Destruction of the insulin-producing beta cells leads to IDDM. The present goal of our work is to ascertain whether islets of adults contain beta precursor cells and to later establish protocols that will promote beta cell neogenesis. We developed a novel system in which new beta cells (NBC's) are induced to differentiate from putative beta cell precursors. Following depletion of existing beta cells by streptozotocin (SZ), a specific beta cell toxin, we found that cells expressing the phenotype characteristic of embryonic beta cells differentiated in islets and that this step was followed by the appearance of NBC's. Moreover, the restoration of normoglycemia by insulin therapy dramatically increased beta cell neogenesis. We now propose to identify the source of the NBC's.
In specific aim #1, we will test whether IN+ cells that reappear in islets of SZ-treated mice following restoration of normoglycemia are NBC's or """"""""old"""""""" beta cells that survived the effect of the toxin. To do this, we will test whether beta cell neogenesis occurs in mice in which """"""""old"""""""" beta cells are identified by the presence of a molecular marker. In the specific aim #2, we will seek to determine whether the NBC's are generated by non-beta cells of the pancreas. To accomplish this goal, we will examine the process of beta cell neogenesis following SZ and insulin treatment in normoglycemic mice in which glucagon and amylase cells and the cells they generate are permanently labeled. These approaches could lend proof to the hypothesis that intra-islet precursors play an important role in beta cell regeneration in vivo in this and other models of IDDM.
| Kedees, Mamdouh H; Guz, Yelena; Vuguin, Patricia M et al. (2007) Nestin expression in pancreatic endocrine and exocrine cells of mice lacking glucagon signaling. Dev Dyn 236:1126-33 |
| Vuguin, Patricia M; Kedees, Mamdouh H; Cui, Lingguang et al. (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147:3995-4006 |
