Loss of Insulin-Positive Cell Clusters Precedes the Decrease in Islet Frequency and β-Cell Area in Type 1 Diabetes

In type 1 diabetes (T1D), insulin (INS) deficiency results from immune-mediated destruction of β-cells. The majority of functional β-cell mass is typically lost within months to years of disease diagnosis, but the timing and nature of this loss, particularly in early disease stages, remain unclear. We developed a whole-slide scanned image analysis pipeline for semiautomated quantitation of endocrine area, islet frequency, interislet distance, and endocrine object size distribution in 145 human pancreata from 60 donors without diabetes, 19 donors with single autoantibody positivity, 10 with multiple autoantibody positivity (mAAb+), 16 with recent-onset T1D (duration 0-1 year), 23 with medium-duration T1D (1-7 years), and 17 with long-duration T1D (≥7 years). We observed age-related differences in endocrine composition and islet frequency in pancreata from donors without diabetes. Age-corrected data revealed decreased islet frequency and greater interislet distance in the T1D pancreas. INS+ single cells (≤10 μm), cell clusters (>10 to <35 μm), and small- and medium-sized islets (35-100 and 100-200 μm, respectively) were significantly lost at T1D onset, whereas large INS+ islets (>200 μm) were preserved. Moreover, changes in endocrine composition also occurred in pancreata from mAAb+ donors, including a significant decrease in the INS+ islet fraction. These data suggest preferential loss of INS+ small endocrine objects early in T1D development.

Understanding the timing and nature of β-cell loss is essential for developing effective strategies to interrupt type 1 diabetes progression. Which types of islets, in terms of size and cellular composition, are lost first during disease development? Insulin-positive single cells and cell clusters are lost before large islets during disease development. Insulin-positive single cells and cell clusters might be more susceptible to destruction in type 1 diabetes.