Taking a closer look at the pancreas

Abstract

Our current understanding of how pancreatic beta cell mass fluctuates during the course of diabetes development is largely based on indirect evidence. Various approaches based on in vivo metabolic testing have been described, each reflecting specific aspects of beta cell function [1]. These measurements are correlated with actual beta cell mass only to a certain extent, and were developed to allow estimates of mass following surgery, therapy or transplantation. Direct visualisation of beta cell mass by means of novel imaging technologies is anticipated to provide more detailed insight into the true kinetics of key processes such as physiological beta cell turnover, islet graft loss and the pathophysiology of type 1 and type 2 diabetes. Likewise, a substantial part of what we know about the autoimmune component of type 1 diabetes has historically been derived from ex vivo, cross-sectional studies in rodents. Improved intravital microscopy techniques could also shed new light on the in situ behaviour of immune cells—after all, seeing is believing. In this issue of Diabetologia, Holmberg and Ahlgren review recent progress in the area of optical imaging technologies that is specifically applicable to monitoring the pancreas [2]. Although most investigators may be familiar with conventional non-optical imaging modalities such as magnetic resonance imaging (MRI) and positron emission tomography (PET), and the ongoing endeavour to optimise these technologies for non-invasive monitoring of beta cell mass in patients, there are a number of lesser known optical strategies that are likely to contribute essential information in the near future. In an effort to improve our understanding of emerging technologies such as optical projection tomography (OPT), bioluminescence imaging, confocal microscopy and optical coherence tomography, the authors outline the characteristics, benefits and limitations of each technique. Perhaps one of the most elegant examples of this new generation of imaging modalities is optical projection tomography, an approach that has recently been advanced by the authors to allow for detailed whole organ assessment and accurate quantification of beta cell mass ex vivo. The three-dimensional OPT image provided in their current review showcases the remarkable quantitative resolution that is characteristic of OPT, enabling us to observe individual islets and their position relative to each other. The authors conclude that, although OPTand the other technologies discussed are at present merely suitable for pre-clinical research, they could prove clinically relevant in the long run. So which questions need to be addressed by optical imaging? (see text box: Questions to be addressed by optical imaging). We and others have recently proposed a cyclical model for type 1 diabetes, describing the disease as a relapsing–remitting condition, based on our understanding of its key cellular constituents [3]. According to this hypothesis, the kinetics of beta cell degeneration are directed by the degree of epitope spreading, the rate of beta cell proliferation in response to autoimmune attack and the immune modulatory action of regulatory T cells (Tregs). As a result of the dominance of the autoreactive effector T cell responses, beta cell mass will gradually decrease in atrisk individuals, ultimately leading to disease manifestation once a critical threshold has been passed. Support for the existence of this delicate balance was obtained in the NOD mouse, still the most widely studied animal model of type 1 diabetes. Sensitive longitudinal detection of alterations in beta cell mass during diabetes development in these animals may put this theory to the test and may Diabetologia (2008) 51:2145–2147 DOI 10.1007/s00125-008-1181-y