Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

Abstract

Despite decades of research in humans and mouse models of disease, substantial gaps remain in our understanding of pathogenic mechanisms underlying the development of type 1 diabetes. Furthermore, translation of therapies from preclinical efforts capable of delaying or halting β-cell destruction has been limited. Hence, a pressing need exists to identify alternative animal models that reflect human disease. Canine insulin deficiency diabetes is, in some cases, considered to follow autoimmune pathogenesis, similar to NOD mice and humans, characterized by hyperglycemia requiring lifelong exogenous insulin therapy. Also similar to human type 1 diabetes, the canonical canine disorder appears to be increasing in prevalence. Whereas islet architecture in rodents is distinctly different from humans, canine pancreatic endocrine cell distribution is more similar. Differences in breed susceptibility alongside associations with MHC and other canine immune response genes parallel that of different ethnic groups within the human population, a potential benefit over NOD mice. The impact of environment on disease development also favors canine over rodent models. Herein, we consider the potential for canine diabetes to provide valuable insights for human type 1 diabetes in terms of pancreatic histopathology, impairment of β-cell function and mass, islet inflammation (i.e., insulitis), and autoantibodies specific for β-cell antigens.

Insulin dysregulation in horses with systemic inflammatory response syndrome

“…In those cases, relative hypoinsulinemia was defined as a failure of insulin secretion in the face of SIRS‐induced hyperglycemia, suggesting a transient diabetes mellitus, which is rarely reported in horses. Type‐1 diabetes mellitus, more commonly diagnosed in humans or in dogs, is observed as a consequence of immune‐mediated damage to the endocrine pancreas whereas type‐2 diabetes mellitus develops after decreased pancreatic β cell function after sustained hyperinsulinemia . In 1 foal with severe SIRS, a transient type‐1 diabetes mellitus has been described suggesting that severe SIRS could lead to pancreatic dysfunction .…”

“…Type-1 diabetes mellitus, more commonly diagnosed in humans or in dogs, is observed as a consequence of immune-mediated damage to the endocrine pancreas whereas type-2 diabetes mellitus develops after decreased pancreatic b cell function after sustained hyperinsulinemia. 42,43 In 1 foal with severe SIRS, a transient type-1 diabetes mellitus has been described suggesting that severe SIRS could lead to pancreatic dysfunction. 44 In agreement with those reports, our data indicate that severe hyperglycemia, in the face of an inadequate insulin response, is associated with non-survival and reflects a possible state of relative hypoinsulinemia or inappropriate lack of insulin secretion.…”

Hybrid lipids, peptides, and lymphocytes: new era in type 1 diabetes research

“…The pathogenesis of autoimmune diabetes is being extensively investigated in both humans and in animal models (9). Though the exact mechanisms that underlie autoimmune destruction of β cells remain elusive, it is generally believed that the disease process is triggered by the activation of autoreactive T cells by islet autoantigens, such as insulin, GAD65, IA2, and ZNT18.…”

Untargeted metabolomic analysis in naturally occurring canine diabetes mellitus identifies similarities to human Type 1 Diabetes

“…Many unknowns still exist with respect to the pathogenesis of canine diabetes, and metabolomic alterations may represent important potential biomarkers to detect diabetes in dogs prior to clinical onset. Indeed, the ability to detect the pre-diabetic state may represent a key component to future discovery in this area 10 and to further define the utility of the dog as a potential model of human…”