Islet alterations in type 2 diabetes

2 型糖尿病中的胰岛改变

• 批准号: 10359028
• 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/10359028
• 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; gene regulatory network; 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; transcription regulatory network; 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 医疗保健系统的一个巨大且日益严峻的挑战，代表着 一组异质性高血糖疾病，涉及胰岛素分泌受损、胰岛素抵抗和 增加肝脏葡萄糖的产生。 β 细胞胰岛素分泌不足和失调，通常 α 细胞分泌的胰高血糖素增加，导致 2 型糖尿病 (T2D) 中的高血糖。虽然有很多假设 尽管模型存在，但造成 T2D 人类胰岛功能障碍的分子机制尚不完全 已定义，但很大程度上未知或未经证实。大多数关于 T2D β 细胞的模型和假设都源自 啮齿动物模型的研究尚未在人类样本中得到证实或测试。因为有很多 人类和啮齿动物胰岛的差异，研究人类胰岛环境中的潜在调节因子至关重要 这将是本提案的重点。这项拟议的研究基于以下证据：来自患有以下疾病的捐赠者的胰岛 短期 T2D 会导致胰岛素分泌受损、胰高血糖素分泌增强以及 PAX6 是一种富含胰岛的转录因子，最近在啮齿类动物系统中发现，对于胰岛 β 细胞的识别和识别至关重要 功能维护。关于 PAX6 在人类胰岛细胞中的作用知之甚少。拟议的研究 将检验以下假设：正常人类 α 和 β 细胞功能需要 PAX6，并且 PAX6 减少 表达有助于 T2D 胰岛 α 和 β 细胞功能障碍，其目的如下：(1) 确定功能和功能 PAX6 转录控制正常人胰岛的体外转录后果； (2) 确定 体内正常人 α 或 β 细胞 PAX6 缺失的功能后果； (3) 评估PAX6是否丢失 在短期 T2D 胰岛中，胰高血糖素样肽 1 (GLP-1) 激动剂治疗可逆转。经过 采用创新的实验方法，例如创建人类伪胰岛，其中基因 可以修改表达并将基因修饰的人类伪胰岛移植到 免疫缺陷、无胰高血糖素小鼠模型 (NSG-GKO)，可用于评估 α 和 β 细胞功能 在体外和体内，这些研究将扩大我们对调节人类分子过程的理解 α 和 β 细胞功能以及胰岛功能障碍，为 T2D 治疗提供新的临床可操作信息。