Islet alterations in type 2 diabetes

2型糖尿病（T2 D）是VA医疗保健系统面临的一个巨大且不断增长的挑战， 涉及胰岛素分泌受损、胰岛素抵抗和 肝葡萄糖生成增加。β细胞胰岛素分泌不足和失调，通常 α细胞胰高血糖素分泌增加，导致T2 D高血糖症。虽然许多假设 尽管存在模型，但T2 D中人类胰岛功能障碍的分子机制尚不完全 定义和大部分未知或未经证实。关于T2 D β细胞的大多数模型和假设来自于 在啮齿类动物模型中进行的研究，尚未在人类样本中得到证实或测试。由于许多 由于人类和啮齿动物胰岛的差异，研究人类胰岛背景下的潜在调节剂至关重要， 这将是本提案的一个重点。这项拟议的研究是基于证据，即来自供体的胰岛， 短持续时间T2 D具有受损的胰岛素分泌、增强的胰高血糖素分泌和降低的 PAX 6，一种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胰岛富集转录因子， 功能维护关于PAX 6在人类胰岛细胞中的作用知之甚少。拟议的研究 将检验PAX 6是正常人α和β细胞功能所必需的假设， 表达有助于T2 D胰岛α和β细胞功能障碍，这些目的是：（1）确定功能和 PAX 6转录控制正常人胰岛的体外转录结果;（2）确定PAX 6转录控制正常人胰岛的体外转录结果。 体内正常人α或β细胞PAX 6损失的功能后果;（3）评估PAX 6损失是否 在短期T2 D胰岛中，通过用胰高血糖素样肽-1（GLP-1）激动剂处理而逆转。通过 采用创新的实验方法，如建立人类假胰岛，其中基因 表达可以被修饰，并且将遗传修饰的人假胰岛移植到 免疫缺陷、无胰高血糖素小鼠模型（NSG-GKO），以评估α和β细胞功能 在体外和体内，这些研究将扩大我们的理解的分子过程调节人类 α和β细胞功能和胰岛功能障碍，为T2 D治疗提供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.