Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

Abstract

T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

“…The NOD mouse has been an important tool in understanding the genetics and pathogenesis of Type 1 diabetes [16]. Indeed a number of genes identified in NOD mice have been found to contribute to Type 1 diabetes susceptibility in humans [17][18][19].…”

“…The NOD mouse has been used extensively in prevention studies, with varying success in predicting clinical outcome [16,23]. Indeed it has been suggested that this model overestimates the clinical success of an interventional experimental drug.…”

Tolerogenic Nanoparticles to Treat Islet Autoimmunity

“…Therefore, the vast majority of research on the pathogenesis of T1D has relied on a number of mouse models. Since its development in the 1980s, the non-obese diabetic (NOD) mouse has become a favored model for studying T1D, with spontaneous disease incidence of up to 80–90% in females [1, 29, 30]. Many different T cell autoantigens have been discovered in NOD mice, though insulin, and particularly the Ins B9–23 peptide, seems to be the dominant and initial target [29, 30, 31••, 32••, 33].…”

“…Since its development in the 1980s, the non-obese diabetic (NOD) mouse has become a favored model for studying T1D, with spontaneous disease incidence of up to 80–90% in females [1, 29, 30]. Many different T cell autoantigens have been discovered in NOD mice, though insulin, and particularly the Ins B9–23 peptide, seems to be the dominant and initial target [29, 30, 31••, 32••, 33]. While many of these antigens overlap with those found in humans, it is important to note that there are many significant differences between T1D in humans and NOD mice, including disease onset time and amount and morphology of islet infiltration [1, 20].…”

Mechanistic Evidence in Support of Alpha1-Antitrypsin as a Therapeutic Approach for Type 1 Diabetes

“…Although the study did raise the possibility of a potential therapeutic role for AAT in T1D, it focused on a mouse model that is currently attracting criticism as to its translatability. 37 Of note, the NOD mouse is the only mouse strain to exhibit steady-state low levels of circulating murine AAT, compared to other strains.…”