Improved Afternoon Hepatic Glucose Disposal and Storage Requires Morning Engagement of Hepatic Insulin Receptors

Glucose tolerance improves significantly upon consuming a second, identical meal later in the day (second-meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic vs. indirect insulin action), it is not known whether insulin’s delivery route affects the second-meal response. To determine whether morning peripheral insulin delivery (as occurs clinically, i.e., subcutaneously) can enhance afternoon HGU, conscious dogs were treated in the morning with insulin delivered either via the portal vein or peripherally (leg vein), while glucose was infused to maintain euglycemia. Consequently, arterial insulin levels increased similarly in both groups, but relative hepatic insulin deficiency occurred with peripheral insulin delivery. In the afternoon, all animals were challenged with the same hyperinsulinemic-hyperglycemic clamp to simulate identical postprandial-like conditions. The substantial enhancement of HGU in the afternoon caused by morning portal vein insulin delivery was lost when insulin was delivered peripherally. This indicates that morning insulin does not cause the second-meal phenomenon via its indirect actions on the liver but, rather, through direct activation of hepatic insulin signaling.

• Morning insulin delivery primes the liver for increased hepatic glucose uptake (HGU) later in the day, but until now, the mechanism (direct hepatic and/or indirect insulin action) remained unclear.

• This study compared insulin infusion via endogenous (hepatic portal vein) and clinical (peripheral) routes to assess their impact on afternoon hepatic glucose disposal.

• Arterial hyperinsulinemia in the morning, without a concomitant increase in insulin at the liver, failed to induce a significant enhancing effect on afternoon HGU and glycogen storage, unlike morning hepatic portal vein insulin delivery, which did.

• These findings highlight the importance of achieving appropriate hepatic insulin exposure in the morning to effectively prime the liver for enhanced glucose disposal later in the day.