Integrated histopathology of the human pancreas throughout stages of type 1 diabetes progression

TL;DR

This study provides a detailed histopathological analysis of the human pancreas across stages of type 1 diabetes, revealing new insights into disease progression and preclinical indicators.

Contribution

The study introduces an integrated approach combining imaging and analysis techniques to uncover novel spatial and architectural features of T1D progression.

Findings

The endocrine pancreas shows a spatially homogenous and islet size-dependent architectural organization.

Organ-wide pathogenic processes are coordinated during T1D progression.

Preclinical T1D cases display histopathological correlates that foreshadow later disease features.

Abstract

Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation and progression yet an integrated perspective onto in situ pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~ 25,000 islets effectively contextualizes established and novel pancreatic hallmarks in health and T1D disease. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities.

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