Morning Meal-Associated Priming of the Liver

肝脏在身体器官中几乎是独一无二的，它能够在餐后条件下提取葡萄糖并将其储存为糖原，以及在空腹或低血糖条件下保持葡萄糖产生的实质性速率。我们以前的工作已经清楚地表明，在下午高胰岛素高血糖钳夹模拟第二餐期间，早晨的高胰岛素血症增强了肝脏葡萄糖摄取和糖原储存。我们目前建议的目标是确定影响膳食反应的因素，这些因素可用于改善胰岛素抵抗和2型糖尿病患者的护理。具体而言，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/或脂肪组织的影响所带来的间接影响）是参与增强下午肝脏葡萄糖摄取的关键因素。此外，在目标2中，我们将确定上午胰岛素给药途径（门静脉内与外周循环）对下午反应的重要性。这个问题与胰岛素依赖型糖尿病患者的治疗高度相关，因为大多数目前可用的胰岛素治疗涉及通过外周途径递送。此外，我们将确定下午反应中的哪些因素最明显地受到早晨高胰岛素血症的影响（目的3）。我们将利用清醒的、长期插管的犬模型，该模型几乎是唯一的，因为它不仅可以将葡萄糖和胰岛素输送到门静脉循环中，这是摄入的营养物质和分泌的胰岛素的通常进入途径，而且还允许从肝和门静脉取样，以评估肝脏对治疗的反应。重要的是，犬模型显示出许多与人类非常相似的生理反应。拟议实验的创新方面包括，该模型使我们能够清楚地分离可能影响一天中最初和随后膳食反应的因素，并单独检查每个因素的影响。拟议的研究是非常重要的，因为通过这些实验获得的知识有很大的潜力，有助于开发新的治疗方法，更准确地定制，使正常的营养处置，为那些葡萄糖耐量受损（前驱糖尿病）和糖尿病。

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.