Exercise and Fuel Metabolism

运动和燃料代谢

• 批准号: 7245871
• 负责人: DAVID H WASSERMAN
• 金额: $ 31.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245871
• 关键词: Brain; Canis familiaris; Complication; Condition; Conscious; Diabetes Mellitus; Effectiveness; Exercise; Fasting; Glucose; Goals; Grant; Hepatic; Hormonal; Hormones; Hyperinsulinism; Hypoglycemia; Infusion procedures; Insulin; Kidney; Limb structure; Liver; Measures; Mediating; Metabolic; Metabolism; Methodology; Nervous system structure; Neural Pathways; Operative Surgical Procedures; Pancreas; Patients; Physical activity; Physiological; Play; Prevention; Protocols documentation; Purine Nucleotides; Regulation; Risk; Role; Signal Transduction; Site; Standards of Weights and Measures; System; Techniques; Testing; Work; counterregulation; design; glucose metabolism; glucose production; glycemic control; in vivo; insight; liver function; novel; prevent; research study; response; tool

DESCRIPTION (provided by applicant): Tight glycernic control is now a standard goal of most patients with diabetes. The consequence is that, while the progression of long-term complications has been reduced, the risk of iatrogenic insulin-induced hypoglycemia as a complication has increased. Physical activity dramatically heightens this risk due to the associated increase in insulin action. Exercise in healthy subjects is characterized by both an increase in the glycemic threshold for counterregulation and an amplification in the magnitude of the counterregulatory response. These are favorable adaptations that protect against hypoglycemia. This robust response to prevent hypoglycemia can be impaired in people with diabetes. Despite the essential role that the counterregulatory response plays during exercise, the mechanism for its increased effectiveness, the factors responsible when it fails, and the means to correct it when it fails are poorly understood. The proposed studies are a continuation of experiments conducted under the auspices of this grant that have identified novel and sensitive mechanisms for glucose sensing and the presence of insulin sensitive neural pathways that modulate systemic metabolism. The experiments will define the importance of specific sites involved in sensing a decrement in glucose during exercise and the means by which glucose counterregulatory responses are amplified by exercise. Identifying mechanisms for sustaining endogenous glucose production (EGP) in people with impaired counterregulatory responses is a key for prevention of insulin-induced hypoglycemia. Intraportal infusion of the purine nucleotide precursor, 5'-aminoimidazole-4-carboxamide-l-Dribofuranoside (AICAR) has provided insight into one potential mechanism. Intraportal AICAR stimulates EGP independent of changes in counterregulatory hormones and is effective even in the presence of elevated insulin levels that would normally completely suppress EGP. Hepatic actions of AICAR have important implications for understanding physiological regulation of liver function under conditions that, like exercise, are characterized by increased EGP. Moreover, the ability of AICAR to act in the presence of high insulin suggests that it, or a compound that works through a related mechanism, may be effective as a means of combating insulin-induced hypoglycemia. Proposed studies use methodology for well-controlled experimentation to be carried out in vivo. Studies will be conducted in chronically catheterized, 18 h fasted conscious dogs using surgical and pharmacological techniques to perturb or control the system. Hormonal, autonomic, and glucose metabolic responses will be measured using sensitive isotopic ([3-3H] glucose, 2H:O, [U-14C] glucose) and arteriovenous difference (liver, gut, pancreas, kidney, limb) techniques. The protocols in this proposal will define mechanisms for the heightened role of the nervous system in mediating responses to hyperinsulinemia and hypoglycemia during physical exercise. There will be an emphasis on understanding physiological and pharmacological mechanisms that counter insulin-induced hypoglycemia. The specific aims are to: (1) identify the sites responsible for the amplified glucose counterregulatory response to exercise; (2) test whether insulin sensitive neural pathways modulate the response to exercise; and (3) characterize the actions of AICAR on the liver and brain and determine whether this compound or a related one might be effective in counteracting insulin-induced hypoglycemia.

描述（由申请人提供）：严格的糖糖控制是大多数糖尿病患者的标准目标。结果是，尽管长期并发症的进展降低了，但医源性胰岛素诱导的低血糖作为并发症的风险增加了。由于胰岛素作用的增加，体育活动极大地增加了这种风险。健康受试者的运动的特征在于血糖阈值的反调节阈值增加，也是对反应反应的大小的扩增。这些是预防低血糖症的有利适应。糖尿病患者的这种防止低血糖的反应可能会受到损害。尽管对锻炼期间的反应反应起着至关重要的作用，但其有效性提高的机制，在失败时造成的因素以及在失败时纠正效果的手段的理解很差。拟议的研究是在该赠款的主持下进行的实验的延续，该实验已经确定了葡萄糖感应的新颖和敏感机制，以及调节全身代谢的胰岛素敏感神经途径的存在。实验将定义涉及在运动过程中涉及葡萄糖减少的特定位点的重要性以及通过运动扩大葡萄糖反调节反应的手段。鉴定对反应受损的人中维持内源性葡萄糖（EGP）的机制是预防胰岛素诱导的低血糖的关键。嘌呤核苷酸前体的肠内输注，5'-氨基咪唑-4-羧酰胺-L-滴虫硫糖苷（AICAR）已提供了对一种潜在机制的见解。体内AICAR刺激EGP独立于反调节激素的变化，即使在胰岛素水平升高的情况下，通常会完全抑制EGP。 AICAR的肝作用对理解肝功能的生理调节具有重要意义，例如锻炼以增加EGP的特征。此外，AICAR在存在高胰岛素的情况下起作用的能力表明，它或通过相关机制起作用的化合物可以有效作为打击胰岛素诱导的低血糖的手段。拟议的研究使用方法可以在体内进行良好控制的实验。研究将在长期导管插入的18小时内使用手术和药理技术来扰动或控制系统。将使用敏感的同位素（[3-3H]葡萄糖，2H：O，O，[U-14C]葡萄糖）和动脉静脉差异（肝，肠，肠，胰腺，pancreas，pancreas，肾脏，肾脏，LIMB）技术来测量激素，自主和葡萄糖代谢反应。该提案中的方案将定义神经系统在体育锻炼过程中介导对高胰岛素血症和低血糖的反应中的作用增强的机制。将重点放在理解抗胰岛素诱导低血糖的生理和药理机制。具体目的是：（1）确定负责放大葡萄糖对运动的反应的部位； （2）测试胰岛素敏感神经途径是否调节对运动的反应； （3）表征AICAR对肝脏和大脑的作用，并确定该化合物或相关化合物是否有效抵消胰岛素诱导的低血糖。