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bioRxiv · 10.1101/2025.05.14.654045

3D imaging of human pancreas suggests islet size and endocrine composition influence their loss in type 1 diabetes

Rippa, A.·Posgai, A. L.·Currlin, S.·Brusko, M.·Williams, M. D.·Kaddis, J. S.·Kusmartseva, I.·Wasserfall, C. H.·Campbell-Thompson, M.·Atkinson, M. A.
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Abstract

A high-definition description of pancreatic islets would prove beneficial for understanding the pathophysiology of type 1 diabetes (T1D), yet significant knowledge voids exist in terms of their size, endocrine cell composition, and number in both health and disease. Here, 3-dimensional (3D) analyses of pancreata from control persons without diabetes (ND) revealed heretofore underappreciated frequencies (approximately 50%) of insulin-positive (INS+) glucagon-negative (GCG-) islets. Non-diabetic individuals positive for a single Glutamic acid decarboxylase autoantibody (GADA+) yet at increased risk for disease consistently demonstrated endocrine features, including islet volume and cell composition, closely resembling the age-matched ND controls. In contrast, pancreata from individuals with short-duration T1D demonstrated significantly reduced islet density and a dramatic loss of INS+GCG- islets with preservation of large INS+GCG+ islets. The size and cellular composition of pancreatic islets may, therefore, represent influential factors that impact {beta}-cell loss during T1D disease progression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/654045v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1d2fdeaorg.highwire.dtl.DTLVardef@11c43edorg.highwire.dtl.DTLVardef@af8a82org.highwire.dtl.DTLVardef@ae8c58_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LI3D imaging of non-diabetic (ND) pancreas suggests up to 50% of INS+ islets lack GCG C_LIO_LIINS+GCG- islets are typically small-sized in ND and preferentially lost in T1D C_LIO_LIIn T1D pancreas, INS+ beta cells are preserved in large INS+GCG+ islets C_LIO_LIIslets from GADA+ individuals appear similar to ND for size and {beta}-to- cell ratios C_LI

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Rippa, A., Posgai, A. L., Currlin, S., Brusko, M., Williams, M. D., Kaddis, J. S., Kusmartseva, I., Wasserfall, C. H., Campbell-Thompson, M., Atkinson, M. A.. 2025-05-18. 3D imaging of human pancreas suggests islet size and endocrine composition influence their loss in type 1 diabetes. https://doi.org/10.1101/2025.05.14.654045

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