Mechanism for Reduced Adrenomedullary Epinephrine Release in Type 1 Diabetes

1 型糖尿病肾上腺髓质肾上腺素释放减少的机制

• 批准号: 8195220
• 负责人: Branly Osvaldo Orban
• 金额: $ 3.04万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195220
• 关键词: Acetylcholine; Acute; Adrenal Glands; Adrenal Medulla; Animals; Attenuated; Binding; Blood Circulation; Blood Glucose; Catecholamines; Cessation of life; Cholinergic Receptors; Chromaffin Cells; Coma; Control Groups; Data; Defect; Development; Diabetes Mellitus; Diabetic Neuropathies; Efferent Neurons; Epinephrine; Etiology; Future; Glucagon; Glucose; Goals; Health; Hormones; Hyperglycemia; Hypoglycemia; Insulin; Insulin-Dependent Diabetes Mellitus; Lead; Measures; Messenger RNA; Modeling; Muscarinic Acetylcholine Receptor; Muscarinics; Names; Nature; Neuraxis; Organ; Peripheral Nerves; Plasma; Property; Proteins; Receptor Signaling; Regulation; Research; Scientist; Signal Transduction; Specificity; Stimulus; Streptozocin; Sympathetic Nervous System; System; Testing; Time; Training; Work; base; career; diabetic; diabetic patient; diabetic rat; in vivo; insight; public health relevance; receptor; research study; response; skills

DESCRIPTION (provided by applicant): Release of glucagon, a principal hormone underlying the normal counter-regulatory response (CRR) to acute hypoglycemia is largely absent in type 1 diabetes mellitus (T1DM). In its absence, other circulating CRR hormones, such as epinephrine, take on primary importance in restoring plasma glucose to basal levels. However, epinephrine release in response to hypoglycemia is also attenuated in T1DM, making diabetic patients particularly prone to asymptomatic hypoglycemia that, if untreated, can lead to coma and death. This defect has been minimally studied at the level of the adrenal medulla (AM) which produces most of all circulating epinephrine in the body. Chromaffin cells in the AM synthesize epinephrine and release it when activated by the central nervous system or other circulating hormones. Our preliminary data show that muscarinic acetylcholine receptor (mAchR) signaling is impaired in adrenomedullary chromaffin cells isolated from streptozocin (STZ)-treated diabetic rats and that type 3 mAchR, a predominant receptor subtype in the adrenal medulla, is internalized to a much greater degree in diabetic chromaffin cells than in controls. These data led me to hypothesize that internalization of adrenomedullary mAchR in T1DM reduces epinephrine release in response to hypoglycemia. To test this hypothesis, I plan to: (1) Determine the time after the on-set of diabetes when this defect occurs, the extent of the reduction, the specificity of the deficit and the involvement of diabetic hyperglycemia and hypoinsulinemia in its development. The STZ model of diabetes will be used in these studies. In vivo experiments will be performed to study the development of reduced adrenomedullary response to hypoglycemic and non-hypoglycemic stimuli during T1DM. Isolated adrenal glands and enzymatically- isolated chromaffin cells will be used to evaluate the contributions of nicotinic and muscarinic acetylcholine signaling and adrenal epinephrine content to this deficit. (2) Investigate the functional properties of acetylcholine receptors in adrenomedullary chromaffin cells during STZ-induced diabetes by measuring mRNA, protein levels, cellular localization and functional properties of nicotinic and muscarinic acetylcholine receptor subtypes in chromaffin cells from diabetic animals. The results of the proposed experiments will establish the cellular basis for the adrenal medullary defect in epinephrine release that contributes to the reduced CRR in T1DM. Health relevance: This project seeks to investigate the cellular basis for defective regulation of the body's response to low blood glucose in diabetic patients. This defect limits insulin-based therapies. PUBLIC HEALTH RELEVANCE: This project seeks to investigate the cellular basis for defective regulation of the body's response to low blood glucose in diabetic patients. This defect limits insulin-based therapies.

描述（由申请方提供）：1型糖尿病（T1DM）患者基本不释放胰高血糖素，胰高血糖素是对急性低血糖的正常反调节反应（CRR）的主要激素。在缺乏它的情况下，其他循环CRR激素，如肾上腺素，在将血糖恢复到基础水平方面发挥主要作用。然而，在T1DM中，响应于低血糖的肾上腺素释放也减弱，使得糖尿病患者特别容易发生无症状低血糖，如果不治疗，可能导致昏迷和死亡。这种缺陷在肾上腺髓质（AM）水平上的研究最少，AM产生体内大部分循环肾上腺素。 AM中的嗜铬细胞合成肾上腺素，并在被中枢神经系统或其他循环激素激活时释放肾上腺素。我们的初步数据表明，毒蕈碱乙酰胆碱受体（mAchR）信号受损的肾上腺髓质嗜铬细胞分离自链脲佐菌素（STZ）治疗的糖尿病大鼠和3型mAchR，在肾上腺髓质的主要受体亚型，在糖尿病嗜铬细胞比对照组内化到更大的程度。这些数据使我假设T1 DM中肾上腺髓质mAchR的内化减少了低血糖时肾上腺素的释放。 为了验证这一假设，我计划：（1）确定糖尿病发病后该缺陷发生的时间，减少的程度，缺陷的特异性以及糖尿病高血糖和低胰岛素血症在其发展中的参与。这些研究将使用STZ糖尿病模型。将进行体内实验，以研究T1DM期间肾上腺髓质对低血糖和非低血糖刺激的反应降低的发展。将使用分离的肾上腺和酶分离的嗜铬细胞来评价烟碱和毒蕈碱乙酰胆碱信号传导和肾上腺肾上腺素含量对该缺陷的贡献。 (2)通过测定糖尿病动物肾上腺髓质嗜铬细胞中烟碱型和毒蕈碱型乙酰胆碱受体亚型的mRNA、蛋白水平、细胞定位和功能特性，研究STZ诱导的糖尿病期间肾上腺髓质嗜铬细胞中乙酰胆碱受体的功能特性。拟定实验的结果将确立肾上腺素释放中肾上腺髓质缺陷的细胞基础，该缺陷导致T1DM患者CRR降低。健康相关性：该项目旨在研究糖尿病患者体内对低血糖反应的调节缺陷的细胞基础。这一缺陷限制了基于胰岛素的治疗。 公共卫生相关性：该项目旨在研究糖尿病患者体内对低血糖反应的调节缺陷的细胞基础。这一缺陷限制了基于胰岛素的治疗。