Glut1 and the microvascular complications of diabetes

Glut1 与糖尿病的微血管并发症

基本信息

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
项目类别：
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

项目摘要

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.

该提案的目标是确定促进性葡萄糖转运蛋白的全身性减少是否， 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/或增强当前的护理标准对于2型糖尿病。严格的血糖控制可以减轻每种微血管并发症，但努力维持血糖糖尿病患者的血糖正常一直难以捉摸。在这里，我们将研究是否系统性地减少了 Glut1 使用遗传方法可预防 1 型和 1 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在视网膜及其组成细胞中高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雪旺细胞。 (2) 减少Glut1 通过药理学、siRNA 或遗传方法减少眼睛的 DR 特征并减少 Glut1 肾单位系膜细胞可预防 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 (Sglt2) 不足以完全预防 DR、DKD 和 DPN 表型。 (4) Glut1 中的小核苷酸多态性与 DR 和 DKD 风险增加相关。 (5) 强化胰岛素治疗可以降低 DR、DKD 和 DPN 的患病率，并且可以在转录和转录后调节 Glut1 翻译水平。由于 Glut1 在糖尿病视网膜和肾脏中升高，Slc2a1/Glut1 表达减少 Glut1 周转率的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假设的前提，即减少 Glut1 将阻止糖尿病的微血管并发症，增强当前 2 型糖尿病的护理标准，以及促进强化胰岛素治疗预防 DR、DKD 的机制和 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+/- 鼠标其含有半合子 Glut1 缺失，以确定 Glut1 的系统性减少是否可以预防 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将系统性 Glut1 减少添加到当前的标准中 2 型糖尿病护理、高血糖治疗（二甲双胍）、高血压（雷米普利）和 Sglt2 抑制（empaglifozin），增强对糖尿病表型的保护。在目标 2 中，我们将检验以下假设：强化胰岛素疗法通过利用 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 Glut1 是否可以通过胰岛素调节转录地。泛素蛋白酶体途径和 Glut1 蛋白水平的激活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 是否有助于 DR、DKD 和 DPN 的发展 1型和/或2型糖尿病，如果有针对性地减少Glut1，可以考虑用于未来的发展治疗这些病症的新疗法。近25%的退伍军人患有糖尿病，使得 DR、DKD 和 DPN 的护理和治疗对于 VHA 具有重要意义。