Glut1 and the microvascular complications of diabetes

Glut1 与糖尿病的微血管并发症

• 批准号: 10539264
• 负责人: Ivy S Samuels
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539264
• 关键词: Advanced Glycosylation End Products; Affect; Amputation; Blindness; Blood Glucose; Blood Vessels; Blood-Retinal Barrier; Breeding; Caring; Cells; Chronic; Clinical Research; Clinical Trials; Complication; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diabetic Retinopathy; Diabetic mouse; Effectiveness; End stage renal failure; Endothelial Cells; Etiology; Eye; FOXO1A gene; Functional disorder; Future; GLUT-1 protein; Genetic Polymorphism; Genetic Transcription; Glucose; Glucose Transporter; Goals; Hyperglycemia; Hypertension; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Low Prevalence; Lower Extremity; Measures; Mediating; Messenger RNA; Metabolic; Metformin; Microvascular Dysfunction; Modeling; Mus; Nephrons; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Oxidative Stress; Pathology; Pathway interactions; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmacology; Phenotype; Preventive; Production; Quality of life; Ramipril; Regulation; Renal tubule structure; Retina; Risk; Risk Factors; Role; Schwann Cells; Severities; Signal Transduction; Small Interfering RNA; Sodium; Sorbitol; Streptozocin; Testing; Tissues; Ubiquitin; Veterans; blood glucose regulation; cell injury; cohort; combinatorial; comorbidity; cost; diabetic; diabetic patient; disease phenotype; effective therapy; euglycemia; experimental study; genetic approach; glucose transport; glycemic control; in vivo; insight; limb amputation; mesangial cell; mortality; mouse model; multicatalytic endopeptidase complex; new therapeutic target; novel; novel therapeutics; prevent; standard of care; symporter; therapy design; transcription factor; translational impact; type I and type II diabetes

The goal of this proposal is to determine whether systemic reduction of the facilitative glucose transporter, Glut1 (Slc2a1), prevents the major microvascular complications of diabetes: diabetic retinopathy (DR), diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) and/or augments the current standard of care for Type 2 diabetes. Each microvascular complication is mitigated by tight glycemic control, but efforts to maintain euglycemia in diabetic patients has been elusive. Here, we will investigate whether the systemic reduction of Glut1 using a genetic approach prevents DR, DKD and DPN phenotypes in mouse models of both Type 1 and Type 2 diabetes for the following reasons: (1) Glut1 is highly expressed in the retina and the cells that comprise the inner and outer blood retinal barriers, throughout the nephron and tubules of the kidney and in the paranodal region of the peripheral nerves as well as the Schwann cells that surround the nerves. (2) Reduction of Glut1 in the eye via pharmacology, siRNA or genetic approaches reduces hallmarks of DR and reduction of Glut1 in mesangial cells of the nephron prevents DKD phenotypes in mouse models of Type 1 diabetes. (3) Inhibition of the sodium-glucose cotransporter-2 (Sglt2) is insufficient to fully prevent DR, DKD and DPN phenotypes. (4) Small nucleotide polymorphisms in Glut1 are associated with increased risk of both DR and DKD. (5) Intensive insulin therapy, which lowers prevalence of DR, DKD and DPN can regulate Glut1 at both transcription and post- translational levels. Because Glut1 is elevated in the diabetic retina and kidney, reduced Slc2a1/Glut1 expression and increased Glut1 turnover may contribute to the mechanism by which intensive insulin therapy reduces DR, DKD and DPN. These observations form the premise for our hypothesis that reduction of Glut1 will prevent the microvascular complications of diabetes, augment the current standard of care for Type 2 diabetes, and contributes to the mechanism by which intensive insulin therapy confers protection against DR, DKD and DPN. We will test this hypothesis with the following specific aims. In Aim 1 we will utilize the Glut1+/- mouse which harbors a hemizygous Glut1 deletion to determine if systemic reduction of Glut1 prevents DR, DKD and DPN in a STZ-induced mouse model of Type 1 diabetes or in the Leprdb/dbeNOS-/- mouse model of progressive Type 2 diabetes. We will further determine if the addition of systemic Glut1 reduction to the current standard of care for Type 2 diabetes, treatment of hyperglycemia (metformin), hypertension (ramipril) and inhibition of Sglt2 (empaglifozin), augments protection from diabetic phenotypes. In Aim 2 we will test the hypothesis that intensive insulin therapy regulates Glut1 by utilizing the STZ-induced mouse model of Type 1 diabetes. Activation of the Forkhead Box O transcription factor, FOXO1, downstream signal transduction molecules, and Slc2a1 mRNA levels will be measured in each microvascular tissue to determine if Glut1 can be regulated by insulin transcriptionally. Activation of the ubiquitin-proteasome pathway and Glut1 protein levels will additionally be measured to interrogate post-translational control of Glut1 by insulin. These experiments will reveal whether Glut1 contributes to the development of DR, DKD and DPN in Type 1 and/or Type 2 diabetes and if targeted reduction of Glut1 can be considered for the future development of novel therapeutics for the treatment of these pathologies. Nearly 25% of veterans are affected by diabetes, making the care and treatment of DR, DKD and DPN of great significance for the VHA.

