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）： 项目概述：肥胖、脂肪代谢障碍、糖尿病和高血压共同构成了“代谢综合征”（MS）。MS通常引起心血管疾病（CVD），这是美国死亡率和发病率的主要原因。胰岛素抵抗是定义MS的核心组成部分。该提案的主要目标是降低高血压，同时最大限度地减少与胰岛素抵抗相关的高血糖症和葡萄糖耐受不良。我们已经鉴定了嗜铬粒蛋白A（Chga）衍生的肽，catestatin（CST），通过抑制儿茶酚胺的释放来降低血压（BP）和心率（HR）。Chga是嗜铬粒蛋白/分泌粒蛋白家族的索引成员，是在神经内分泌组织中普遍表达的前蛋白。Chga的蛋白水解加工产生生物活性肽，如血糖障碍激素胰抑素、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，我们已经产生了Chga敲除小鼠（Chga-KO），其显示高血压、高血浆儿茶酚胺、增加的肝脏对胰岛素的敏感性和肌肉胰岛素抵抗。Chga-KO小鼠中的CST替代使BP正常化，抑制胰岛素清除，将胰岛素水平升高至正常并改善葡萄糖处置。CST的功能之一是调节肝脏代谢性胰岛素清除率（MIC）。原发性高血压与MIC降低之间存在强相关性。CST缺陷型Chga-KO小鼠显示高MIC，如通过C-肽/胰岛素摩尔比判断的，导致低水平的胰岛素。我们假设原发性高血压引起的MIC降低需要与CST相互作用。因此，CST可以在MIC的调节中发挥重要作用。在不存在CST的情况下，当用葡萄糖激发时，仅来自胰腺2-细胞的胰岛素分泌将不足以处理血糖。因此，需要CST通过抑制肝脏胰岛素清除来维持Euclide。CST通过平衡增加的糖原合成与增加的葡萄糖处置和减少的糖原分解来维持葡萄糖稳态。CST通过减弱内皮型一氧化氮合酶（eNOS）和5 '-腺苷一磷酸活化蛋白激酶（AMPK）瞬时刺激糖原合成，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作用的脱敏来增强葡萄糖处理和糖原储存。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“拯救”Chga-KO小鼠免于升高的BP和更高的血浆儿茶酚胺。该提案将集中于在基因工程Chga-KO和CST-KO小鼠中发现CST调节胰岛素和葡萄糖水平的新途径。基于我们对Chga-KO小鼠的研究结果，我们建议在完善的2型糖尿病（db/db）小鼠模型中测试CST功能。为此，我们提出两个具体目标：1。确定野生型、Chga-KO和CST-KO小鼠中CST诱导的胰岛素敏感性、胰岛素清除率和葡萄糖稳态调节的途径。2.评价CST及其变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和压力反射敏感性以及心率变异性的潜在治疗作用。 公共卫生关系： 项目叙述：有大量的退伍军人患有2型糖尿病（T2 DM）和心血管疾病（CVD）。大多数肥胖、2型糖尿病和血脂紊乱患者最终会发展为心血管疾病，包括高血压。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降低高血压，同时尽量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），可以通过执行（i）降低高血压和（ii）使代谢紊乱最小化的双重工作而充当适当的治疗剂。CST通过（i）降低压力激素（如儿茶酚胺）以及参与血压调节的化学物质（如一氧化氮）的水平，（ii）调节胰岛素水平，以及（iii）改善对过量葡萄糖和脂质的利用。本研究拟在基因工程小鼠中探讨CST的上述作用机制。