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 hyperinsulinemia is a key mediator, priming the liver for enhanced net hepatic glucose uptake (NHGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic clamp. Postprandial NHGU is regulated by three primary mechanisms: insulin action, 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 remains unclear, however, which of these mechanisms govern the increase in afternoon NHGU following morning insulin exposure. To address this, dogs underwent a morning clamp with either a 4-h hyperinsulinemic prime (prime group) (n = 8) or basal insulin delivery (no-prime group) (n = 8). After a 1.5-h rest, both groups underwent an afternoon hyperglycemic clamp with portal glucose delivery under basal insulin conditions to isolate the effects of a morning insulin prime on afternoon glucose-mediated hepatic signals (GE and the PGS). Mean afternoon NHGU was significantly greater in the prime group (2.2 ± 0.3 mg/kg/min) compared with 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 afternoon NHGU independently of a rise in afternoon insulin. However, maximal second-meal NHGU also requires elevated afternoon insulin. Together, these findings suggest 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 HIGHLIGHTS: Elevated morning insulin primes the liver for enhanced afternoon net hepatic glucose uptake (NHGU), but it is unclear whether augmentation of insulin action, glucose effectiveness, or the portal glucose signal mediates this effect. Dogs 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 glucose effectiveness and the portal glucose signal. Morning insulin priming enhanced afternoon NHGU via increased glucose-mediated mechanisms, though maximal afternoon NHGU also required elevated afternoon insulin. These findings identify mechanisms underlying insulin-induced hepatic metabolic memory, providing a framework to inform strategies improving postprandial glucose handling in diabetes.