Abstract
Canine diabetes mellitus (DM) affects 0.6% of the canine population and yet, its etiology is poorly understood. 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.
Highlights
Canine diabetes mellitus (DM) affects 0.6% of the canine population and yet, its etiology is poorly understood
The etiology of canine DM is poorly understood, we report for the first time in this study on the sympathetic denervation of the islets of Langerhans as a key characteristic of this disease that helps narrow down possible etiologies
Sympathetic denervation of islets was reported in three animal models of autoimmune DM as well as in Type 1 diabetes mellitus (T1DM) in people, but not in type 2 DM11–13, leading to the suggestion that this phenomenon is tightly linked with autoimmune insulitis
Summary
Canine diabetes mellitus (DM) affects 0.6% of the canine population and yet, its etiology is poorly understood. In humans with T1DM and in rodent models, pancreatic pathology is characterized by a predominately lymphocytic insulitis, and by early, sustained, islet-selective loss of sympathetic innervation[11] The pathogenesis of this neuropathy is unclear but it appears to be a result of the combination of beta cell loss together with the inflammatory milieu of the autoimmune process within the islet. In a recent consensus guideline, the threshold for diagnosis of insulitis in people with T1DM has been established as a minimum of three affected islets and a minimum of 15 CD45+ (leukocyte common antigen) cells per islet (either intra-islet, or at the periphery of the islet)[10] These standards were established based on a comparison to a nondiabetic control group because it is recognized that background inflammation (as well as presence of resident lymphocytes) in the exocrine pancreas is common in humans. We aimed to compare the number and distribution of CD45+ leukocytes in pancreata from dogs with sDM and sDMPanc to dogs that have no evidence of either DM or pancreatitis and dogs with pancreatitis but no DM
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