The dark side of islet vasculature

Abstract

Pancreatic islets are highly vascularised and contain about five times more capillaries than exocrine pancreatic tissue [1, 2]. In addition, the islets receive 5–15% of the entire pancreatic blood supply, even though they represent only 1–2% of the pancreatic mass [3]. Moreover, as determined by beta cellor pancreas-specific deletion of vascular endothelial growth factor-A (VEGF-A), the islet microvasculature is required for normal insulin release and physiological blood glucose levels [4, 5], indicating that a dense islet vasculature is needed for proper islet function. In addition, VEGF-A is necessary for proper islet revascularisation following islet transplantation [5, 6]. Interestingly, Carlsson and colleagues recently suggested that there are two populations of islets within a healthy rodent pancreas: (1) a large islet population that is well bloodperfused and oxygenated, contains a dense vascular network and has a high beta cell proliferation rate and strong secretory function, and (2) a small population of islets representing about 20–25% of all islets within a rat pancreas that are not well perfused or well oxygenated, contain only very few proliferating beta cells and have a low secretory function [7, 8]. The authors employ fluorescent microspheres that they inject into the arterial blood stream to discriminate between microsphere-containing, well-perfused islets and non-perfused islets harbouring no microspheres [9]. Importantly, the latter islets can be recruited on demand into the well-perfused and functional islet population, as evidenced by the conversion of all islets into well-perfused ones following partial pancreatectomy [7]. The correlation between vascular density and islet function can be partially explained by the fact that islet beta cells metabolise glucose almost exclusively via aerobic glycolysis, making them heavily dependent on a high and continuous supply of oxygen [10]. Moreover, the blood vessels within the islets also contribute to islet function by supplying paracrine factors, such as components of the vascular basement membrane or hepatocyte growth factor [11, 12]. In their present study, reported in this issue ofDiabetologia [13], Ullsten and colleagues report that highly perfused islets are more susceptible to cell death induced by the inflammatory cytokines TNFα, IFNγ and IL-1β or hypoxia in vitro. In addition, despite being better vascularised and oxygenated in the host, the highly perfused, microparticle-containing islets were found to be more prone to cell death and fibrosis. Therefore, the findings reveal for the first time the other side of the vascularisation coin: strongly vascularised islets seem to be more susceptible to cell death following islet transplantation. This finding could be explained by the highly perfused islets being more accessible to inflammatory cytokines and immune cells. Alternatively, or additionally, these islets are metabolically more active and therefore more prone to the induction of cell death. A high glycolytic flux in islets that are more metabolically active, in combination with the relatively limited capability of islet cells to remove reactive oxygen P. In’t Veld (*) Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium e-mail: intveld@vub.ac.be