这项提案的目的是确定是否系统性减少促进葡萄糖转运蛋白， Glut 1（Slc 2a 1），预防糖尿病的主要微血管并发症：糖尿病视网膜病变（DR），糖尿病性视网膜病变（DR）。 肾脏疾病（DKD）和糖尿病周围神经病变（DPN）和/或增强当前标准治疗 治疗2型糖尿病每种微血管并发症都可以通过严格的血糖控制来减轻，但要努力维持 糖尿病患者中的Euclidin是难以捉摸的。在这里，我们将调查是否系统性减少 Glut 1使用遗传方法预防1型和2型糖尿病小鼠模型中的DR、DKD和DPN表型 2型糖尿病的发病原因如下：（1）Glut 1在视网膜和包括视网膜的细胞中高度表达， 内部和外部血视网膜屏障，遍及肾单位和肾小管以及结旁 周围神经区域以及神经周围的许旺细胞。(2)Glut 1的减少 通过药理学、siRNA或遗传方法减少DR的标志和Glut 1的减少， 肾单位的系膜细胞防止1型糖尿病小鼠模型中的DKD表型。(3)抑制 钠-葡萄糖协同转运蛋白-2（Sglt 2）不足以完全预防DR、DKD和DPN表型。（四） Glut 1的小核苷酸多态性与DR和DKD的风险增加相关。(5)密集 降低DR、DKD和DPN患病率的胰岛素治疗可在转录和后 翻译水平。由于Glut 1在糖尿病视网膜和肾脏中升高，Slc 2a 1/Glut 1表达降低， 并且Glut 1周转增加可能有助于强化胰岛素治疗减少DR的机制， DKD和DPN。 这些观察结果构成了我们的假设前提，即Glut 1的减少将阻止 糖尿病的微血管并发症，提高了2型糖尿病的当前护理标准，并且 有助于强化胰岛素治疗对DR、DKD的保护机制 DPN。我们将通过以下具体目标来检验这一假设。在目标1中，我们将利用Glut 1 +/-小鼠 其具有半合子Glut 1缺失，以确定Glut 1的系统性减少是否预防DR、DKD和 STZ诱导的1型糖尿病小鼠模型或进行性糖尿病Leprdb/dbeNOS-/-小鼠模型中的DPN 2型糖尿病我们将进一步确定是否增加系统性Glut 1减少到目前的标准， 护理2型糖尿病，治疗高血糖症（二甲双胍），高血压（雷米普利）和抑制Sglt 2 （恩格列净），增强对糖尿病表型的保护。在目标2中，我们将检验密集型的假设， 胰岛素治疗通过利用STZ诱导的1型糖尿病小鼠模型调节Glut 1。激活 叉头盒O转录因子、FOXO 1、下游信号转导分子和Slc 2a 1 mRNA 将测量每个微血管组织中的Glut 1水平，以确定Glut 1是否可以由胰岛素调节 转录。泛素-蛋白酶体途径和Glut 1蛋白水平的激活将另外被 测量以询问胰岛素对Glut 1的翻译后控制。 这些实验将揭示Glut 1是否有助于糖尿病患者DR、DKD和DPN的发生。 1型和/或2型糖尿病，以及是否可以考虑在未来开发中靶向降低Glut 1 治疗这些疾病的新疗法。近25%的退伍军人患有糖尿病， 使DR、DKD和DPN的护理和治疗对于VHA具有重要意义。