Pancreatic regeneration in type 1 diabetes: dreams on a deserted islet?

Abstract

It is easy to see that Meier and colleagues have set out to gain our collective attention with their report in this issue of Diabetologia [1]. Many notions concerning the pathogenesis of type 1 diabetes have been repeated so often that they have hardened into dogma [2]. This list of unquestioned yet unconfirmed concepts might include the assumed autoimmune basis for the disorder, the notion that symptomatic onset is preceded by 85–90% loss of beta cells, and the belief that beta cell destruction is orchestrated by T lymphocytes. Yet another popular postulate maintains that beta cell mass is irrevocably lost in the months or years that follow initiation of insulin therapy, leaving the pancreas devoid of cells capable of insulin production. The proposal that this exocrine desert contains an oasis of insulinproducing cells would therefore be considered, at least by most, to represent a mirage. The dogma of islet cell extinction is supported on many fronts: C-peptide eventually becomes undetectable in virtually everyone with type 1 diabetes, and vanishingly few cases of true ‘spontaneous and permanent’ disease remission have been documented. Autopsy specimens from people with long-term type 1 diabetes rarely describe appreciable, let alone healthy, islet cell mass. This picture of islet desolation has, however, been opposed by the concept of ‘pancreatic regeneration’ [3]. Although ‘islet cell regeneration’ might be a more appropriate term, the concept has revived hope that endogenous pancreatic insulin secretion might one day be restored to those with type 1 diabetes. This rapidly growing field of investigation, liberally invested with both hype and hope, draws upon observations from stem cell biology, gene therapy, incretin pharmacology, pancreatic transgenic animals and more. The ‘more’ includes the interpretations set forward by Peter Butler and colleagues from UCLA [1]. Their study focuses on the immunocytochemical detection of insulin-producing cells in the pancreas of subjects with a duration of type 1 diabetes ranging from 4 to 67 years. In addition to ascertaining the presence of insulinpositive cells, the pancreases were also evaluated for beta cell apoptosis, replication, inflammation and periductal fibrosis, and the results compared with those for pancreases from non-diabetic individuals. The investigators observed, somewhat surprisingly—and certainly in contrast to established dogma—that 88% of the type 1 diabetes patients had insulin-producing cells, and that this was unrelated to duration of disease or age at death. They also observed that beta cell apoptosis was more frequent in cases of type 1 diabetes than in controls, and was often accompanied by macrophages, T lymphocytes and periductal fibrosis. The authors put forward the interesting, but highly speculative, proposal that beta cells are subject to continuous rebirth in type 1 diabetes, but that the net effect of this ‘regenerative process’ is counteracted by low-grade inflammatory autoimmunity. Some may say that there is nothing new in this, and the work does, by and large, confirm earlier findings by Gepts & De Mey [4], Foulis & Stewart [5] and Lohr & Kloppel [6], among others. However, these new studies represent an important extension of those seminal works, and demonstrate, with some fervour, the potential for islet beta cell regeneration. At least three distinct mechanisms have been proposed for this: replication of existing beta cells; emergence of new beta cells from the pancreatic ductal epithelium (often referred to as neogenesis, and considered by some to indicate the existence of adult pancreatic stem cells); and apparent ‘transdifferentiation’ of exocrine into endocrine beta cells (Fig. 1). Meier et al. observed negligible replication of beta cells, comparable to that in control subjects, and concluded from this that the residual beta M. A. Atkinson (*) Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610, USA e-mail: atkinson@ufl.edu Tel.: +1-352-3920048 Fax: +1-352-3928464