Glut1 and the microvascular complications of diabetes

Glut1 与糖尿病的微血管并发症

• 批准号: 10368340
• 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/10368340
• 关键词: Address; Advanced Glycosylation End Products; Affect; Amputation; Blindness; Blood Glucose; Blood-Retinal Barrier; 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; Play; Preventive; 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; Translations; 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; therapy design; transcription factor

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.

这项提议的目标是确定系统性减少促进性葡萄糖转运体， Glut1(SLC2A1)，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 肾脏疾病(DKD)和糖尿病周围神经病变(DPN)和/或加强目前的护理标准 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缓解，但努力维持 糖尿病患者的正常血糖一直难以捉摸。在这里，我们将调查系统性的削减是否 使用遗传方法的Glut1阻止1型和2型小鼠模型中的DR、DKD和DPN表型 2型糖尿病的原因如下：(1)Glut1在视网膜和构成 视网膜内外血屏障，遍及肾单位、肾小管和结旁 周围神经的区域以及围绕神经的雪旺细胞。(2)体内Glut1的降低 眼睛通过药理学、siRNA或遗传方法减少DR的特征和Glut1的减少 肾单位系膜细胞可预防1型糖尿病小鼠的DKD表型。(3)抑制 钠-葡萄糖共转运体-2(SGLT2)不足以完全阻止DR、DKD和DPN的表型。(4) Glut1的小核苷酸多态与DR和DKD的风险增加相关。(5)集约化 胰岛素治疗可以降低DR、DKD和DPN的患病率，可以在转录和转录后调节Glut1。 翻译级别。由于Glut1在糖尿病视网膜和肾脏中升高，SLC2A1/Glut1的表达减少 而Glut1周转增加可能是强化胰岛素治疗减少DR的机制之一。 DKD和DPN。 这些观察结果构成了我们假设的前提，即减少Glut1将防止 糖尿病的微血管并发症，增加了目前对2型糖尿病的护理标准，以及 有助于强化胰岛素治疗提供对DR、DKD的保护机制 和DPN。我们将通过以下具体目标来检验这一假设。在目标1中，我们将使用Glut1+/-鼠标 其中包含半合子Glut1缺失，以确定全身性Glut1减少是否阻止DR、DKD和 链脲佐菌素诱导的1型糖尿病小鼠模型或Leprdb/dbeNOS-/-小鼠进行性糖尿病模型中的DPN 2型糖尿病。我们将进一步确定是否在目前的标准基础上增加系统性Glut1降低 治疗2型糖尿病、治疗高血糖(二甲双胍)、高血压(雷米普利)和抑制SGLT2 (Empaglifozin)，增强了对糖尿病表型的保护。在目标2中，我们将检验这一假设 胰岛素治疗通过利用STZ诱导的1型糖尿病小鼠模型来调节Glut1。激活 Forkhead Box O转录因子、FOXO1、下游信号转导分子和SLC2A1 mRNA 将测量每个微血管组织中的水平，以确定胰岛素是否可以调节Glut1 从转录上讲。泛素-蛋白酶体途径的激活和Glut1蛋白水平将另外 测量以询问胰岛素对Glut1的翻译后控制。 这些实验将揭示Glut1是否在DR、DKD和DPN的发生中起作用 1型和/或2型糖尿病以及是否可以考虑在未来的发展中靶向降低Glut1 治疗这些疾病的新疗法。近25%的退伍军人患有糖尿病， 因此，对DR、DKD和DPN的护理和治疗对VHA具有重要意义。