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

Area of Science:

• Endocrinology
• Immunology
• Pathology

Background:

• Type 1 diabetes (T1D) involves immune-mediated destruction of insulin-producing beta cells.
• The precise timing and nature of beta cell loss, especially in early T1D, are not fully understood.
• Identifying early changes in islet composition is key to developing strategies to halt T1D progression.

Purpose of the Study:

• To investigate the changes in pancreatic islet size and cellular composition during the development of T1D.
• To determine which specific islet components are lost first in the progression of T1D.
• To analyze the impact of autoantibody positivity and disease duration on islet structure.

Main Methods:

• Developed a whole-slide image analysis pipeline for quantitative assessment of pancreatic tissue.
• Analyzed 145 human pancreata from donors without diabetes, with autoantibody positivity, and with varying durations of T1D.
• Quantified endocrine area, islet frequency, interislet distance, and endocrine object size distribution.

Main Results:

• T1D pancreata showed decreased islet frequency and increased interislet distance compared to controls.
• Significant loss of insulin-positive (INS+) single cells, cell clusters, and small-to-medium sized islets was observed at T1D onset.
• Large INS+ islets (>200 μm) were preserved, and changes in INS+ islet fraction were noted even in multiple autoantibody-positive donors.
• These findings suggest a preferential loss of smaller INS+ endocrine objects early in T1D.

Conclusions:

• The early stages of T1D are characterized by the preferential loss of smaller insulin-positive endocrine cells and cell clusters.
• Preservation of larger islets suggests a specific vulnerability of smaller structures to autoimmune destruction in T1D.
• These insights are critical for understanding T1D pathogenesis and for designing targeted therapeutic interventions.