Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis.

Julia K Panzer,Sirlene Cechin,Mollie K Huber,Denise M Drotar,Mirza Muhammad Fahd Qadir,Alberto Pugliese,John R Weitz,Mark A Atkinson,Maria Beery,Stephan Speier,Helmut Hiller,Edward A Phelps,Alejandro Caicedo,Jorge Santini,Stephen J Enos,Christian M Cohrs,Ricardo L Pastori,Irina Kusmartseva,Joana Almaça,Juan Domínguez‐Bendala

doi:10.1172/jci.insight.134525

Abstract

In type 1 diabetes (T1D), autoimmune destruction of pancreatic β cells leads to insulin deficiency and loss of glycemic control. However, knowledge about human pancreas pathophysiology in T1D remains incomplete. To address this limitation, we established a pancreas tissue slice platform of donor organs with and without diabetes, facilitating the first live cell studies of human pancreas in T1D pathogenesis to our knowledge. We show that pancreas tissue slices from organ donors allow thorough assessment of processes critical for disease development, including insulin secretion, β cell physiology, endocrine cell morphology, and immune infiltration within the same donor organ. Using this approach, we compared detailed pathophysiological profiles for 4 pancreata from donors with T1D with 19 nondiabetic control donors. We demonstrate that β cell loss, β cell dysfunction, alterations of β cell physiology, and islet infiltration contributed differently to individual cases of T1D, allowing insight into pathophysiology and heterogeneity of T1D pathogenesis. Thus, our study demonstrates that organ donor pancreas tissue slices represent a promising and potentially novel approach in the search for successful prevention and reversal strategies of T1D.

Highlights

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the selective destruction of insulin-producing β cells, resulting in massive reduction of β cell mass, insulin deficiency, and subsequent hyperglycemia [1,2,3]
The living pancreas slice technique has allowed us and others to assess numerous parameters of islet cell function from tissues containing the intact endocrine and exocrine compartments [23, 25,26,27,28,29,30,31,32,33]. We posited that this technological approach would facilitate investigation of structurally altered, infiltrated, or damaged islets during T1D disease pathogenesis, which are thought to be lost during classical islet isolation procedures
We applied the slice technology to fresh tissue samples obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD) program within a few hours after organ arrival to characterize islet function and morphology in ND organs and during T1D pathogenesis

Summary

Introduction

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the selective destruction of insulin-producing β cells, resulting in massive reduction of β cell mass, insulin deficiency, and subsequent hyperglycemia [1,2,3]. Much of our knowledge about the disease pathogenesis has been derived from studies performed in rodent models [7, 8] These models allow for insights into this complex disease, immune intervention strategies developed based on rodent data have not translated well to human T1D [9,10,11], likely due to species differences in disease processes [12,13,14]. Developing successful therapeutic approaches requires a comprehensive understanding of how human islet biology is affected during T1D pathogenesis.

Methods

Results

Conclusion