Nutrition Infection and Hepatic Carbohydrate Metabolism

描述（由申请人提供）：肥胖、糖尿病和感染是炎症性疾病，其中葡萄糖处理受损，需要代偿性高胰岛素血症和/或高血糖。肝脏具有独特的适应性反应，在葡萄糖可用性增加时显著增加其吸收葡萄糖的能力。炎症性疾病的共同特征是：1)肝脏不能适应葡萄糖可用性的增加；2)胰高血糖素分泌不当。在每个设置胰高血糖素分泌不被抑制，并可能升高。在糖尿病患者中，胰岛素对营养输送的反应是迟钝的，这也可能限制了适应性反应。肝脏适应的失败将葡萄糖去除的责任转移到外周组织。此外，我们的数据表明胰高血糖素损害外周组织对葡萄糖的摄取。当伴有潜在的胰岛素抵抗和胰腺功能障碍时，发生高血糖的风险增加。本提案探讨以下问题：胰高血糖素是否在促进肝脏对葡萄糖可用性增加的反应中起重要作用？胰高血糖素损害肌肉葡萄糖摄取的机制是什么？炎症如何改变胰岛素、葡萄糖和胰高血糖素在调节葡萄糖处理中的作用？实验将在长期插管的有意识的狗身上进行。肝糖代谢（单向肝糖摄取和产生，葡萄糖氧化）和后肢将使用示踪剂和动静脉差异技术的组合进行评估。我们的模型提供了一种独特的能力，可以直接检查单个器官（肝脏和肌肉）在调节营养处置中所起的作用，以及导致葡萄糖处置受损的因素及其发生的机制。因此，这些研究的目的是确定胰岛素和胰高血糖素对肝脏和外周组织长期控制葡萄糖处理的影响，以及炎症如何破坏这种适应。这些结果将有助于确定为什么当肥胖、糖尿病或感染的人暴露于持续过量的营养物质时，肝脏不能适当地适应。我们的目标是，有了这些知识，我们将能够制定更好的治疗策略，以限制胰岛素抵抗个体的高血糖。

DESCRIPTION (provided by applicant): Obesity, diabetes, and infection are inflammatory diseases in which glucose disposal is impaired, necessitating compensatory hyperinsulinemia and/or hyperglycemia. The liver has a unique adaptive response, markedly increasing its capacity to take up glucose during increases in glucose availability. Common features of inflammatory diseases are 1) the inability of the liver to adapt to increases in glucose availability and 2) inappropriate glucagon secretion. In each setting glucagon secretion is not suppressed and may be elevated. In individuals with diabetes the insulin response to nutrient delivery is blunted, which may also limit the adaptive response. The failure of the liver to adapt shifts the responsibility of glucose removal to peripheral tissues. Moreover our data suggest that glucagon impairs glucose uptake by peripheral tissues. When accompanied by underlying insulin resistance and pancreatic dysfunction, the risk of developing hyperglycemia increases. The present proposal examines the following questions: Does glucagon play an essential role in facilitating the liver's response to increased glucose availability? What is the mechanism by which glucagon impairs muscle glucose uptake? How does inflammation alter the roles insulin, glucose and glucagon play in modulating glucose disposal? Experiments will be carried out in chronically catheterized conscious dogs. Hepatic glucose metabolism (unidirectional hepatic glucose uptake and production, glucose oxidation) and hindlimb will be assessed using a combination of tracer and arterio-venous difference techniques. Our model provides the unique ability to directly examine the role that individual organs (liver and muscle) play in modulation of nutrient disposition and the factors responsible for the impairment in glucose disposal and the mechanisms by which they occur. Thus, the goal of these studies is to determine the impact insulin and glucagon have in chronically controlling the disposal of glucose by the liver and peripheral tissues and how inflammation disrupts this adaptation. These results would help determine why the liver fails to appropriately adapt when exposed to a continuous plethora of nutrients in individuals with obesity and diabetes or infection. Our goal is that with this knowledge we will be able to develop better treatment strategies to limit hyperglycemia in insulin resistant individuals. PUBLIC HEALTH RELEVANCE: Obesity, diabetes and infection are inflammatory diseases that cause marked alterations in glucose metabolism. Our goal is to understand why inflammation and the excess glucagon secretion that accompanies inflammation alters glucose metabolism. We hope that by determining the mechanisms for the disturbances in glucose metabolism approaches in addition to infusing insulin can be developed to help maintain normal glucose concentrations.