Metabolic crosstalk through vascular endothelium-secreted factors

通过血管内皮分泌因子的代谢串扰

• 批准号: 10463840
• 负责人: Xinchun Pi
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE 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: 2020-09-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463840
• 关键词: Adult; Antidiabetic Drugs; Binding Proteins; Body Weight decreased; Bone Morphogenetic Proteins; Cholesterol; Clinical; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endocrine; Endocytosis; Endocytosis Inhibition; Endosomes; Endothelial Cells; Endothelium; Glucose Intolerance; Hepatic; Hepatocyte; Hormones; Human; Hyperglycemia; Hyperinsulinism; Individual; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Integral Membrane Protein; Knock-out; Knowledge; Link; Liver; Lysosomes; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Pore Complex; Nutrient; Obese Mice; Obesity; Organ; Pathway interactions; Peripheral; Plasma; Play; Prevalence; Proteins; Proteomics; Recombinants; Role; Stress; Testing; Tissues; Vascular Endothelium; Viral; Weight Gain; blood glucose regulation; db/db mouse; diabetic; experimental study; glucose production; glucose tolerance; glucose uptake; improved; insight; insulin regulation; insulin sensitivity; insulin signaling; intracellular protein transport; knock-down; mouse model; non-alcoholic fatty liver disease; novel therapeutics; screening; small molecule; systemic inflammatory response; therapeutic target

Abstract The metabolic disorders of obesity and type 2 diabetes mellitus (T2DM) impact one in three adults. The inability of insulin to suppress hepatic glucose production and promote glucose uptake into peripheral tissues is a hallmark of T2DM. However, the underlying mechanism of liver insulin resistance remains incompletely understood. This gap in knowledge is an important problem because it hinders the development of targeted metabolic therapies to manage the growing clinical burden of T2DM. The vascular endothelium coordinates the delivery of endocrine hormones and small molecules to target tissues. Yet, how specific endothelial factors exert impacts in metabolic tissues remains undefined. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER), highly secreted from vascular endothelium, adapts endothelial cells (ECs) to inflammatory and nutrient stress in diverse organ microenvironments. In new studies, we observed inducible knockout of BMPER (iKO) globally or specifically in endothelium caused hyperinsulinemia, glucose intolerance and insulin resistance independently from obesity and inflammation. These results suggest the vascular endothelium secretes BMPER to maintain glucose homeostasis. Subsequent experiments demonstrated adeno-associated viral BMPER delivery dramatically alleviated diabetes in mice. In humans, BMPER plasma levels are reduced in insulin resistant subjects compared to normoglycemic subjects, supporting an important role for BMPER in defending insulin sensitivity. Mechanistically, we observed BMPER transactivated the insulin signaling pathway in metabolic tissues. Therefore, we hypothesize that BMPER endocytosis promotes insulin sensitivity. To test this hypothesis, we propose the following aims: 1) determine the metabolic consequences of BMPER depletion; 2) establish the anti-diabetic potential of recombinant BMPER; and 3) define the mechanisms that govern BMPER regulation of insulin action. Collectively, these studies suggest an uncharacterized pathway that may define new therapies to minimize the long-term clinical burden of T2DM.

抽象的 肥胖和2型糖尿病（T2DM）的代谢疾病影响三个成年人中的一种。这 胰岛素无法抑制肝葡萄糖的产生并促进葡萄糖吸收到周围组织 T2DM的标志。但是，肝胰岛素抵抗的潜在机制仍然不完全 理解。知识差距是一个重要的问题，因为它阻碍了目标的发展 代谢疗法来管理T2DM日益增长的临床负担。 血管内皮协调内分泌激素和小分子的递送到靶 组织。然而，特定的内皮因子如何在代谢组织中发挥影响仍未定义。骨 形态发生蛋白（BMP） - 结合内皮调节剂（BMPER），高度分泌 内皮，使内皮细胞（EC）适应各种器官的炎症和营养应激 微环境。在新的研究中，我们在全球或特别是在 内皮引起高胰岛素血症，葡萄糖不耐症和胰岛素抵抗，独立于肥胖症 和炎症。这些结果表明血管内皮分泌BM以维持葡萄糖 稳态。随后的实验证明了与腺相关的病毒BMPer递送 减轻小鼠的糖尿病。在人类中，胰岛素抵抗受试者的BMPER血浆水平降低 与正常血糖受试者相比，支持BMPER在捍卫胰岛素敏感性中的重要作用。 从机械上讲，我们观察到BMPER反式激活代谢组织中的胰岛素信号通路。 因此，我们假设BMPER内吞作用会促进胰岛素敏感性。为了检验这一假设，我们 提出以下目的：1）确定BMPER消耗的代谢后果； 2）建立 重组BMPER的抗糖尿病潜力； 3）定义控制BMPER调节的机制 胰岛素作用。总的来说，这些研究提出了一种未表征的途径，可以定义新的疗法 为了最大程度地减少T2DM的长期临床负担。