The loss of insulin-positive cell clusters precedes the decrease of islet frequency and beta cell area in type 1 diabetes

In type 1 diabetes, insulin deficiency results from immune-mediated destruction of beta cells. The majority of functional beta 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 (WSI) analysis pipeline for semi-automated quantitation of endocrine areas, islet frequencies, inter-islet distances, and endocrine object size distribution in 145 human pancreata from 60 non-diabetic (ND), 19 single autoantibody positive (sAAb+), 10 multiple autoantibody positive (mAAb+), 16 recent-onset (0-1 year duration), 23 medium-duration (1-7 years), and 17 long-duration type 1 diabetes (7+ years) donors. We observed age-related differences in endocrine composition and islet frequency in ND. Age-corrected data revealed decreased islet frequency and increased inter-islet distances in the type 1 diabetes pancreas. Insulin-positive (INS+) single cells (≤10µm), cell clusters (>10 to <35µm), small- and medium-sized islets (35-100µm and 100-200µm) were significantly lost at type 1 diabetes onset, while large INS+ islets (>200µm) were preserved. Moreover, changes in endocrine composition also occurred in mAAb+ donors, including a significant decrease in the INS+ islet fraction. These data suggest preferential loss of INS+ small endocrine objects early in type 1 diabetes development.