Morning Glucagon Disrupts Insulin Induced Hepatic Metabolic Memory and Subsequent Afternoon Glucose Metabolism in Canines

The Staub-Traugott effect describes the improved glycemic response observed after consuming a second identical meal. We previously showed that morning (AM) hyperinsulinemia primes the liver for enhanced afternoon (PM) meal-associated net hepatic glucose uptake (NHGU) and glycogen storage. However, depending on the meal composition, both insulin and glucagon may rise. Therefore, we investigated whether AM hyperglucagonemia alters the priming effect of AM hyperinsulinemia on subsequent hepatic glucose metabolism. Dogs underwent a 4h AM hyperinsulinemic-euglycemic clamp paired with either basal (AM INS, n=8) or elevated glucagon (AM INS+GCG, n=8). After a 1.5h rest, dogs underwent a 2.5h PM hyperinsulinemic-hyperglycemic clamp designed to mimic postprandial conditions. AM hyperglucagonemia reduced PM NHGU through additive shifts in both hepatic glucose uptake and production, leading to lower direct glycogen synthesis and less glycolytic flux. Mechanistically, hepatic glucokinase protein was reduced in the AM INS+GCG vs. AM INS group, suggesting diminished capacity for glucose phosphorylation and lower intracellular G6P, a central node regulating downstream hepatic glucose metabolism. Thus, morning hepatic glucagon exposure diminishes insulins ability to prime the liver, limiting net hepatic glucose uptake during a later meal. These results underscore how antecedent hormonal signals govern subsequent postprandial hepatic glucose metabolism.