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Most affected dogs are diagnosed as adults and are insulin-dependent. We compared pan-leukocyte and sympathetic innervation markers in pancreatic islets of adult dogs with spontaneous DM (sDM), spontaneous pancreatitis (sPanc), both (sDMPanc), toxin-induced DM (iDM) and controls. We found evidence of decreased islet sympathetic innervation but no significant infiltration of islets with leukocytes in all disease groups. We show that loss of sympathetic innervation is ongoing in canine DM and does not necessarily precede it. We further found selective loss of islet-associated beta cells in dogs with sDM and sDMPanc, suggesting that collateral damage from inflammation in the exocrine pancreas is not a likely cause of DM in these dogs. The cause of this selective loss of beta cells needs to be further elucidated but overall, our findings are not supportive of an autoimmune process as a cause of sDM in adult dogs. The loss of sympathetic innervation in sPanc in dogs that do not suffer from DM links the disease in the exocrine pancreas to a pathological process in the endocrine pancreas, suggesting pancreatitis might be a potential precursor to DM.<\/jats:p>","DOI":"10.1038\/s41598-020-76091-5","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T11:03:19Z","timestamp":1604574199000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Loss of sympathetic innervation to islets of Langerhans in canine diabetes and pancreatitis is not associated with insulitis"],"prefix":"10.1038","volume":"10","author":[{"given":"Chen","family":"Gilor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jully","family":"Pires","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Greathouse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Horn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark O.","family":"Huising","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley L.","family":"Marks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Kol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,11,5]]},"reference":[{"key":"76091_CR1","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/s1090-0233(02)00242-3","volume":"165","author":"L Guptill","year":"2003","unstructured":"Guptill, L., Glickman, L. & Glickman, N. Time trends and risk factors for diabetes mellitus in dogs: Analysis of veterinary medical data base records (1970\u20131999). Vet. J. 165, 240\u2013247. https:\/\/doi.org\/10.1016\/s1090-0233(02)00242-3 (2003).","journal-title":"Vet. J."},{"issue":"4","key":"76091_CR2","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1111\/jvim.14357","volume":"30","author":"C Gilor","year":"2016","unstructured":"Gilor, C., Niessen, S. J., Furrow, E. & DiBartola, S. P. What\u2019s in a name? Classification of diabetes mellitus in veterinary medicine and why it matters. J. Vet. Intern. Med. 30(4), 927\u2013940. https:\/\/doi.org\/10.1111\/jvim.14357 (2016).","journal-title":"J. Vet. Intern. Med."},{"key":"76091_CR3","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1097\/mpa.0000000000000937","volume":"46","author":"Y Wang","year":"2017","unstructured":"Wang, Y. et al. 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