Glycogen Metabolism in Hypoglycemia Counterregulation

低血糖反调节中的糖原代谢

• 批准号: 7057282
• 负责人: ILAN GABRIELY
• 金额: $ 13.23万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057282
• 关键词: blood glucose; catecholamines; clinical research; cortisol; diabetes mellitus therapy; glucagon; glucose clamp technique; glucose metabolism; glucose transport; glycogenesis; glycogenolysis; hormone regulation /control mechanism; human subject; human therapy evaluation; hypoglycemia; insulin; insulin dependent diabetes mellitus; liver metabolism; nuclear magnetic resonance spectroscopy; patient oriented research; somatotropin

DESCRIPTION (provided by applicant): The applicant for this Mentored Career Development Award (K23) is an M.D. scientist who has performed a productive research fellowship in the mentor?s laboratory. The resources at the Albert Einstein College of Medicine (AECM) include a recently renewed GCRC, a Diabetes Research Center, Core Laboratories with expertise in state-of-the-art technologies pertinent to this application, as well as a K30-funded Clinical Research Training Program that will form the backbone of the training environment. Severe hypoglycemia is the major limitation of intensive treatment of Type 1 diabetes mellitus (T1DM), though such therapy can effectively prevent the microvascular complications of diabetes. It is now well-established that the liver plays a central role in the physiologic response to hypoglycemia by rapidly increasing glucose production (GP), and that this response is dependent in turn on the secretion of the primary counterregulatory hormones glucagon and epinephrine. Dr. Shamoon's laboratory was the first to demonstrate that patients with T1DM have defective GP due to absent glucagon and impaired epinephrine responses to experimental hypoglycemia. Recently, Dr. Shamoon has also identified a non-hormonal component of GP, activated at mild hypoglycemia (approximately 70mg/dl), that is also defective in T1DM. This latter component of the GP response is likely to be due to glucose per se, previously thought to be only activated at much deeper levels of hypoglycemia (< 40 mg/dl). Hepatic glucose fluxes that are involved in GP must include both glycogenolysis and gluconeogenesis, though there is a paucity of data regarding the precise quantitative contributions of each. The central role of the GP in T1DM is emphasized by studies suggesting that glycogenolysis after overnight fasting is defective, and only partially restored by short-term normalization of glycemia. The applicant hypothesizes that the early GP response to hypoglycemia is predominantly dependent on glycogenolysis, and is similarly defective in T1DM. Furthermore, defective glycogenolysis may account for the impaired GP responses due to glucose per se and to the reduced adrenergic drive of secreted epinephrine. The introduction of in vivo nuclear magnetic resonance (NMR) spectroscopy to the study of liver glycogen metabolism provides a powerful new approach. The specific aims are: 1) to study the time course of glycogenolysis and gluconeogenesis in a model of fixed hypoglycemia in non-diabetic and intensively-treated T1DM subjects; and 2) to examine the specific relationship between the GP components due to glucose per se or to glucagon and epinephrine in stepped hypoglycemic clamps in non-diabetic and intensively-treated T1DM subjects. These experiments will involve the combined use of sophisticated metabolic physiology and state-of-the-art 4 Tesla NMR spectroscopy to understand the mechanisms of defective glucose counterregulation.

描述（由申请人提供）： 该指导职业发展奖（K23）的申请人是一位医学博士学家 在导师的实验室中进行了富有成效的研究奖学金。阿尔伯特·爱因斯坦医学院（AECM）的资源包括最近更新的GCRC，糖尿病研究中心，具有与此应用有关的最先进技术专业知识的核心实验室以及K30资助的临床研究培训计划将构成培训环境的骨干。严重的低血糖是对1型糖尿病（T1DM）进行密集治疗的主要局限性，尽管这种疗法可以有效防止糖尿病的微血管并发症。现在良好的肝脏通过快速增加葡萄糖产生（GP）在对低血糖的生理反应中起着核心作用，并且这种反应依赖于主要的反调节激素胰高血糖素和肾上腺素的分泌。 Shamoon博士的实验室是第一个证明T1DM患者由于缺乏胰高血糖素和肾上腺素对实验性低血糖症的反应受损而患有GP的人。最近，Shamoon博士还确定了 GP的非激素成分，在轻度低血糖症（约70mg/dl）处被激活，在T1DM中也有缺陷。 GP反应的后一个成分可能是由于葡萄糖本身，以前被认为仅在更深层次的低血糖（<40 mg/dl）上被激活。 GP涉及的肝葡萄糖通量必须包括糖原分解和糖异生，尽管关于每种的精确定量贡献的数据很少。 GP在T1DM中的核心作用是通过研究表明，过夜禁食后的糖原分解有缺陷，仅通过糖血症的短期归一化而部分恢复。申请人假设早期的GP对低血糖的反应主要取决于糖原分解，并且在T1DM中同样有缺陷。此外，有缺陷的糖原分解可能是由于葡萄糖本身而导致的GP反应受损，并且是分泌肾上腺素的肾上腺素能减少的。将体内核磁共振（NMR）光谱引入肝糖原代谢的研究提供了一种强大的新方法。具体目的是：1）研究 在非糖尿病和强化治疗的T1DM受试者中，糖原分解和糖异生的时间过程； 2）在非糖尿病和强化治疗的T1DM受试者中，检查由于葡萄糖本身或胰高血糖素和肾上腺素而引起的GP成分之间的特定关系。这些实验将涉及复杂的代谢生理学和最先进的4 Tesla NMR光谱的共同使用，以了解有缺陷的葡萄糖反调节的机制。