Morning glucagon disrupts insulin induced hepatic metabolic memory and subsequent afternoon glucose metabolism in canines

Introduction The Staub-Traugott effect, or second-meal phenomenon, describes improved glucose disposal after a second identical meal. We previously showed that morning hyperinsulinemia primes the liver to enhance afternoon net hepatic glucose uptake and glycogen storage. However, mixed meals trigger co-secretion of insulin and glucagon, and glucagon is traditionally viewed as opposing insulin’s hepatic actions. Whether glucagon modifies the persistence of insulin’s priming effects across sequential metabolic challenges is unknown. Therefore, we investigated whether morning hyperglucagonemia alters the ability of morning hyperinsulinemia to prime subsequent hepatic glucose metabolism. Methods Conscious dogs underwent two pancreatic clamp periods separated by a 1.5h rest period. Endogenous insulin and glucagon were suppressed with somatostatin and replaced intraportally at defined rates. During a 4h morning hyperinsulinemic-euglycemic clamp, dogs received matched insulin prime infusions with either basal glucagon (AM INS; n=8) or elevated glucagon (AM INS+GCG; n=8). After the rest period, both groups underwent a 2.5h afternoon hyperinsulinemic-hyperglycemic clamp under identical hormonal conditions. Afternoon net hepatic glucose uptake, glycogen, glycolytic, and gluconeogenic flux rates were quantified using arteriovenous difference methods and 3-3H-glucose tracer kinetics. Liver biopsies were collected before and after the afternoon clamp to assess gene transcription and protein regulators of hepatic glucose metabolism. Results During the afternoon clamp, despite matched insulin, glucagon, and glucose levels, net hepatic glucose uptake was 41% lower in AM INS+GCG (3.6±0.4 mg/kg/min) than in AM INS (6.1±0.6 mg/kg/min; p0.003). This was accompanied by a trend toward incomplete suppression of hepatic glucose production in AM INS+GCG (1.4±0.4 mg/kg/min), whereas it was fully suppressed in the AM INS group (p=0.06). Direct glycogen synthesis was also 44% lower in AM INS+GCG (1.8±0.2 vs 3.2±0.7 mg/kg/min; p0.015), along with reductions in net glycogen synthesis and glycolytic flux. Morning insulin with basal glucagon increased hepatic glucokinase mRNA and protein before the afternoon clamp, whereas concurrent glucagon prevented this induction. Discussion In summary, antecedent morning hyperglucagonemia attenuates insulin-mediated hepatic priming, reducing hepatic glucose flux during a later hyperinsulinemic-hyperglycemic challenge. These findings identify glucagon as a regulator of hepatic metabolic memory alongside insulin and demonstrate that early-day insulin-glucagon dynamics shape the liver’s response to subsequent challenges, providing mechanistic insight into postprandial glucose regulation and implications for metabolic health and diabetes risk.