Islet alterations in type 2 diabetes

2型糖尿病(T2D)是退伍军人管理局医疗保健系统面临的一个艰巨且日益严峻的挑战，它代表着一种 一组异质性高血糖疾病，包括胰岛素分泌受损、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调节失调，通常 α细胞分泌的胰升糖素增加，是T2D患者高血糖的原因之一。虽然许多假说 和模型存在，人类胰岛功能障碍的分子机制在T2D中还不完全 明确的，很大程度上未知或未经证实的。关于T2Dβ细胞的大多数模型和假设源于 这是对啮齿动物模型的研究，尚未在人体样本中得到证实或测试。因为有很多人 人类和啮齿动物胰岛的差异，关键是研究人类胰岛环境中潜在的调节因子和 这将是这项提案的重点。这项拟议的研究基于来自捐赠者的胰岛 短期的T2D可损害胰岛素的分泌，促进胰升糖素的分泌，并降低 Pax6是最近在啮齿动物系统中发现的一种胰岛丰富的转录因子，对胰岛β细胞的鉴定和鉴定至关重要 功能维护。目前对PAX6在人胰岛细胞中的作用知之甚少。建议进行的研究 将检验这样一种假设，即PAX6是正常的人类α和β细胞功能所必需的，而降低PAX6 表达有助于T2D胰岛α和β细胞功能障碍的这些目的：(1)确定功能和 体外正常人胰岛PAX6转录调控的转录结果；(2) 体内正常人α或β细胞中PAX6缺失的功能后果；(3)评估PAX6缺失 在短期内，T2D胰岛可通过高血糖素样肽-1(GLP-1)激动剂进行逆转。通过 使用创新的实验方法，例如创建人类伪胰岛，在其中 可修饰表达并将转基因人伪胰岛移植到 用于评估α和β细胞功能的免疫缺陷、无胰高血糖素小鼠模型 在体外和体内，这些研究将扩大我们对调节人类行为的分子过程的理解 α和β细胞功能和胰岛功能障碍，为T2D治疗提供了新的临床可操作信息。

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.