Morning Meal-Associated Priming of the Liver

早餐相关的肝脏启动

• 批准号: 10341641
• 负责人: Alan D Cherrington
• 金额: $ 57.64万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341641
• 关键词: Accounting; Address; Adrenal Glands; Adult; Affect; Animal Model; Blood Circulation; Blood Glucose; Brain; Buffers; Canis familiaris; Caring; Catheters; Chronic; Clinical; Closure by clamp; Complex; Conscious; Control Groups; Development; Diabetes Mellitus; Drug Kinetics; Duodenum; Eating; Elements; Epinephrine; Fasting; Fatty acid glycerol esters; Fiber; Frequencies; Generations; Glucagon; Glucose; Glycogen; Goals; Hepatic; Hepatic artery; Hormonal; Hormone secretion; Human; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Iatrogenesis; Individual; Infusion procedures; Ingestion; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Knowledge; Leg; Light; Limb structure; Liver; Liver Glycogen; Measures; Metabolic; Modeling; Muscle; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oral; Oral Ingestion; Organ; Pattern; Peripheral; Physiological; Play; Population; Portal vein structure; Prediabetes syndrome; Process; Regulation; Risk; Role; Route; Saline; Sampling; Signal Transduction; Site; Skeletal Muscle; Spinal; Techniques; Teenagers; Tissues; Vagus nerve structure; Veins; Withdrawal; Work; blood glucose regulation; design; diabetic; experimental study; feeding; glucose disposal; glucose production; glucose uptake; glycemic control; hepatic vein; impaired glucose tolerance; improved; incretin hormone; innovation; non-diabetic; novel therapeutic intervention; relating to nervous system; response; treatment response

The liver is near-unique among the body organs in its ability to extract glucose and store it as glycogen under postprandial conditions, as well as to maintain a substantial rate of glucose production under fasting or hypoglycemic conditions. Our previous work has clearly shown that a morning period of hyperinsulinemia enhances hepatic glucose uptake and glycogen storage during an afternoon hyperinsulinemic hyperglycemic clamp mimicking a second meal. The goal of our current proposal is to identify factors influencing meal responses that can be utilized in improving the care of those with insulin resistance and type 2 diabetes. Specifically, in Aim 1 we will determine which aspect of morning hyperinsulinemia (direct effects on the liver or indirect effects brought about by insulin’s impact on the brain and/or fat tissues) is the key element involved in enhancement of afternoon hepatic glucose uptake. Furthermore, in Aim 2 we will determine the importance of the route of insulin delivery (intraportal vs peripheral circulation) in the morning on the afternoon response. This question is highly relevant to the treatment of those with insulin-dependent diabetes since most of the currently available insulin therapy involves delivery by a peripheral route. In addition, we will determine what factor or factors in the afternoon response are most clearly impacted by morning hyperinsulinemia (Aim 3). We will utilize the conscious, chronically catheterized dog model which is near-unique in that it not only makes possible the delivery of glucose and insulin into the portal circulation, the usual route of entry for ingested nutrients and secreted insulin, but also permits sampling from the hepatic and portal veins to allow the assessment of the liver’s response to the treatments. Importantly, the canine model has been shown to display many physiologic responses very similar to those in the human. The innovative aspects of the proposed experiments include the fact that the model allows us to clearly separate factors that may impact the response to the initial and subsequent meals of the day and examine the effect of each factor individually. The proposed studies are highly significant because the knowledge gained through these experiments has great potential to contribute to the development of new therapeutic approaches, more accurately tailored to bring about normal nutrient disposition, for those with impaired glucose tolerance (prediabetes) and diabetes.

在身体器官中，肝脏在餐后条件下提取葡萄糖并将其储存为糖原的能力几乎是独一无二的，并且在空腹或低血糖条件下维持大量的葡萄糖产生率我们之前的工作已经清楚地表明，上午的高胰岛素血症增强了下午高胰岛素高血糖模拟期间的肝脏葡萄糖摄取和糖原储存，我们当前提议的目标是确定可利用的影响进餐反应的因素。具体来说，在目标 1 中，我们将确定早晨高胰岛素血症的哪个方面（对肝脏的直接影响或胰岛素对大脑和/或脂肪组织的影响带来的间接影响）。是参与下午肝脏葡萄糖摄取增强的关键因素。此外，在目标 2 中，我们将确定上午胰岛素输送途径（门脉内与外周循环）对下午反应的重要性。治疗由于目前大多数可用的胰岛素治疗都涉及通过外周途径给药，因此我们将确定下午反应中哪些因素最明显受到早晨高胰岛素血症的影响（目标 3）。利用有意识的、长期插入导管的狗模型，该模型几乎是独一无二的，因为它不仅可以将葡萄糖和胰岛素输送到门静脉循环（摄入营养物质和分泌胰岛素的通常进入途径），而且还可以从肝脏取样和门静脉重要的是，犬类模型已显示出许多与人类非常相似的生理反应，该模型使我们能够清楚地了解这一事实。分离可能影响一天中最初和随后进餐反应的因素，并单独检查每个因素的影响。拟议的研究非常重要，因为通过这些实验获得的知识具有巨大的潜力，有助于开发新的治疗方法。 ，更准确地定制以实现正常的营养配置，糖耐量受损（糖尿病前期）和糖尿病的人。