Waterman Hannah L, Moore Mary Courtney, Smith Marta S, Farmer Ben, Yankey Kalisha, Scott Melanie, Edgerton Dale S, Cherrington Alan D
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
Diabetes. 2025 Mar 1;74(3):270-281. doi: 10.2337/db24-0786.
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.
在一天晚些时候进食第二顿相同的餐食后，葡萄糖耐量会显著改善（第二餐现象）。我们之前已经证实，早晨的高胰岛素血症会使肝脏做好准备，以增加下午的肝脏葡萄糖摄取（HGU）。尽管胰岛素的给药途径是胰岛素调节肝脏葡萄糖代谢机制（直接肝脏作用与间接胰岛素作用）的一个重要决定因素，但尚不清楚胰岛素的给药途径是否会影响第二餐反应。为了确定早晨外周胰岛素给药（如临床上通过皮下注射）是否能增强下午的HGU，对清醒的狗在早晨分别通过门静脉或外周（腿部静脉）给药胰岛素进行治疗，同时输注葡萄糖以维持血糖正常。结果，两组的动脉胰岛素水平相似升高，但外周胰岛素给药时出现了相对的肝脏胰岛素缺乏。下午，所有动物都接受相同的高胰岛素-高血糖钳夹试验，以模拟相同的餐后样状态。当胰岛素通过外周给药时，早晨门静脉胰岛素给药所导致的下午HGU的显著增强消失了。这表明早晨胰岛素不是通过其对肝脏的间接作用引起第二餐现象，而是通过直接激活肝脏胰岛素信号。
早晨胰岛素给药使肝脏做好准备，以增加当天晚些时候的肝脏葡萄糖摄取（HGU），但直到现在，其机制（直接肝脏作用和/或间接胰岛素作用）仍不清楚。本研究比较了通过内源性（肝门静脉）和临床（外周）途径输注胰岛素，以评估它们对下午肝脏葡萄糖处置的影响。与早晨肝门静脉胰岛素给药不同，早晨的动脉高胰岛素血症，在肝脏胰岛素没有相应增加的情况下，未能对下午的HGU和糖原储存产生显著的增强作用。这些发现突出了早晨实现适当的肝脏胰岛素暴露以有效使肝脏做好准备，从而增强当天晚些时候葡萄糖处置的重要性。
