Beta cell mass expansion in glucose-infused rats

描述（由申请人提供）：用于未来胰岛素依赖型糖尿病管理的β细胞替代策略将需要在体外扩增胰岛组织用于移植或通过刺激糖尿病患者体内的胰岛生长来诱导新的胰岛。因此，在实现这些目标之前，需要解决的基本问题将是识别和操纵有效扩大功能性β细胞质量的机制。我们已经开发和表征了正常血糖和短暂高血糖输注的大鼠，其中β细胞团快速扩增而不增殖。这些大鼠表现出与导管上皮和腺泡组织相关的β细胞新生的患病率显著增加。这些新生的β细胞对新的或已存在的胰岛的潜在贡献尚不清楚。我们最近还发现了与这些组织中β细胞转录因子表达相关的关键胰岛素信号传导中间体。然而，控制代偿性β细胞新生和胰岛肿块扩张的生长因子和综合信号通路的相互作用远未得到解决。

DESCRIPTION (provided by applicant): Beta-cell replacement strategies for the future management of insulin-dependent diabetes will require amplification of pancreatic islet tissue in vitro for transplantation or induction of new islets by stimulating islet growth within the diabetic patient. Accordingly, fundamental issues to address before these goals can be met will be the identification and manipulation of mechanisms that efficiently expand functional beta-cell mass. We have developed and characterized both normoglycemic and transiently hyperglycemic glucose-infused rats whereby a rapid expansion of beta-cell mass occurs without proliferation. These rats exhibit striking increases in the prevalence of beta-cell neogenesis associated with both the ductal epithelium and acinar tissue. The potential contribution of these nascent beta-cells to new or pre-existing islets is not known. We have also recently identified key insulin-signaling intermediates associated with the expression of beta-cell transcription factors in these tissues. However, the interplay of growth factors and integrated signaling pathways that control compensatory beta-cell neogenesis and islet mass expansion are far from being resolved. We propose that a principal mechanism mediating beta-cell neogenesis and islet mass expansion during a glucose challenge is activation of the insulin-signaling pathway through IRS-2 and the downstream serine/threonine protein kinase B/Akt (Akt). Using our glucose infusion models, we propose to initially focus on the insulin-signaling pathway's activation of beta-cell neogenic events occurring in ducts. We will then examine the nature and mechanisms by which islet beta-cell mass rapidly increases. Finally, we will determine the source of the "acinar-associated" beta-cells and investigate the mechanism of how they may contribute to pre-existing or, possibly, new islets. These studies will establish the foundation for future endeavors to exploit signaling pathways and the factors involved to manipulate and efficiently expand functional beta-cell mass for potential therapies to treat type 1 and severe type 2 diabetic patients.