Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes

Abstract

The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been proposed regarding the underlying cause of canine diabetes, from pancreatic atrophy to chronic pancreatitis to autoimmune mediated β-cell destruction. It remains unclear to what extent β-cell loss contributes to canine diabetes, as precise quantifications of islet morphometry have not been performed. We used high-throughput microscopy and automated image processing to characterize islet histology in a large collection of pancreata of diabetic dogs. Diabetic pancreata displayed a profound reduction in β-cells and islet endocrine cells. Unlike humans, canine non-diabetic islets are largely comprised of β-cells. Very few β-cells remained in islets of diabetic dogs, even in pancreata from new onset cases. Similarly, total islet endocrine cell number was sharply reduced in diabetic dogs. No compensatory proliferation or lymphocyte infiltration was detected. The majority of pancreata had no evidence of pancreatitis. Thus, canine diabetes is associated with extreme β-cell deficiency in both new and longstanding disease. The β-cell predominant composition of canine islets and the near-total absence of β-cells in new onset elderly diabetic dogs strongly implies that similar to human type 1 diabetes, β-cell loss underlies the pathophysiology of canine diabetes.

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“…In another study, histopathologic evidence of chronic pancreatitis was found in 6 of 18 diabetic dogs and acute pancreatitis was found in 5 of 18 . In contrast, other studies on diabetic dogs have found histopathologic evidence of pancreatitis to be lacking or rare . In both dogs and people, it is difficult to identify a cause and effect relationship between DM and pancreatitis, and both could result from the same primary disease process.…”

“…In an earlier study, infiltrating mononuclear cells (predominantly lymphocytes) were observed in 6 of 18 dogs (33%) with DM whereas in 5 dogs (28%), extensive pancreatic damage appeared to be responsible for the development of DM . An absence or decreased numbers of islets together with degeneration and vacuolization but no inflammation was described in 3 studies evaluating pancreatic histopathology in a total of 74 diabetic dogs …”

“…There is evidence of cell-mediated autoimmune destruction of b-cells in up to 50% of diabetic dogs [26][27][28][29][30] in some studies whereas others have found no evidence of autoimmune destruction. [31][32][33][34][35] In a study evaluating serum from 48 dogs with recently diagnosed but untreated DM, autoantibodies reactive against the cytoplasmic content of normal canine islet cells were not detectable in any sample. 32 Similarly, a recent study found no evidence of islet cell autoimmunity in 121 diabetic dogs of 40 different breeds.…”

“…28 An absence or decreased numbers of islets together with degeneration and vacuolization but no inflammation was described in 3 studies evaluating pancreatic histopathology in a total of 74 diabetic dogs. 31,33,35 A complicating factor in determining the prevalence of autoimmune DM is that the presence of autoantibodies and an inflammatory infiltrate depends on the residual insulin content of the cells. Insulitis rarely is detected once b-cells become insulin deficient.…”

“…33 In contrast, other studies on diabetic dogs have found histopathologic evidence of pancreatitis to be lacking or rare. 31,35 In both dogs and people, it is difficult to identify a cause and effect relationship between DM and pancreatitis, and both could result from the same primary disease process. Human patients with T2DM have 1.5-1.8 fold increased risk of developing acute pancreatitis, 52,53 and both insulin resistance and hyperglycemia might be key factors in this process.…”