Morning Elevation in Insulin Enhances Afternoon Hepatic Glucose Disposal in Dogs by Increasing Both Insulin Signaling and Glucose Action

The second-meal phenomenon refers to the improved glycemic response to a subsequent identical meal. We previously showed that morning (AM) hyperinsulinemia is a key mediator, priming the liver for enhanced net hepatic glucose uptake (NHGU) and glycogen storage during an afternoon (PM) hyperinsulinemic-hyperglycemic clamp. Postprandial NHGU is regulated by three primary mechanisms: insulin action (IA), initiated by hyperinsulinemia; glucose effectiveness (GE), driven by hyperglycemia; and the portal glucose signal (PGS), a neurally-mediated signal activated by glucose delivery into the hepatoportal circulation. It remained unclear, however, which of these mechanisms govern the increase in PM NHGU following AM insulin exposure. To address this, dogs underwent an AM clamp with either a 4-hour 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 to isolate the effects of an AM insulin prime on PM glucose-mediated hepatic signals (GE/the PGS). Mean PM NHGU was significantly greater in the Prime group (2.2 {+/-} 0.3 mg/kg/min) compared to the No Prime group (0.1 {+/-} 0.3 mg/kg/min, p=0.005), accompanied by augmented net glycolytic and glycogen flux. These findings indicate that morning insulin can enhance glucose-mediated PM NHGU independently of a rise in PM insulin. However, maximal second-meal NHGU also requires elevated PM insulin. Together, this suggests that strategically timed early-day insulin or insulinotropic interventions could potentially improve hepatic responsiveness in settings of impaired postprandial glycemic control, such as insulin resistance or diabetes. Article HighlightsO_LIElevated morning insulin primes the liver for enhanced afternoon net hepatic glucose uptake (NHGU), but it was unclear whether augmentation of insulin action (IA), glucose effectiveness (GE), or the portal glucose signal (PGS) mediates this effect. C_LIO_LIDogs underwent a morning euglycemic clamp with either elevated or basal insulin delivery, followed by an afternoon euinsulinemic-hyperglycemic clamp to isolate the effect of morning insulin priming on afternoon GE/PGS. C_LIO_LIMorning insulin priming enhanced afternoon NHGU via increased glucose-mediated mechanisms, though maximal afternoon NHGU also requires elevated afternoon insulin. C_LIO_LIThese findings identify mechanisms underlying insulin-induced hepatic metabolic memory, providing a framework to inform strategies improving postprandial glucose handling in diabetes. C_LI