Gluconeogenesis and Glycogenolysis - Role and Regulation

糖异生和糖原分解 - 作用和调节

基本信息

批准号：
8305094
负责人：
Alan D Cherrington
金额：
$ 69.07万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-06-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305094
关键词：
Address Adrenalectomy Alanine Animal Model Animals Area Biopsy Blood Glucose Blood Volume Brain Canis familiaris Carbohydrates Carotid Arteries Catheterization Catheters Cerebral Ventricles Conscious Databases Denervation Development Diabetes Mellitus Diet Fasting Fatty acid glycerol esters Feedback Gluconeogenesis Glucose Grant Health Hepatic Hormonal Hormones Human Hyperglycemia Hypoglycemia Hypothalamic structure In Vitro Individual Infusion procedures Insulin Insulin Resistance Limb structure Liver Measures Mediator of activation protein Metabolic Metabolism Methods Molecular Mus Muscle Obesity Operative Surgical Procedures Patients Physiological Portal vein structure Proteins Protocols documentation Rattus Regulation Rodent Role Sampling Signal Transduction Solutions Somatostatin Techniques Therapeutic Intervention Time Tracer diabetic enzyme activity experience glucose metabolism glucose production glycogenolysis hepatic vein hormone regulation improved in vivo insulin signaling interest lipid metabolism liver biopsy mRNA Expression neuroregulation protein metabolism relating to nervous system research study tool treatment strategy vertebral artery

项目摘要

DESCRIPTION (provided by applicant): The objective of this application is to better understand the hormonal and neural regulation of glucose production (gluconeogenesis and glycogenolysis) in vivo in the normal and insulin resistant state. The specific aims are to understand 1) the physiologic relevance of brain insulin signaling in the control of hepatic glucose production, 2) the mechanisms by which the body defends itself against hypoglycemia through modulation of hormone secretion and action, and 3) the interplay between gluconeogenesis and glycogenolysis in determining hepatic glucose production in the insulin resistant state with a view to directing therapeutic intervention. Studies will be carried out in fasted conscious dogs prepared surgically and fitted with a variety of sampling and infusion catheters (e.g. adrenalectomy, catheters placed in the portal and hepatic veins, vertebral and carotid arteries, 3rd cerebral ventricle, etc.) as required by the protocol. Glucose metabolism will be assessed using A-V difference (liver, gut, hind limb) and tracer (3H-glucose) techniques. Gluconeogenesis and glycogenolysis will be determined using A-V difference and isotopic (2H2O,3H-glucose, 13C-alanine) methods. In addition, to explore molecular mechanisms of control, biopsies (liver, hypothalamus, muscle, fat, etc) will be taken for assessment of various cellular signaling cascades, mRNA expression, protein levels and enzyme activities. Hormonal levels will be controlled using somatostatin or adrenalectomy and hormone replacement. Neural mediators will be controlled using blocker infusion or surgical denervation. Substrate levels will be controlled by exogenous infusion or pharmacologic manipulation. The results from the proposed studies should enhance our understanding of the control of glucose production in vivo and thereby facilitate the development of solutions to metabolic problems evident in the diabetic and obese patient. PUBLIC HEALTH RELEVANCE: Overproduction of glucose by the liver is a major contributor to hyperglycemia in diabetes and may result from hepatic and central insulin resistance; this grant will address the mechanisms by which insulin regulates the liver. Low blood sugar following insulin treatment is the major limitation to tight control of glycemia in the individual with diabetes; this project will further elucidate the mechanisms by which the body defends itself against hypoglycemia. Diet induced obesity is associated with insulin resistance and is a major cause of diabetes; this project will explore the mechanisms involved in the development of insulin resistance and potential treatment strategies will be investigated.

描述（由申请人提供）：本申请的目的是更好地了解正常和胰岛素抵抗状态下体内葡萄糖生成（糖异生和糖原分解）的激素和神经调节。具体目标是了解 1) 脑胰岛素信号传导在控制肝脏葡萄糖生成中的生理相关性，2) 身体通过调节激素分泌和作用来防御低血糖的机制，以及 3) 糖异生之间的相互作用和糖原分解以确定胰岛素抵抗状态下肝脏葡萄糖的产生，以指导治疗干预。研究将在禁食、神志清醒的狗身上进行，这些狗经过手术准备，并根据要求安装了各种取样和输液导管（例如肾上腺切除术、放置在门静脉和肝静脉、椎动脉和颈动脉、第三脑室等的导管）。协议。将使用 A-V 差异（肝脏、肠道、后肢）和示踪剂（3H-葡萄糖）技术评估葡萄糖代谢。糖异生和糖原分解将使用 A-V 差异和同位素（2H2O、3H-葡萄糖、13C-丙氨酸）方法测定。此外，为了探索控制的分子机制，将进行活检（肝脏、下丘脑、肌肉、脂肪等）以评估各种细胞信号级联、mRNA 表达、蛋白质水平和酶活性。将使用生长抑素或肾上腺切除术和激素替代来控制激素水平。将使用阻滞剂输注或手术去神经术来控制神经介质。底物水平将通过外源性输注或药物操作来控制。拟议研究的结果应增强我们对体内葡萄糖产生控制的理解，从而促进糖尿病和肥胖患者明显代谢问题的解决方案的开发。公共卫生相关性：肝脏过度产生葡萄糖是糖尿病高血糖的主要原因，可能是由于肝脏和中枢胰岛素抵抗所致；这笔赠款将研究胰岛素调节肝脏的机制。胰岛素治疗后的低血糖是糖尿病患者严格控制血糖的主要限制；该项目将进一步阐明身体防御低血糖的机制。饮食引起的肥胖与胰岛素抵抗有关，是糖尿病的主要原因；该项目将探讨胰岛素抵抗发展的机制，并研究潜在的治疗策略。