Islet alterations in type 2 diabetes

2 型糖尿病中的胰岛改变

• 批准号: 10012458
• 负责人: ALVIN C POWERS
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012458
• 关键词: Affect; Agonist; Alpha Cell; Beta Cell; Binding; Cell physiology; Cells; ChIP-seq; Color; Data; Defect; Diabetes Mellitus; Disease; Environment; Exposure to; Functional disorder; GLP-I receptor; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucagon; Grant; Healthcare Systems; Hepatic; Hormones; Human; Hyperglycemia; Immunodeficient Mouse; Impairment; In Vitro; Individual; Insulin; Insulin Resistance; Investigation; Islet Cell; Islets of Langerhans; Knockout Mice; Knowledge; Maintenance; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Paracrine Communication; Pathogenesis; Play; Process; Production; Rodent; Rodent Model; Role; Sampling; System; Testing; Transcriptional Regulation; Transplantation; Veterans; base; cell type; clinically actionable; clinically relevant; common treatment; exenatide; gene product; genetic manipulation; glucagon-like peptide 1; glucose production; human model; improved; improved functioning; in vivo; innovation; insulin secretion; islet; knock-down; mouse model; new technology; non-diabetic; single cell sequencing; small hairpin RNA; transcription factor; transcriptome

Type 2 diabetes mellitus (T2D), a formidable and growing challenge to the VA healthcare system, represents a heterogenous set of hyperglycemic disorders involving impaired insulin secretion, insulin resistance, and increased hepatic glucose production. Both insufficient insulin secretion from β cells and dysregulated, typically increased, glucagon secretion from α cells, contribute to the hyperglycemia in T2D. While many hypotheses and models exist, the molecular mechanisms responsible for human islet dysfunction in T2D are incompletely defined and largely unknown or unproven. Most models and hypotheses about the T2D β cell arise from studies of rodent models and have not been confirmed or tested in human samples. Because of the many differences in human and rodent islets, it is critical to study potential regulators in a human islet context and that will be a focus of this proposal. This proposed studies are based on evidence that islets from donors with short-duration T2D have impaired insulin secretion, enhanced glucagon secretion, and reduced expression of PAX6, an islet-enriched transcription factor recently shown in rodent systems critical to islet β cell identify and functional maintenance. Very little is known about the role of PAX6 is human islet cells. The proposed studies will test the hypothesis that PAX6 is required for normal human α and β cell function and that reduced PAX6 expression contributes to T2D islet α and β cell dysfunction in these aims: (1) Determine the functional and transcriptional consequences of PAX6 transcriptional control normal human islets in vitro; (2) Determine the functional consequences of PAX6 loss from normal human α or β cells in vivo; (3) Assess whether PAX6 loss in short-duration T2D islets is reversed by treatment with a Glucagon-like Peptide-1 (GLP-1) agonist. By employing innovative experimental approaches such as creation of human pseudoislets in which gene expression can be modified and transplantation of genetically modified human pseudoislets into immunodeficient, glucagon-less mouse model (NSG-GKO) to allow for the assessment of α and β cell function in vitro and in vivo, these studies will expand our understanding of the molecular processes regulating human α and β cell function and islet dysfunction, leading to new clinically actionable information for T2D treatment.

2型糖尿病（T2D）是对VA医疗系统的巨大挑战，代表了一个 涉及胰岛素分泌受损，胰岛素抵抗和 增加肝葡萄糖的产生。从β细胞中分泌胰岛素不足和失调，通常是 增加的，从α细胞中分泌的臀部分泌，导致T2D中的高血糖症。而许多假设 并且存在模型，T2D中负责人胰岛功能障碍的分子机制并不完全 定义且在很大程度上未知或未经证实。关于T2Dβ细胞的大多数模型和假设来自 啮齿动物模型的研究尚未在人类样品中得到证实或测试。因为很多 人类和啮齿动物胰岛的差异，在人类胰岛环境中研究潜在调节剂至关重要 这将是该提议的重点。这项拟议的研究是基于证据表明的证据表明 短期T2D损害了胰岛素的分泌，增强的臀部分泌和降低的表达 PAX6，富含胰岛的转录因子最近在啮齿动物系统中显示的对胰岛β细胞鉴定至关重要的 功能维护。关于PAX6的作用是人类胰岛细胞，知之甚少。提出的研究 将检验以下假设：正常人α和β细胞功能需要PAX6，并且降低了PAX6 在这些目的中，表达有助于T2D小岛α和β细胞功能障碍：（1）确定功能和 PAX6转录控制正常人胰岛在体外的转录后果； （2）确定 PAX6在体内受到正常人α或β细胞损失的功能后果； （3）评估PAX6是否损失 在短期中，用胰高血糖素样肽-1（GLP-1）激动剂处理T2D胰岛可以逆转。经过 采用创新的实验方法，例如创建人类伪书的基因 可以修改表达，并将一般修改的人类伪源移植到 免疫缺陷，无胰小鼠模型（NSG-GKO），以评估α和β细胞功能 在体外和体内，这些研究将扩展我们对调节人类的分子过程的理解 α和β细胞功能和胰岛功能障碍，导致T2D处理的新临床可行信息。