A tale of two pancreases: exocrine pathology and endocrine dysfunction

Abstract

The islets of Langerhans are well embedded within the exocrine pancreas (the latter comprised of ducts and acini), but the nature of interactions between these pancreatic compartments and their role in determining normal islet function and survival are poorly understood. However, these interactions appear to be critical, as when pancreatic exocrine disease occurs, islet function and insulin secretion frequently decline to the point that diabetes ensues, termed pancreatogenic diabetes. The most common forms of pancreatogenic diabetes involve sustained exocrine disease leading to ductal obstruction, acinar inflammation, and fibro-fatty replacement of the exocrine pancreas that predates the development of dysfunction of the endocrine pancreas, as seen in chronic pancreatitis-associated diabetes and cystic fibrosis-related diabetes and, more rarely, MODY type 8. Intriguingly, a form of tumour-induced diabetes has been described that is associated with pancreatic ductal adenocarcinoma. Here, we review the similarities and differences among these forms of pancreatogenic diabetes, with the goal of highlighting the importance of exocrine/ductal homeostasis for the maintenance of pancreatic islet function and survival and to highlight the need for a better understanding of the mechanisms underlying these diverse conditions. Graphical abstract.

Keywords: Cystic fibrosis; Diabetes; Exocrine; Islet; Pancreas; Pancreatitis; Review.

Fig. 1

Schematic showing normal pancreatic morphology (a) with close proximity between pancreatic ducts, acini and islets, the latter comprising beta cells, alpha cells, delta cells and PP cells with resident macrophages (cell types shown in key). Capillaries and autonomic nerve fibres supply all pancreatic compartments. Generalised alterations in pancreatic morphology that occur with pancreatogenic diabetes (b), i.e. ductal plugging (shown in pink within the duct lumen)/dilation, fibro-fatty replacement of acinar tissue and lymphocyte infiltration, with macrophages in the exocrine pancreas but not within the islet, and islet remodelling (modest loss of beta cells and increase in alpha cells). Micrographs showing H&E-stained pancreas sections from a control individual without pancreatic disease (c) an individual with chronic pancreatitis (d) and a person with cystic fibrosis (e). Islets are demarcated with dotted black lines, a normal duct is shown with an arrow in (c), fibrosis is shown surrounding degenerating acini (the latter denoted by arrowheads) in (d) and extensive fatty replacement of exocrine pancreas is shown in (e). Strikingly, despite the severe disruption to the exocrine pancreas in (d) and (e), islets remain readily visible. Scale bar, 100 μm.