Role of Chromogranin A in Metabolic Syndrome

嗜铬粒蛋白 A 在代谢综合征中的作用

• 批准号: 7931801
• 负责人: SUSHIL K MAHATA
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931801
• 关键词: Adenosine Monophosphate; Adipocytes; Adrenal Cortex Hormones; Adrenergic Receptor; Affect; Attenuated; Baroreflex; Blood Glucose; Blood Pressure; C-Peptide; CHGA gene; Cardiovascular Diseases; Catecholamines; Cells; Chromogranin A; Chromogranins; Chronic; Corticosterone; Coupled; Development; Diabetes Mellitus; Diabetic mouse; Diet; Drosophila pros protein; Engineering; Equilibrium; Essential Hypertension; Euglycemic Clamping; Fatty acid glycerol esters; Gluconeogenesis; Gluconeogenesis Inhibition; Glucose; Glucose Clamp; Glucose Intolerance; Glycogen; Goals; Heart Rate; Hepatic; Hepatocyte; Hormones; Hyperglycemia; Hypertension; Hypoglycemia; Hypotension; Insulin; Insulin Resistance; Knockout Mice; Lipids; Lipodystrophy; Liver; Malaise; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Mus; Muscle; Neurosecretory Systems; Nicotine; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathway interactions; Patients; Peptides; Phenotype; Plasma; Play; Protein Family; Protein Kinase; Proteolytic Processing; Pyruvate; Regulation; Role; Structure of beta Cell of islet; Supplementation; Testing; Therapeutic Effect; Time; Tissues; United States; Variant; Vasodilator Agents; Wild Type Mouse; alpha-adrenergic receptor; base; beta-adrenergic receptor; blood glucose regulation; cardiovascular risk factor; chromogranin A (344-364); db/db mouse; desensitization; diabetic; feeding; glucose disposal; glucose production; glucose tolerance; glucose transport; glucose uptake; glycogenolysis; heart rate variability; human NOS3 protein; improved; indexing; insight; insulin secretion; insulin sensitivity; insulin tolerance; member; mortality; mouse model; novel; pancreastatin; peptide hormone; prevent; receptor function; secretogranins; vasostatin

DESCRIPTION (provided by applicant): Project Summary: Obesity, lipodystrophy, diabetes and hypertension collectively constitute "Metabolic Syndrome" (MS). MS generally causes cardiovascular disease (CVD), which is the leading cause of mortality and morbidity in the United States. Insulin resistance is a central component defining the MS. The primary goal of this proposal is to reduce hypertension and at the same time minimize hyperglycemia and glucose intolerance associated with insulin resistance. We have identified that chromogranin A (Chga)-derived peptide, catestatin (CST), lowers blood pressure (BP) and heart rate (HR) by inhibiting release of catecholamines. Chga, an index member of the chromogranin/secretogranin protein family, is a pro-protein that is ubiquitously expressed in neuroendocrine tissues. Proteolytic processing of Chga gives rise to biologically active peptides such as the dysglycemic hormone pancreastatin, vasodilator vasostatin, and the catecholamine release inhibitory peptide CST. To gain a better insight into the role of Chga in metabolic disorder, we have generated Chga knockout mice (Chga-KO), which display hypertension, high plasma catecholamines, increased hepatic sensitivity to insulin and muscle insulin resistance. CST replacement in Chga-KO mice normalizes BP, suppresses insulin clearance, elevates insulin level to normal and improves glucose disposal. One of the intriguing functions of CST is the regulation of metabolic insulin clearance (MIC) in liver. Strong association exists between essential hypertension and decreased MIC. CST deficient Chga-KO mice show high MIC, as judged by C-peptide/insulin molar ratio, leading to low level of insulin. We hypothesize that essential hypertension-induced decrease in MIC requires interaction with CST. Therefore, CST could play an important role in regulation of MIC. In absence of CST, when challenged with glucose, insulin secretion from pancreatic 2-cells alone will not be adequate to dispose blood glucose. Therefore, CST is required to maintain euglycemia through suppression of hepatic insulin clearance. CST maintains glucose homeostasis by balancing increased gluconeogenesis with increased glucose disposal and decreased glycogenolysis. CST transiently stimulates gluconeogenesis by attenuating endothelial nitric oxide synthase (eNOS) and 5'-adenosine monophosphate-activated protein kinase (AMPK), and enhances glucose disposal and glycogen storage by preventing desensitization of adrenergic receptor actions via suppression of insulin clearance and by maintaining of low NO levels. In addition, CST promotes lipid and glucose disposal and thereby protects against excessive rise in glucose level. Moreover, CST pretreatment "rescues" Chga-KO mice from elevated BP and higher plasma catecholamines. This proposal will focus on the discovery of novel pathways for regulation of insulin and glucose levels by CST in genetically engineered Chga-KO and CST-KO mice. On the basis of our findings on Chga-KO mice, we propose to test CST functions in a well-established type 2 diabetic (db/db) mouse model. Towards that end, we propose two Specific Aims: 1. Determine the pathway of CST-induced regulation of insulin sensitivity, insulin clearance and glucose homeostasis in wild-type, Chga-KO and CST-KO mice. 2. Evaluate the potential therapeutic effects of CST and its variants on insulin sensitivity and baroreflex sensitivity and heart rate variability in high fat diet-induced insulin resistant and in db/db diabetic mice. PUBLIC HEALTH RELEVANCE: Project Narrative: There are a large number of veterans with type 2 diabetes (T2DM) and cardiovascular diseases (CVD). Most people with obesity, T2DM and lipid disorders eventually develop CVD including hypertension. CVD is the leading cause of mortality and morbidity in the United States. The primary goal of this proposal is to reduce hypertension and at the same time minimize diabetic conditions associated with insulin resistance. The applicant proposes that an endogenous peptide, catestatin (CST), may serve as an appropriate therapeutic agent by performing dual jobs of (i) reducing hypertension and (ii) minimizing metabolic disorders. CST does that by (i) reducing the levels of stress hormones like catecholamines as well as chemicals like nitric oxide which are involved in the regulation of blood pressure, (ii) regulating insulin level, and by (iii) improving utilization of excess glucose and lipids. The present proposal will explore the mechanisms underlying the above functions of CST in genetically engineered mice.

