β-Cell Replication Is Increased in Donor Organs From Young Patients After Prolonged Life Support

Abstract

OBJECTIVEThis study assesses β-cell replication in human donor organs and examines possible influences of the preterminal clinical conditions.RESEARCH DESIGN AND METHODSβ-Cell replication was quantified in a consecutive series of n = 363 human organ donors using double immunohistochemistry for Ki67 and insulin. Uni- and multivariate analysis was used to correlate replication levels to clinical donor characteristics and histopathologic findings.RESULTSβ-Cell replication was virtually absent in most donors, with ≤0.1% Ki67-positive β-cells in 72% of donors. A subpopulation of donors, however, showed markedly elevated levels of replication of up to 7.0% Ki67-positive β-cells. β-Cell replication was accompanied by the increased replication of glucagon-, somatostatin-, and CA19.9-positive cells. Prolonged life support, kidney dysfunction, relatively young donor age, inflammatory infiltration, and prolonged brain death before organ retrieval were all found to be significantly associated with an increased level (≥90th percentile) of β-cell replication, with the first three risk factors being independent predictors. Increased β-cell replication was most often noted in relatively young donors (≤25 years) who received prolonged (≥3 days) life support (68%); in contrast, it was rare in donors with a short duration of life support regardless of age (1%). Prolonged life support was accompanied by increased levels of CD68+ and LCA/CD45+ infiltration in the pancreatic parenchyma.CONCLUSIONThese results indicate that preterminal clinical conditions in (young) organ donors can lead to increased inflammatory infiltration of the pancreas and to increased β-cell replication.

Development of a conditionally immortalized human pancreatic β cell line

“…In the adult pancreas, human β cell proliferation is extremely low (5,31). It was found that human β cell replication could be activated not only upon glucose stimulation (32), but also by adenovirus-mediated overexpression of cell-cycle regulators (33).…”

The diagnosis of insulitis in human type 1 diabetes

“…These thresholds range from two to 15 CD3 + or CD45 + cells adjacent to or infiltrating the islet [6,[9][10][11][12][13][14]. However, recent observations in a cohort of 363 non-diabetic donor pancreases indicate that the level of background infiltration in the pancreatic parenchyma is highly variable and dependent on the clinical conditions surrounding organ retrieval, with the highest levels of infiltration observed in patients with a prolonged duration of life support [15]. Therefore, it was generally agreed that the threshold level should be substantially higher than the highest levels found in published controls; a level of 15 CD45 + cells (approximately twice the highest number of CD45 + cells found in a single islet in a cohort of 62 control donor pancreases [14]) was accepted as a suitable threshold (Fig.…”

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

“…Although islet-autoreactive CD8 + T cells were detected [3], the level of insulitis remains surprisingly mild, even in patients with recent-onset type 1 diabetes and death due to ketoacidosis [4]. This picture is complicated by background infiltration in the exocrine pancreas, partly due to peri-mortem changes, with the highest levels of infiltration observed in young patients after prolonged life support [5]. Even independently of postmortem changes, type 1 diabetes affects the exocrine as well as the endocrine pancreas [6]; this raises the question whether the limited infiltration of leucocytes is specifically targeted to pancreatic beta cells.…”