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: 8259050
• 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/8259050
• 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）： 项目摘要：肥胖，脂肪营养不良，糖尿病和高血压集体构成“代谢综合征”（MS）。 MS通常会引起心血管疾病（CVD），这是美国死亡率和发病率的主要原因。胰岛素电阻是定义MS的中心分量。该提案的主要目标是减少高血压，同时最大程度地减少与胰岛素抵抗相关的高血糖和葡萄糖不耐症。我们已经确定，通过抑制儿茶酚胺的释放，降低了染色体A（CHGA）衍生的肽，Catestatin（CST），降低血压（BP）和心率（HR）。 Chga是铬烷蛋白/秘诀家族的指数成员，是一种蛋白质，在神经内分泌组织中无处不在。 CHGA的蛋白水解加工会引起生物活性肽，例如血糖激素胰腺蛋白，血管扩张剂血管毒素和儿茶酚胺释放抑制性肽CST。为了更好地了解CHGA在代谢疾病中的作用，我们产生了CHGA敲除小鼠（CHGA-KO），这些小鼠表现出高血压，高血浆儿茶酚胺，增加了对胰岛素和肌肉胰岛素耐药的敏感性。 CST在CHGA-KO小鼠中的替换使BP归一化，抑制胰岛素清除率，将胰岛素水平提高至正常水平并改善葡萄糖处置。 CST的有趣功能之一是对肝脏中代谢胰岛素清除率（MIC）的调节。基本高血压和麦克风降低之间存在牢固的关联。 CST缺乏的CHGA-KO小鼠显示出高度MIC，由C肽/胰岛素摩尔比判断，导致胰岛素水平较低。我们假设基本高血压诱导的MIC降低需要与CST相互作用。因此，CST可以在麦克风调节中发挥重要作用。在没有CST的情况下，如果受到葡萄糖的挑战，仅胰腺2细胞的胰岛素分泌就不足以使血糖处置。因此，需要CST通过抑制肝胰岛素清除来维持尤利克血症。 CST通过平衡葡萄糖生成与葡萄糖处置增加并减少糖原分解来维持葡萄糖稳态。 CST通过减轻内皮一氧化氧化物合酶（ENOS）和5'-腺苷单磷酸激活的蛋白激酶（AMPK）来暂时刺激糖生成，并通过维护抑制胰岛素的降低，并通过预防抑制胰岛素的降低，从而增强葡萄糖分配和糖原储存。此外，CST促进脂质和葡萄糖处置，从而防止葡萄糖水平过度升高。此外，CST预处理“营救”了BP升高和较高血浆儿茶酚胺的CHGA-KO小鼠。该建议将集中于CST在基因工程的CHGA-KO和CST-KO小鼠中调节胰岛素和葡萄糖水平的新途径。根据我们对CHGA-KO小鼠的发现，我们建议在建立良好的2型糖尿病（DB/DB）小鼠模型中测试CST功能。为此，我们提出了两个具体目标：1。确定CST诱导的胰岛素敏感性，胰岛素清除率和葡萄糖稳态的调节途径，野生型，CHGA-KO和CST-KO小鼠的途径。 2。评估CST及其变体对高脂饮食诱导的胰岛素耐药性和DB/DB糖尿病小鼠中胰岛素敏感性和压力反射敏感性的潜在治疗作用。 公共卫生相关性： 项目叙述：有大量的退伍军人患有2型糖尿病（T2DM）和心血管疾病（CVD）。大多数患有肥胖症，T2DM和脂质疾病的人最终会出现包括高血压在内的CVD。 CVD是美国死亡率和发病率的主要原因。该提案的主要目标是减少高血压，同时最大程度地减少与胰岛素抵抗相关的糖尿病状况。申请人提出，内源性肽Catestatin（CST）可以通过（i）减少高血压和（ii）最小化代谢障碍的双重作业来作为适当的治疗剂。 CST通过（i）降低涉及血压调节的压力激素等应激激素的水平以及一氧化氮等化学物质，（ii）调节胰岛素水平，以及（iii）改善过量葡萄糖和脂质的利用。本提案将探讨CST在基因工程小鼠中的上述功能的基础机制。