Revisiting type 1 diabetes progression in the non-obese diabetic mouse

As conventional diagnostic criteria in non-obese diabetic (NOD) mice may not reflect the early phase of type 1 diabetes, the applicability of NOD mouse models for early type 1 diabetes in humans can be limited. We therefore aimed to assess stages of beta cell loss in early type 1 diabetes at blood glucose (BG) levels of 80–200 mg/dl in age-stratified NOD mice. Islet composition of five pancreas sections each from 38 female NOD mice was determined using multiplexed-immunohistochemistry staining and Cell2Grid/rule-based automated islet identification. Visual analysis of fm-IHC images led to classification of islet stages. Average islet stage per animal (Islet Score) was correlated with average BG to identify NOD mice subgroups of disease progression. We categorized 3324 islets into islet stages, describing beta cell loss from 0 to 4.The proportion of insulin-deficient islets increased from BG > 126 mg/dl onwards. Three disease progression subgroups in NOD mice were identified: Non-diabetic (Islet Score < 1.0, BG < 126 mg/dl), pre-diabetic (Islet Score > 1.0, BG < 126 mg/dl) and early-diabetic (Islet Score > 1.0, BG > 126 mg/dl and diabetes progression model was established. The revised classification of type 1 diabetes in NOD mice and the resulting type 1 diabetes progression model improves adaptation of the NOD model to human pathophysiology.