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Their impact on the lacrimal functional unit (LFU) is poorly known. This work evaluates the changes in the LFU in DM and HT. Adult male Wistar rats had the disease induced as follows: (a) DM: streptozotocin and (b) HT: methimazole. The tear film (TF) and blood osmolarity were measured. Cytokine mRNA was compared in the lacrimal gland (LG), trigeminal ganglion (TG), and cornea (CO). Oxidative enzymes were evaluated in the LG. The DM group showed lower tear secretion (p = 0.02) and higher blood osmolarity (p &lt; 0.001). The DM group presented lower mRNA expression of TRPV1 in the cornea (p = 0.03), higher Il1b mRNA expression (p = 0.03), and higher catalase activity in the LG (p &lt; 0.001). The DM group presented higher Il6 mRNA expression in the TG (p = 0.02). The HT group showed higher TF osmolarity (p &lt; 0.001), lower expression of Mmp9 mRNA in the CO (p &lt; 0.001), higher catalase activity in the LG (p = 0.002), and higher expression of Il1b mRNA in the TG (p = 0.004). The findings revealed that DM and HT induce distinct compromises to the LG and the entire LFU.<\/jats:p>","DOI":"10.3390\/ijms24086974","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:49:29Z","timestamp":1681098569000},"page":"6974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Distinct Inflammatory and Oxidative Effects of Diabetes Mellitus and Hypothyroidism in the Lacrimal Functional Unit"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5873-622X","authenticated-orcid":false,"given":"Jacqueline Ferreira","family":"Faustino-Barros","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariane Mirela","family":"Saranzo Sant\u2019Ana","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara Cristina","family":"Dias","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"de Andrade Batista Murashima","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-264X","authenticated-orcid":false,"given":"Lilian Eslaine","family":"Costa Mendes da Silva","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Z\u00edlio","family":"Fantucci","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9123-2728","authenticated-orcid":false,"given":"Denny Marcos","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9888-7313","authenticated-orcid":false,"given":"Eduardo Melani","family":"Rocha","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ajo.2019.01.026","article-title":"Estimated Prevalence and Incidence of Dry Eye Disease Based on Coding Analysis of a Large, All-age United States Health Care System","volume":"202","author":"Dana","year":"2019","journal-title":"Am. J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II Epidemiology Report","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Alves, M., Reinach, P.S., Paula, J.S., e Cruz, A.A.V., Bachette, L., Faustino, J., Aranha, F.P., Vigorito, A., De Souza, C.A., and Rocha, E.M. (2014). Comparison of diagnostic tests in distinct well-defined conditions related to dry eye disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097921"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.jtos.2014.02.002","article-title":"Rethinking dry eye disease: A perspective on clinical implications","volume":"12","author":"Bron","year":"2014","journal-title":"Ocul. Surf."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Qian, L., and Wei, W. (2022). Identified risk factors for dry eye syndrome: A systematic review and meta-analysis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0271267"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.exer.2003.09.003","article-title":"The role of the lacrimal functional unit in the pathophysiology of dry eye","volume":"78","author":"Stern","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nrendo.2011.183","article-title":"The worldwide epidemiology of type 2 diabetes mellitus\u2014Present and future perspectives","volume":"8","author":"Chen","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1007\/s00125-005-0010-9","article-title":"Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats","volume":"48","author":"Alves","year":"2005","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s12020-009-9208-9","article-title":"Influence of insulin treatment on the lacrimal gland and ocular surface of diabetic rats","volume":"36","author":"Jorge","year":"2009","journal-title":"Endocrine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"158","DOI":"10.5935\/0004-2749.20150041","article-title":"Insulin replacement restores the vesicular secretory apparatus in the diabetic rat lacrimal gland","volume":"78","author":"Dias","year":"2015","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1167\/iovs.06-1309","article-title":"Influence of Thyroid Hormone on Thyroid Hormone Receptor \u03b2-1 Expression and Lacrimal Gland and Ocular Surface Morphology","volume":"48","author":"Dias","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/ICU.0b013e32836227bf","article-title":"Hormones and dry eye syndrome: An update on what we do and don\u2019t know","volume":"24","author":"Rocha","year":"2013","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jtos.2017.04.001","article-title":"TFOS DEWS II Sex, Gender, and Hormones Report","volume":"15","author":"Sullivan","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1600-0404.1979.tb02906.x","article-title":"Diabetic polyneuropathy. Corneal sensitivity, vibratory perception and Achilles tendon reflex in diabetics","volume":"59","author":"Nielsen","year":"1979","journal-title":"Acta Neurol. Scand."