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

• 批准号: 10589085
• 负责人: Henry H Ruiz
• 金额: $ 10.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10589085
• 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

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.

项目总结 背景：胰岛素抵抗(IR)是糖尿病的一个标志，与循环水平升高有关 晚期糖基化终末产物(AGEs)及其在脂肪组织中的积累。年龄是年龄的副产品 糖和/或脂类与蛋白质的非酶结合，这是一个由特殊酶阻止的过程 如乙醛酸酶1(GLO1)。以“西式”饮食为特色的精加工食品是营养物质的主要来源 外源性AGE并可能与肥胖症和糖尿病发病率的增加有关。年龄信号主要是 由晚期糖基化终产物受体(RAGE)介导，而RAGE又在细胞质中相互作用 与透明蛋白1(DIAPH1)一起启动下行细胞信号转导。因此，确定年龄诱导的 IR需要RAGE/DIAPH1信号轴可能识别新的治疗靶点来治疗或预防胰岛素 抵抗力和糖尿病。 假设：我们假设过多的年龄，沿着RAGE/DIAPH1轴起作用，诱导胰岛素 通过未知的机制进行抵抗，我的目标是揭示这一点。因此，预计会抑制RAGE/DIAPH1 以防止年龄引起的代谢损伤。此外，由于GLO1代谢AGE前体， GLO1的过度表达被认为是为了增强AGE前体的解毒作用，从而导致较低的 循环和组织积聚AGEs，从而防止AGE诱导的胰岛素抵抗。 研究方法：初步数据表明，羧甲基赖氨酸(CML-AGE)是一种典型的AGE，会损害血糖 新陈代谢而不改变胰岛素分泌，可能是通过在代谢活跃的组织中积累和改变 胰岛素敏感性。目前尚不清楚的是：1)慢性粒细胞白血病的年龄是否对代谢相关的器官有不同的影响， 2)它是否直接影响参与胰岛素信号级联反应的蛋白质，或者3)如果它需要 RAGE/DIAPH1信号轴发挥其有害的代谢效应。为了检验这些假说，我们将 瘦、雄、雌野生型小鼠急性或慢性CML-AGE及其机制的研究 CML-AGE诱导胰岛素抵抗的机制。没有RAGE和/或DIAPH1的小鼠将被用来测试CML-AGE- 诱导IR需要RAGE/DIAPH1信号轴。我们还将确定年龄的增加是否 通过在小鼠中过表达Glo1来解毒，可以保护小鼠免受肥胖、IR和代谢失调的影响。这个 我们在老鼠身上的发现与人类的翻译相关性将通过测量年龄、GLO1、RAGE、 非人皮下脂肪组织中DIAPH1和炎症标志物的表达 糖尿病患者减肥手术前后与胰岛素敏感性改善有关。 意义：这些研究的结果可能会在年龄和新陈代谢受损之间建立因果联系 并有可能确定两种独立的方法来抑制/抑制AGE活性， 如果成功，可能为胰岛素抵抗和糖尿病的治疗提供新的治疗靶点。