Beta cell mass expansion in glucose-infused rats

注射葡萄糖的大鼠中β细胞质量扩张

• 批准号: 7214158
• 负责人: THOMAS JETTON
• 金额: $ 26.5万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214158
• 关键词: Acinar Cell; Address; Amylases; Animals; Apoptosis; Appearance; Award; B-Lymphocytes; Beta Cell; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Data; Development; Duct (organ) structure; Ductal; Ductal Epithelium; Employee Strikes; Event; Exhibits; Financial compensation; Foundations; Funding; Future; G Cells; Gene Expression; Generations; Glucose; Goals; Growth; Growth Factor; Hyperglycemia; Hypertrophy; In Vitro; Infusion procedures; Insulin Signaling Pathway; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Mediating; Modeling; Natural regeneration; Nature; Numbers; Organ Size; Pancreas; Patients; Play; Prevalence; Process; Proto-Oncogene Proteins c-akt; Rattus; Recruitment Activity; Role; Serine; Signal Pathway; Signal Transduction; Source; Threonine; Tissues; Transplantation; Work; beta cell replacement; day; diabetic; forkhead protein; human FRAP1 protein; in vivo; insulin signaling; islet; paired box 5 protein (B-cell lineage specific activator); progenitor; size; time interval; transcription factor; transdifferentiation

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.

描述（由申请人提供）：未来管理胰岛素依赖性糖尿病的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。我们已经开发并表征了血糖正常和短暂高血糖的葡萄糖输注大鼠，其中β细胞质量快速扩张而不增殖。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着增加。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中间体。然而，生长因子和控制代偿性β细胞新生和胰岛质量扩张的整合信号通路之间的相互作用还远未得到解决。 我们提出，在葡萄糖挑战期间介导 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，我们建议首先关注胰岛素信号通路对导管中发生的β细胞新生事件的激活。然后我们将研究胰岛β细胞质量快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。这些研究将为未来利用信号通路和相关因素来操纵和有效扩大功能性β细胞质量奠定基础，以用于治疗1型和严重2型糖尿病患者的潜在疗法。