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s12020-009-9151-9","article-title":"Aspirin prevents diabetic oxidative changes in rat lacrimal gland structure and function","volume":"35","author":"Jorge","year":"2009","journal-title":"Endocrine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jdiacomp.2006.05.008","article-title":"Tear production and corneal sensitivity in diabetes","volume":"21","author":"Cousen","year":"2007","journal-title":"J. Diabetes Complicat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1111\/jns5.12044","article-title":"Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin","volume":"18","author":"Chen","year":"2013","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1111\/aos.12063","article-title":"Meta-analysis and review on the changes of tear function and corneal sensitivity in diabetic patients","volume":"92","author":"Lv","year":"2014","journal-title":"Acta Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1167\/iovs.14-14307","article-title":"Diabetes mellitus leads to accumulation of dendritic cells and nerve fiber damage of the subbasal nerve plexus in the cornea","volume":"55","author":"Leppin","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","first-page":"375","article-title":"Low tear production in patients with diabetes mellitus is not due to Sj\u00f6gren\u2019s syndrome","volume":"12","author":"Russell","year":"1994","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8067","DOI":"10.1167\/iovs.12-10826","article-title":"Early loss of innervation of cornea epithelium in streptozotocin-induced type 1 diabetic rats: Improvement with ilepatril treatment","volume":"53","author":"Davidson","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1167\/iovs.13-13794","article-title":"Differences and similarities in development of corneal nerve damage and peripheral neuropathy and in diet-induced obesity and type 2 diabetic rats","volume":"55","author":"Davidson","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.archger.2004.04.065","article-title":"Oxidative stress and antioxidant status in elderly diabetes mellitus and glucose intolerance patients","volume":"39","author":"Atli","year":"2004","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.archoralbio.2011.01.005","article-title":"Alterations of antioxidant biomarkers and type I collagen deposition in the parotid gland of streptozotocin-induced diabetic rats","volume":"56","author":"Deconte","year":"2011","journal-title":"Arch. Oral. Biol."},{"key":"ref_25","first-page":"4583742","article-title":"Oxidative Damage to the Salivary Glands of Rats with Streptozotocin-Induced Diabetes-Temporal Study: Oxidative Stress and Diabetic Salivary Glands","volume":"2016","author":"Maciejczyk","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1167\/iovs.03-1055","article-title":"Animal models of dry eye: A critical assessment of opportunities and limitations","volume":"45","author":"Barabino","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Garcia, D.M., de Oliveira, F.R., M\u00f3dulo, C.M., Faustino, J., Barbosa, A.P., Alves, M., and Rocha, E.M. (2018). Is Sj\u00f6gren\u2019s syndrome dry eye similar to dry eye caused by other etiologies? Discriminating different diseases by dry eye tests. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0208420"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1097\/ICO.0000000000000256","article-title":"Short-time exposure of hyperosmolarity triggers interleukin-6 expression in corneal epithelial cells","volume":"33","author":"Igarashi","year":"2014","journal-title":"Cornea"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"261","DOI":"10.4103\/amhsr.amhsr_39_16","article-title":"Peripheral and Central Nervous System Involvement in Recently Diagnosed Cases of Hypothyroidism: An Electrophysiological Study","volume":"6","author":"Gupta","year":"2016","journal-title":"Ann. Med. Health Sci. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cbf.1119","article-title":"Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: Effect of vitamin E supplementation","volume":"23","author":"Dirican","year":"2005","journal-title":"Cell Biochem. Funct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1167\/iovs.13-11791","article-title":"Transcription factors Runx1 to 3 are expressed in the lacrimal gland epithelium and are involved in regulation of gland morphogenesis and regeneration","volume":"54","author":"Voronov","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4399","DOI":"10.1167\/iovs.08-1730","article-title":"Mechanisms of murine lacrimal gland repair after experimentally induced inflammation","volume":"49","author":"Zoukhri","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S1542-0124(12)70070-8","article-title":"Mechanisms involved in injury and repair of the murine lacrimal gland: Role of programmed cell death and mesenchymal stem cells","volume":"8","author":"Zoukhri","year":"2010","journal-title":"Ocul. Surf."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.exer.2004.07.002","article-title":"Tear film and ocular surface tests in animal models of dry eye: Uses and limitations","volume":"79","author":"Barabino","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"68","DOI":"10.5935\/0034-7280.20150016","article-title":"Lacrimal osmolarity and ocular surface in experimental model of dry eye caused by toxicity","volume":"74","author":"Marques","year":"2015","journal-title":"Rev. Bras. Oftalmol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/6974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:12:55Z","timestamp":1760123575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/6974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,10]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24086974"],"URL":"https:\/\/doi.org\/10.3390\/ijms24086974","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,10]]}}}