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

Abstract

The second meal phenomenon refers to the improved glucose tolerance observed after consuming a second identical meal. This dissertation explores the physiologic and cellular mechanisms by which morning insulin exposure establishes a form of metabolic memory in the liver, enhancing hepatic glucose uptake and glycogen storage during subsequent glucose loads. Using clamping techniques in conscious canine models, we found that the duration of morning insulin delivery is critical for priming the liver. Despite equal total doses, a prolonged four-hour, lower-rate morning infusion improved afternoon hepatic glucose disposal and storage more effectively than a shorter two-hour, higher-rate infusion. The route of insulin delivery was also a key determinant of the liver’s priming response. Arterial hyperinsulinemia in the morning without increased hepatic insulin failed to enhance afternoon glucose metabolism, whereas morning hepatic portal vein insulin infusion did, demonstrating that engagement of hepatic insulin receptors in the morning is required for the priming effect. Elevated morning glucagon disrupted insulin’s priming effect, reducing net hepatic glucose uptake, limiting glycolysis and glycogen synthesis, and attenuating suppression of hepatic glucose production during a subsequent hyperinsulinemic-hyperglycemic clamp. Morning insulin exposure coordinated improvements in both insulin-dependent and insulin-independent glucose disposal, enhancing hepatic glucose clearance through combined insulin action and glucose effectiveness. Integrating physiological and transcriptomic analyses, we identified molecular pathways reprogrammed by morning insulin, including upregulation of genes for glucose metabolism, insulin signaling, and lipogenesis, alongside downregulation of gluconeogenesis, glycogenolysis, beta-oxidation, and ketogenesis, providing a cellular basis for this metabolic memory. Collectively, these findings demonstrate that early-day hormonal conditions prime the liver to improve postprandial glucose clearance and storage, establishing it as a central integrator of hormonal and nutrient signals. By linking physiologic responses with molecular adaptations, this work provides new insight into strategies for optimizing glycemic regulation in health and metabolic disease through meal timing and composition as well as targeted pharmaceutical interventions.