Advanced Glycation Endproducts, RAGE/DIAPH1 Signaling and Metabolic Dysfunction

高级糖基化终产物、RAGE/DIAPH1 信号传导和代谢功能障碍

基本信息

批准号：
10888085
负责人：
Henry H Ruiz
金额：
$ 5.45万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10888085
关键词：
Acute Adipose tissue Advanced Glycosylation End Products Affect Alleles Attention Binding Biological Availability Body Weight Body Weight decreased Brain Cell Surface Receptors Characteristics Chief Cell Chronic Circulation Cytoplasm Data Diabetes Mellitus Diet Drug Metabolic Detoxication Enzymes Female Food Future Health Homeostasis Human Hyperglycemia Hyperlipidemia Impairment Incidence Inflammation Insulin Resistance Intake Knockout Mice Knowledge Laboratories Lactoylglutathione Lyase Link Lipids Liver Measures Mediating Metabolic Metabolic dysfunction Metabolic syndrome Mus Muscle N(6)-carboxymethyllysine Obesity Organ Pathologic Patients Population Process Proteins Pyruvaldehyde Receptor Inhibition Regulation Rodent Model Signal Transduction Skeletal Muscle Source Testing Therapeutic Thinness Tissue Sample Tissues Transgenic Mice Wild Type Mouse bariatric surgery compliance behavior diet-induced obesity dietary dietary restriction effective therapy glucose metabolism human subject improved inflammatory marker insulin secretion insulin sensitivity insulin signaling male new therapeutic target non-diabetic overexpression prevent prototype receptor for advanced glycation endproducts response skeletal tissue subcutaneous sugar therapeutic target tool western diet

项目摘要

PROJECT SUMMARY Background: Insulin resistance (IR), a hallmark of diabetes, is associated with elevated levels of circulating advanced glycation endproducts (AGEs) and their accumulation in adipose tissue. AGEs are the byproduct of non-enzymatic binding of sugars and/or lipids to proteins, a process that is prevented by specialized enzymes such as glyoxalase 1 (GLO1). Highly processed foods, characteristic of “Western” diets, are a major source of exogenous AGEs and may be linked to the raise in incidence of obesity and diabetes. AGE signaling is primarily mediated by the receptor for advanced glycation endproducts (RAGE), which in turn interacts in the cytoplasm with diaphanous 1 (DIAPH1) to initiate downstream cellular signaling. Thus, determining whether AGE-induced IR requires the RAGE/DIAPH1 signaling axis may identify novel therapeutic targets to treat or prevent insulin resistance and diabetes. Hypothesis: We hypothesize that excessive AGEs, acting along the RAGE/DIAPH1 axis, induce insulin resistance via unknown mechanisms which I aim to unveil. Thus, inhibition of the RAGE/DIAPH1 is anticipated to prevent AGE-induced metabolic impairment. Furthermore, since GLO1 metabolizes AGE precursors, overexpression of GLO1 is hypothesized to enhance AGE-precursor detoxification leading to lower levels of circulating and tissue accumulated AGEs, and therefore protect against AGE-induced insulin resistance. Approach: Preliminary data suggest that carboxymethyllysine (CML-AGE), a prototypic AGE, impairs glucose metabolism without altering insulin secretion, likely by accumulating in metabolically active tissues and altering insulin sensitivity. What is not known is 1) whether CML-AGE differentially affects metabolically-relevant organs, 2) whether it directly affects proteins involved in the insulin signaling cascade or 3) if it requires the RAGE/DIAPH1 signaling axis to exert its detrimental metabolic effects. To test these hypotheses, we will treat lean, male and female wild type mice with CML-AGE either acutely or chronically and determine the mechanisms by which CML-AGE induces IR. Mice devoid of RAGE and/or DIAPH1 will be used to test whether CML-AGE- induced IR requires the RAGE/DIAPH1 signaling axis. We will also determine whether increasing AGE detoxification by overexpressing Glo1 in mice protects from obesity, IR and metabolic dysregulation. The translational relevance of our findings in mice to humans will be assessed by measuring AGEs, GLO1, RAGE, DIAPH1 and inflammatory markers in subcutaneous human adipose tissue samples derived from the non- diabetic patients before and after weight loss surgery which is associated with improved insulin sensitivity. Significance: Results from these studies will likely establish a causal link between AGEs and impaired metabolic homeostasis and have the potential to identify two independent approaches to inhibit/suppress AGE activity that if successful, may provide novel therapeutic targets for the treatment of insulin resistance and diabetes.

项目摘要背景：糖尿病的标志胰岛素抵抗（IR）与循环水平升高有关晚期糖基化最终产物（年龄）及其在脂肪组织中的积累。年龄是糖和/或脂质与蛋白质的非酶结合，该过程由专门的酶预防例如乙二醇酶1（GLO1）。高度加工的食物是“西方”饮食的特征，是外源年龄，可能与肥胖和糖尿病的发生率增加有关。年龄信号是主要的由接收器介导的高级糖基化最终产物（RAGE），又在细胞质中相互作用用diaphanous 1（diaph1）启动下游细胞信号传导。那是确定年龄引起的 IR需要愤怒/diaph1信号轴可能识别出新的热目标以治疗或预防胰岛素抗药性和糖尿病。假设：我们假设沿Rage/Diaph1轴作用的超级年龄会诱导胰岛素我旨在揭露未知机制的抵抗。那是预计愤怒/diaph1的抑制作用为了防止年龄引起的代谢障碍。此外，由于GLO1代谢年龄前体，因此假设GLO1的过表达以增强年龄前体排毒，从而导致较低水平循环和组织积累了年龄，因此可以防止年龄引起的胰岛素抵抗。方法：初步数据表明羧甲基氨（CML-AGE）是一种原型年龄，会损害葡萄糖代谢而不改变胰岛素分泌，可能是通过在代谢活性组织中积聚并改变胰岛素灵敏度。尚不清楚的是1）CML-AGE是否对代谢相关的器官的影响是否有所不同， 2）它直接影响胰岛素信号级联涉及的蛋白质还是3）如果需要 rage/diaph1信号轴执行其有害的代谢作用。为了检验这些假设，我们将对待倾斜，雄性和雌性野生型小鼠，具有CML-AGE的敏锐或慢性时代，并确定了机制 CML-AGE诱导IR。没有愤怒和/或Diaph1的小鼠将用于测试CML-AGE-是否是否诱导的IR需要RAGE/DIAPH1信号轴。我们还将确定年龄是否增加小鼠中过度表达GLO1的排毒可防止肥胖，IR和代谢失调。这我们在小鼠中与人类发现的转化相关性将通过测量年龄，glo1，rage，源自非 - 非 - 减肥手术前后的糖尿病患者与胰岛素敏感性提高有关。意义：这些研究的结果可能会在年龄和代谢受损之间建立因果关系体内平衡，有可能识别两种独立的方法来抑制/抑制年龄活动如果成功，可以为治疗胰岛素抵抗和糖尿病的新型热靶标提供。