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.