Morning Elevation in Insulin Enhances Afternoon Hepatic Postprandial Glucose Disposal in the Dog by Increasing Both Insulin Signaling and Glucose Action

The second-meal phenomenon refers to the improved glycemic response to a subsequent identical meal. Postprandial net hepatic glucose uptake (NHGU) is governed by the combined effects of three regulatory factors: insulin action (IA), initiated by hyperinsulinemia; glucose effectiveness (GE), driven by hyperglycemia; and the portal glucose signal (PGS), activated by glucose delivery into the hepatoportal circulation. Previous studies demonstrated that morning (AM) hyperinsulinemia primes the liver, causing substantially enhanced NHGU later in the day; however, it remained unclear which component of the afternoon (PM) response is augmented. To address this, we assessed how AM insulin elevation influences PM IA, GE, and the PGS. Dogs underwent an AM clamp with either a 4h hyperinsulinemic prime (Prime, n=8 ) or basal insulin delivery (No Prime, n=8 ). After a 1.5-hour rest, both groups underwent a PM hyperglycemic clamp (with portal glucose delivery) under basal insulin conditions. During the PM clamp, NHGU was significantly greater in the Prime versus No Prime group (2.2±0.3 vs. 0.1±0.3 mg/kg/min, P <0.005), indicating priming enhanced GE and/or PGS effects. In prior experiments with all three stimuli present in the PM (IA, GE, and PGS), AM insulin priming increased PM NHGU by 3.8 mg/kg/min. Thus, while AM insulin priming alone enhanced GE and/or PGS, the full effect requires an elevation in PM insulin, suggesting that morning insulin exposure primes the liver by augmenting both afternoon insulin action and glucose action.