authors.affiliation: Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Meifang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: W Matthew
authors.initials: WM
authors.lastname: Petroll
authors.affiliation: Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Vindhya
authors.initials: V
authors.lastname: Koppaka
authors.affiliation: Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: danielle.robertson@utsouthwestern.edu.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D002452:Cell Count; D054893:Cone-Beam Computed Tomography; D003315:Cornea / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D003316:Corneal Diseases / Q000209:etiology / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000294:innervation* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009412:Nerve Fibers / Q000473:pathology; D013311:Streptozocin
chemical_list: D001786:Blood Glucose; D013311:Streptozocin
references.citation: Exp Eye Res. 2013 Oct;115:255-62
references.pmid: 23920154
references.citation: Curr Eye Res. 2009 Oct;34(10):905-11
references.pmid: 19895318
references.citation: Invest Ophthalmol Vis Sci. 2000 Sep;41(10):2915-21
references.pmid: 10967045
references.citation: Endocrine. 2009 Aug;36(1):161-8
references.pmid: 19551521
references.citation: Exp Eye Res. 2011 Oct;93(4):363-70
references.pmid: 21689647
references.citation: J Diabetes Complications. 2007 Nov-Dec;21(6):371-3
references.pmid: 17967709
references.citation: Arq Bras Oftalmol. 2008 Nov-Dec;71(6 Suppl):96-103
references.pmid: 19274419
references.citation: Br J Ophthalmol. 2000 Jan;84(1):19-21
references.pmid: 10611093
references.citation: Eye (Lond). 2006 Mar;20(3):315-8
references.pmid: 15832184
references.citation: BMC Ophthalmol. 2008 Jun 02;8:10
references.pmid: 18513455
references.citation: Curr Eye Res. 2012 Oct;37(10):898-906
references.pmid: 22632054
references.citation: Arch Ophthalmol. 2009 Nov;127(11):1468-73
references.pmid: 19901212
references.citation: Diabetes Care. 2007 Oct;30(10):2608-12
references.pmid: 17623821
references.citation: Invest Ophthalmol Vis Sci. 2011 Aug 22;52(9):6589-96
references.pmid: 21715347
references.citation: Cornea. 2002 Aug;21(6):628-31
references.pmid: 12131049
references.citation: Diabetes. 2013 Jan;62(1):254-60
references.pmid: 23002037
references.citation: Diabetes Care. 2004 Jun;27(6):1458-86
references.pmid: 15161806
references.citation: Diabetes Care. 2010 Aug;33(8):1792-7
references.pmid: 20435796
references.citation: Cornea. 2005 Aug;24(6):705-9
references.pmid: 16015090
references.citation: Invest Ophthalmol Vis Sci. 2012 Mar 09;53(3):1182-7
references.pmid: 22273725
references.citation: Invest Ophthalmol Vis Sci. 2012 Dec 07;53(13):8067-74
references.pmid: 23169880
references.citation: Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3648-54
references.pmid: 19264894
references.citation: Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5155-8
references.pmid: 19553615
references.citation: Cornea. 2004 Jan;23(1):35-7
references.pmid: 14701955
references.citation: Invest Ophthalmol Vis Sci. 2014 Mar 03;55(3):1222-30
references.pmid: 24519423
references.citation: Cornea. 2013 Apr;32(4):e36-43
references.pmid: 23051907
references.citation: Ophthalmology. 2001 Mar;108(3):586-92
references.pmid: 11237914
references.citation: Eye Contact Lens. 2011 Sep;37(5):326-7
references.pmid: 21617538
references.citation: J Comp Neurol. 2013 Mar 1;521(4):877-93
references.pmid: 22886778
references.citation: Acta Ophthalmol. 2012 Sep;90(6):e447-51
references.pmid: 22691299
references.citation: Br J Ophthalmol. 1981 Oct;65(10):687-90
references.pmid: 7317320
references.citation: Eye Contact Lens. 2009 Nov;35(6):302-8
references.pmid: 19901584
references.citation: Am J Ophthalmol. 2005 Mar;139(3):498-503
references.pmid: 15767060
references.citation: Diabet Med. 2011 Oct;28(10):1261-7
references.pmid: 21699561
references.citation: Graefes Arch Clin Exp Ophthalmol. 2010 Sep;248(9):1307-12
references.pmid: 20490534
references.citation: Am J Ophthalmol. 2006 Sep;142(3):488-90
references.pmid: 16935596
references.citation: Invest Ophthalmol Vis Sci. 2003 Jan;44(1):124-9
references.pmid: 12506064
references.citation: Diabetes Care. 2012 Apr;35(4):821-8
references.pmid: 22323412
references.citation: Invest Ophthalmol Vis Sci. 2012 Jul 27;53(8):5077-84
references.pmid: 22695965
references.citation: Ocul Surf. 2012 Apr;10(2):100-7
references.pmid: 22482470