描述(由申请人提供)： 项目简介：肥胖、脂肪营养不良、糖尿病和高血压共同构成代谢综合征(MS)。多发性硬化症通常导致心血管疾病(CVD)，这是美国死亡和发病的主要原因。胰岛素抵抗是定义多发性硬化的核心因素，这项建议的主要目标是降低高血压，同时将与胰岛素抵抗相关的高血糖和葡萄糖耐量降低到最低。我们已经证实，嗜铬粒蛋白A(Chga)衍生的多肽，儿茶素(CST)，通过抑制儿茶酚胺的释放而降低血压(BP)和心率(HR)。CHGA是嗜铬粒蛋白/分泌颗粒蛋白家族的索引成员，是一种在神经内分泌组织中广泛表达的前体蛋白。CHGA的蛋白分解过程产生生物活性多肽，如降血糖激素胰腺抑素、血管扩张剂血管抑素和儿茶酚胺释放抑制肽CST。为了更好地了解CHGA在代谢紊乱中的作用，我们产生了CHGA基因敲除小鼠(CHGA-KO)，这些小鼠表现出高血压、高儿茶酚胺、肝脏对胰岛素的敏感性增加和肌肉胰岛素抵抗。在CHGA-KO小鼠中，CST替代使血压正常化，抑制胰岛素清除，将胰岛素水平提高到正常水平，并改善葡萄糖处置。CST的一个有趣的功能是调节肝脏的代谢胰岛素清除(MIC)。原发性高血压与MIC降低之间存在很强的相关性。Cst基因缺陷的CHGA-KO小鼠表现出较高的MIC，以C-肽/胰岛素摩尔比为指标，导致胰岛素水平较低。我们假设，高血压引起的MIC降低需要与CST相互作用。因此，Cst可能在MIC的调节中发挥重要作用。在没有CST的情况下，当用葡萄糖挑战时，仅从胰腺2-细胞分泌胰岛素将不足以处理血糖。因此，CST需要通过抑制肝脏胰岛素清除来维持正常血糖。CST通过平衡增加的糖异生与增加的葡萄糖处置和减少的糖原分解来维持葡萄糖的动态平衡。CST通过抑制内皮型一氧化氮合酶(ENOS)和5‘-单磷酸腺苷活化蛋白激酶(AMPK)瞬时刺激糖异生，并通过抑制胰岛素清除和维持低NO水平防止肾上腺素能受体活动的脱敏而增强葡萄糖处置和糖原储存。此外，CST促进脂肪和葡萄糖的处置，从而防止血糖水平的过度上升。此外，CST预处理可将CHGA-KO小鼠从升高的血压和较高的血浆儿茶酚胺中“拯救”出来。这项建议将侧重于发现CST在基因工程CHGA-KO和CST-KO小鼠中调节胰岛素和血糖水平的新途径。基于我们在CHGA-KO小鼠上的发现，我们建议在一个公认的2型糖尿病(db/db)小鼠模型上测试CST功能。为此，我们提出了两个特定的目标：1.确定CST对野生型CHGA-KO和CST-KO小鼠的胰岛素敏感性、胰岛素清除和葡萄糖稳态的调节途径。2.评价CST及其变异体对高脂饮食诱导的胰岛素抵抗和db/db糖尿病小鼠的胰岛素敏感性、压力反射敏感性和心率变异性的潜在治疗作用。 公共卫生相关性： 项目简介：有大量患有2型糖尿病(T2 DM)和心血管疾病(CVD)的退伍军人。大多数患有肥胖症、2型糖尿病和血脂紊乱的人最终会患上包括高血压在内的心血管疾病。在美国，心血管疾病是导致死亡和发病的主要原因。这项建议的主要目标是降低高血压，同时将与胰岛素抵抗相关的糖尿病情况降至最低。申请人提出，一种内源性多肽，儿茶素(CST)，可以通过执行(I)降低高血压和(Ii)最小化代谢紊乱的双重任务而作为适当的治疗剂。CST通过(I)降低儿茶酚胺等应激激素以及一氧化氮等参与调节血压的化学物质的水平，(Ii)调节胰岛素水平，以及(Iii)提高对多余葡萄糖和脂肪的利用，来做到这一点。本提案将探索CST在基因工程小鼠中上述功能的潜在机制。