The emerging role of pancreatic exocrine fibrosis as a common aetiological driver of islet dysfunction and diabetes: opportunities for novel disease-modifying interventions

Abstract Three diseases primarily affecting the exocrine pancreas—chronic pancreatitis, cystic fibrosis and pancreatic ductal adenocarcinoma—are all associated with a high incidence of diabetes. Together, they may account for more cases of diabetes than autoimmune type 1 diabetes. All forms of pancreatogenic (type 3c) diabetes are characterised by impaired insulin secretion but maintenance of significant islet beta cell mass, even in the presence of virtually complete destruction of the exocrine component of the gland. Pancreatic ductal injury and associated fibrosis are common features in chronic pancreatitis, cystic fibrosis and ductal adenocarcinoma. Increased peri-ductal fibrosis is also seen in type 2 and type 1 diabetes. Here, we review the literature regarding a potential common aetiological role of pancreatic fibrosis in the pathogenesis of type 3c, type 2 and type 1 diabetes. A vicious profibrotic signalling cycle involving injured ducts, pancreatic stellate cells and macrophages with increased levels of pancreatic tissue TGF-β at the core has increasingly been recognised as an essential driver of pancreatic exocrine fibrosis. We propose a second diabetogenic perpetual cycle comprising paracrine signalling between activated pancreatic stellate cells, macrophages and the islets themselves, leading to potentially reversible beta cell failure. The antifibrotic agents pirfenidone and nintedanib, thought to work primarily through suppression of TGF-β function, are used routinely in clinical practice for non-pancreatic indications, with a first trial in pancreatitis underway. Trials evaluating these licensed therapeutics that include primary diabetes-related endpoints and measures aiming to elucidate the underlying mechanisms of action merit consideration in type 3c diabetes and ultimately in type 2 diabetes and in combinatorial regimens in type 1 diabetes. Graphical Abstract