RESOURCE IMPACT

Abstract

Insulin deficiency underlies both major forms of diabetes. In type 1 diabetes, the immune system attacks and destroys the insulin-producing β-cells in the pancreatic islets of Langerhans, leaving few, if any, of these crucial cells. Patients with type 2 diabetes have reduced numbers of β-cells, which are not sufficient to overcome the insulin resistance that comes with weight gain and a sedentary lifestyle. Insulin production declines further in type 2 diabetics as the disease progresses, eventually causing the failure of all currently available therapies for normalizing blood glucose except for insulin replacement. Therapies that enable replacement of β-cells are needed for both type 1 and type 2 diabetes, and we need animal models for identifying and testing these therapies.As islet cells develop from progenitor cells, they transiently express the transcription factor neurogenin-3. The authors have made transgenic mice in which developing islet cells can be detected in living tissues, by using the regulatory regions of the human neurogenin-3 gene to drive expression of secreted alkaline phosphatase (SeAP) and enhanced green florescent protein (EGFP) in these developing cells. They show in both intact animals and pancreatic organ cultures that EGFP fluorescence and secretion of SeAP accurately mark neurogenin-3-expressing cells, thus serving as indicators of islet cell genesis. Using cells from the transgenic mice, the authors then look at regulation of neurogenin-3 expression in fetal pancreatic organ cultures: neurogenin-3 expression can be inhibited by growth and differentiation factor 11 (GDF11), and is induced by blocking expression of a known inhibitor of neurogenin-3 signaling, the Notch protein. Interestingly, blocking Notch only induces neurogenin-3 expression during a narrow developmental time window corresponding to the normal peak in neurogenin-3 expression. In adult mice, partial pancreatectomy decreases circulating SeAP levels, whereas duct ligation increases them.This model provides a convenient tool for following the differentiation of new islet cells in living cells, tissues and animals, and for testing the impact of differentiation interventions. It can be used to dissect the pathways that regulate islet cell generation, both during the critical fetal period that sets the initial size of the β-cell population, and during β-cell regeneration in the adult. An understanding of these processes will provide a basis for explaining why βcell genesis fails in type 2 diabetes. In addition, this mouse can be used to screen and test potential methods for generating β-cells for the treatment of both type 1 and type 2 diabetes.