TXNIP REGULATION OF ENDOGENOUS BETA CELL MASS

TXNIP 对内源性 β 细胞质量的调节

基本信息

批准号：
10202563
负责人：
Anath Shalev
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202563
关键词：
Affect Agonist Apoptosis Award Beta Cell Cell Line Cell Survival Cells Data Development Diabetes Mellitus Diabetic mouse Dipeptidyl Peptidases GLP-I receptor Glucose High Fat Diet Human Injectable Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Knock-out Knockout Mice Knowledge Light Link Mediating Metabolic MicroRNAs Mus Non-Insulin-Dependent Diabetes Mellitus Oral Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiology Play Process Production Receptor Signaling Regulation Role Signal Pathway Signal Transduction Streptozocin Structure of beta Cell of islet System TXNIP gene Testing Treatment Protocols Type 2 diabetic Work base blood glucose regulation diabetes mellitus therapy glucagon-like peptide 1 glucose tolerance in vivo inhibitor/antagonist insulin secretion islet mRNA Expression morphometry novel novel strategies overexpression protein expression receptor receptor expression receptor function response transcription factor

项目摘要

Diabetes is characterized by loss of pancreatic beta cell mass and over the course of this award we have established thioredoxin-interacting protein (TXNIP) as a critical factor in this process. Recently, we found that TXNIP regulates beta cell microRNA expression and particularly induces beta cell expression of a specific, beta cell-enriched microRNA, miR-204 and thereby inhibits insulin production. Now, we discovered that miR-204 also directly targets the glucagon-like peptide-1 (GLP-1) receptor (GLP1R), revealing a novel link between microRNA and incretin signaling. The GLP1R is essential for incretin-mediated insulin secretion and control of glucose homeostasis as well as for the function of GLP-1-based diabetes therapies that have become widely used in patients with type 2 diabetes. Intriguingly, our preliminary data further demonstrate that miR-204 overexpression downregulates GLP1R in INS-1 beta cells and primary mouse as well as human islets. Moreover, miR-204 as well as TXNIP deletion in vivo in mice promoted islet GLP1R expression and GLP-1-induced insulin secretion and glucose tolerance. In addition, miR-204 knockout (204KO) mice were found to retain a higher beta cell mass in the context of streptozotocin (STZ)-induced diabetes. Together with our extensive previous work on TXNIP and miR-204 and the well documented importance of GLP1R, these findings provide a strong scientific premise for the proposed studies. Our overall hypothesis is that inhibition of TXNIP-induced miR-204 enhances GLP1R expression and function as well as compensatory beta cell mass adaptation. To test this hypothesis, we propose 3 Specific Aims: 1. Elucidate the effects of miR-204 and TXNIP on beta cell GLP1R, using our established miR-204 mimics and inhibitors and TXNIP overexpression system as well as INS-1 cells, human islets and type 2 diabetic human islets. 2. Determine how deletion of miR-204 and TXNIP affect GLP1R expression and function in vivo. By taking advantage of the availability of our novel miR-204 knockout (204KO) mice and our beta cell-specific TXNIP knockout (bTKO) mice we will assess GLP1R expression, responsiveness to GLP1R agonists, glucose-stimulated insulin secretion and glucose homeostasis, under normal conditions and in the context of high fat diet (HFD)-induced insulin resistance and diabetes. 3. Study the mechanisms by which TXNIP-induced miR-204 regulates beta cell mass adaptation. We will investigate any potential differences in beta cell mass, apoptosis, proliferation and/or differentiation resulting from miR-204 deletion in the context of STZ-induced beta cell loss as well as HFD-induced insulin resistance and diabetes. The results of these studies will provide new knowledge in terms of the role TXNIP-induced miR-204 signaling plays in the control of beta cell GLP1R, insulin secretion, glucose homeostasis and beta cell mass adaptation and will shed new light onto the regulation of GLP1R, which currently serves as the target for a large number of diabetes drugs.

糖尿病的特征是胰腺β细胞量的丧失，在此奖项的过程中，我们确定了硫氧还蛋白相互作用的蛋白（TXNIP）作为此过程的关键因素。最近，我们发现TXNIP调节β细胞microRNA的表达，特别是诱导特定的β细胞富含microRNA，miR-204的β细胞表达，从而抑制胰岛素的产生。现在，我们发现miR-204还直接靶向胰高血糖素样肽-1（GLP-1）受体（GLP1R），揭示了microRNA和降量素信号传导之间的新联系。 GLP1R对于肠6介导的胰岛素分泌和葡萄糖稳态的控制以及GLP-1基于GLP-1的糖尿病疗法的功能至关重要，这些糖尿病疗法已广泛用于2型糖尿病患者。有趣的是，我们的初步数据进一步表明，miR-204的过表达下调了INS-1β细胞和原代小鼠以及人类胰岛中的GLP1R。此外，小鼠体内miR-204以及体内的TxNIP缺失促进了胰岛GLP1R表达和GLP-1诱导的胰岛素分泌和葡萄糖耐受性。此外，发现在链蛋白酶（STZ）诱导的糖尿病的背景下，发现miR-204敲除（204KO）小鼠保留了较高的β细胞肿块。加上我们先前在TXNIP和MIR-204的广泛工作以及GLP1R的重要重要性，这些发现为拟议的研究提供了强大的科学前提。我们的总体假设是，抑制TxNIP诱导的miR-204可以增强GLP1R表达和功能以及代偿性β细胞质量适应。为了检验这一假设，我们提出了3个具体目的：1。使用我们已建立的miR-204模拟物和抑制剂以及TXNIP过表达系统以及INS-1细胞，人类和人类胰岛和2型糖尿病人类小岛，阐明了miR-204和TxNIP对β细胞GLP1R的影响。 2。确定miR-204和TxNIP的缺失如何影响GLP1R的表达和体内功能。通过利用我们新型的miR-204敲除（204KO）小鼠的可用性以及我们的β细胞特异性TXNIP敲除（BTKO）小鼠，我们将评估GLP1R的表达，对GLP1R激动剂的反应，在正常情况和饮食中，葡萄糖对GLP1R刺激的胰岛素分泌和葡萄糖的稳态（在疾病和饮食中）的影响（HFD）（HFD）在正常情况下（HFD）。 3。研究TXNIP诱导的miR-204调节β细胞质量适应的机制。我们将研究在STZ诱导的β细胞丢失以及HFD诱导的胰岛素抵抗和糖尿病的情况下，由miR-204缺失导致miR-204缺失引起的β细胞质量，凋亡，增殖和/或分化的任何潜在差异。这些研究的结果将根据TXNIP诱导的miR-204信号传导在控制β细胞GLP1R，胰岛素分泌，葡萄糖稳态和β细胞质量适应中的作用方面提供新的知识，并将为GLP1R的调节提供新的光，目前是大量糖尿病药物的目标。