The Impact of Morning Insulin Delivery on Hepatic Glucose Metabolism Later in the Day

PROJECT SUMMARY The 2nd meal phenomenon describes the substantial improvement in glucose tolerance that occurs during a subsequent identical meal (e.g. improved glycemic response at lunch vs. breakfast). We have shown that 1) hyperinsulinemia is the essential factor during the 1st meal, and 2) the enhanced glycemic response during the 2nd meal is due to increased hepatic glucose uptake and glycogen storage. This proposal seeks to elucidate the mechanisms by which morning (AM) hyperinsulinemia enhances the liver’s subsequent response. These studies will be executed using complex metabolic clamping experiments performed in the multi-catheterized conscious dog model. Aim 1 will determine the impact of the AM insulin route of delivery (i.e. we will compare the effect of portal vein insulin infusion, as occurs with endogenous insulin secretion, vs. peripheral insulin delivery, as typically occurs with therapeutic treatment for individuals with insulin-dependent diabetes). Secretion of insulin into the portal vein results in exposure of the liver to 3-times more insulin than the rest of the body. Intravenous (peripheral) insulin infusion eliminates that gradient, exposing the liver to relative insulin deficiency. We hypothesize that AM hyperinsulinemia generated by peripheral (vs portal vein) insulin delivery will severely impair the liver’s amplified afternoon (PM) meal response. This is highly relevant to the treatment of patients with insulin- dependent diabetes since most of the currently available insulin therapies involve delivery by the peripheral route (e.g. subcutaneous insulin injection). Previous work has shown that 3 factors are primarily responsible for regulating hepatic glucose uptake: 1) insulin action, 2) the effect of glucose itself (glucose effectiveness), and 3) the portal glucose signal of neural origin, generated when glucose concentrations are greater in the portal vein compared to the hepatic artery, such as occurs when glucose is absorbed from the gut during a meal. Aim 2 will investigate which of these factors are contributing to the enhancement of hepatic glucose metabolism during the 2nd meal phenomenon. We hypothesize that AM hyperinsulinemia primes the liver for greater PM glucose uptake and storage via an enhancement of insulin action in the afternoon. The proposed studies are significant because they will provide a more thorough understanding of the impact of AM feeding on hepatic glucose metabolism during the remainder of the day, leading to new ways to improve glycemic management in individuals with impaired glucose tolerance and diabetes. The training plan will be carried out with the support of the excellent resources that the Cherrington lab and Vanderbilt University have to offer. The Cherrington lab has over 50 years of experience with the techniques outlined in this proposal. Paired with the career development opportunities that The Biomedical Research Education and Training office provides for biomedical research graduate students and the longstanding history of excellent physiology and diabetes research conducted in the Department of Molecular Physiology and Biophysics, Ms. Waterman is placed in the ideal environment to successfully obtain the necessary expert training and skill acquisition to shape her into an independent researcher.