Beta cell mass expansion in glucose-infused rats

描述（由申请人提供）：用于胰岛素依赖型糖尿病的未来管理的β细胞替代策略将需要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诱导新的胰岛。因此，在实现这些目标之前要解决的基本问题将是鉴定和操纵有效扩增功能性β细胞群的机制。我们已经开发并表征了正常血糖和短暂高血糖葡萄糖输注大鼠，由此β细胞群快速扩增而不增殖。这些大鼠表现出与导管上皮和腺泡组织相关的β细胞新生的发生率显著增加。这些新生β细胞对新的或预先存在的胰岛的潜在贡献尚不清楚。我们最近还确定了与这些组织中β细胞转录因子表达相关的关键胰岛素信号中间体。然而，控制代偿性β细胞新生和胰岛质量扩张的生长因子和整合信号通路的相互作用远未得到解决。 我们提出，在葡萄糖挑战过程中介导β细胞新生和胰岛质量扩张的主要机制是通过IRS-2和下游丝氨酸/苏氨酸蛋白激酶B/Akt（Akt）激活胰岛素信号通路。使用我们的葡萄糖输注模型，我们建议最初集中在胰岛素信号通路的激活β细胞新生事件发生在导管。然后，我们将研究胰岛β细胞质量迅速增加的性质和机制。最后，我们将确定“腺泡相关”β细胞的来源，并研究它们如何促进预先存在的或可能的新胰岛的机制。这些研究将为未来努力开发信号通路和相关因素奠定基础，以操纵和有效扩大功能性β细胞群，用于治疗1型和严重2型糖尿病患者的潜在疗法。

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.