Hepatic Metabolic Memory Triggered by AM Exposure to Glucagon Alters Afternoon Glucose Metabolism

The second meal effect describes an improved glycemic response observed after consuming a second identical meal. We previously showed that morning (AM) exposure to hyperinsulinemia primes the liver for enhanced hepatic glucose uptake and glycogen storage in the afternoon (PM), with no significant effect on PM non-hepatic glucose uptake. Given that meals often trigger both insulin and glucagon secretion, we aimed to determine if AM hyperglucagonemia alters the priming effect of AM hyperinsulinemia on PM hepatic glucose metabolism. To test this, dogs were exposed to a 4h AM hyperinsulinemic-euglycemic clamp, with insulin delivered in a pattern mimicking the insulin profile observed earlier during a 4h AM duodenal glucose infusion. This period of hyperinsulinemia was paired with either basal (Prime, n=8) or elevated (Prime + ↑GGN, n=8) glucagon, maintaining a consistent insulin-to-glucagon molar ratio throughout the AM clamp. After a 1.5h rest period, the dogs underwent a 2.5h PM hyperinsulinemic-hyperglycemic clamp, during which glucose, insulin, and glucagon levels, along with the artery-to-portal vein glucose gradient, were carefully controlled to replicate postprandial conditions. During the PM clamp, the mean net hepatic glucose uptake (NHGU) in the Prime + ↑GGN group was only 59% of that in the Prime group (3.6±0.4 vs. 6.1±0.6 mg/kg/min, P<0.0027, respectively). Additionally, PM direct glycogen synthesis was two-fold greater in the Prime group compared to the Prime + ↑GGN group (3.2±0.7 vs. 1.5±0.2 mg/kg/min, P<0.0014, respectively). The observed difference in PM NHGU between the groups was not due to enhanced PM hepatic glucose uptake (HGU), which was similar in both groups (5.7±0.5 mg/kg/min in the Prime group vs. 5.2±0.3 mg/kg/min in the Prime + ↑GGN group), but rather a prolonged effect of AM hyperglucagonemia on PM hepatic glucose production (HGP) (-0.3±0.3 mg/kg/min in the Prime group vs. 1.7±0.4 mg/kg/min in the Prime + ↑GGN group, P<0.0072). This increase in PM HGP in the Prime + ↑GGN group was not driven by differences in PM gluconeogenic flux but by futile glucose cycling between glucose and glucose-6-phosphate, as well as hepatic glycogen storage and breakdown. In summary, these findings suggest that morning exposure to elevated glucagon shifts the insulin-driven priming effect on afternoon hepatic glucose metabolism by promoting sustained glucose cycling at the expense of glycogen synthesis and glycolysis, leading to persistent HGP despite identical PM insulin, glucose, and glucagon levels.