Waterman Hannah L, Smith Marta S, Farmer Ben, Yankey Kalisha, Howard Tristan, Kraft Guillaume, Cherrington Alan D, Edgerton Dale S
Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine.
bioRxiv. 2025 Jul 5:2025.07.01.662587. doi: 10.1101/2025.07.01.662587.
The second meal phenomenon refers to the improved glycemic response observed after consuming a second identical meal. It is well known that postprandial hepatic glucose uptake (HGU) is determined by the combined effects of three regulatory factors: insulin action (hyperinsulinemia; HI), glucose effectiveness (hyperglycemia; GE), and glucose delivery into the hepatoportal circulation (portal glucose signal; PGS). While our previous studies demonstrated the importance of morning (AM) hyperinsulinemia in priming the liver for increased HGU later in the day, the question remains as to which aspect of the afternoon (PM) response is enhanced by morning insulin. Thus, to provide insight into the underlying mechanism of the 2 meal effect, we sought to determine the extent to which PM HI, GE, and the PGS are impacted by AM hyperinsulinemia. Dogs underwent an AM clamp with either a 4h hyperinsulinemic prime (Prime, ) or basal insulin delivery (No Prime, ). After a 1.5h non-clamp period, both groups were challenged with a PM hyperglycemic clamp (with the PGS) in the presence of basal insulin. During the PM clamp, net HGU was significantly elevated in Prime vs. No Prime group (mean of 2.2±0.3 vs. 0.1±0.3 mg/kg/min, respectively, P<0.005), indicating an enhancement of GE and/or the PGS. There was no difference in PM non-HGU (4.5±0.3 vs. 4.0±0.3 mg/kg/min). In previous experiments, when all three factors (HI, GE, PGS) were present in the PM, net HGU was 6.3±1.7 vs. 2.4±1.1 mg/kg/min in groups receiving an AM insulin prime vs. basal insulin, respectively. Therefore, the AM insulin prime enhanced the effects of HI, GE, and the PGS on PM HGU by 3.9 mg/kg/min, whereas it enhanced the effects of glucose (GE and the PGS), in the absence of a rise in insulin, by 2.1 mg/kg/min. Taken together, the data show that AM HI enhanced PM insulin action and GE (including the PGS) to an equal extent. This suggests that AM insulin priming enhances cellular targets common to both insulin and glucose signaling in the PM.
第二餐现象是指在食用第二顿相同餐食后观察到的血糖反应改善。众所周知，餐后肝脏葡萄糖摄取（HGU）由三种调节因素的综合作用决定：胰岛素作用（高胰岛素血症；HI）、葡萄糖效能（高血糖症；GE）以及葡萄糖向肝门静脉循环的输送（门静脉葡萄糖信号；PGS）。虽然我们之前的研究证明了早晨（AM）高胰岛素血症在使肝脏做好准备以在当天晚些时候增加HGU方面的重要性，但早晨胰岛素增强下午（PM）反应的哪个方面这一问题仍然存在。因此，为了深入了解两餐效应的潜在机制，我们试图确定PM HI、GE和PGS受AM高胰岛素血症影响的程度。犬只接受AM钳夹，钳夹方式为4小时高胰岛素预充（预充组，Prime）或基础胰岛素输注（无预充组，No Prime）。在1.5小时的非钳夹期后，两组在基础胰岛素存在的情况下接受PM高血糖钳夹（伴有PGS）。在PM钳夹期间，预充组的净HGU显著高于无预充组（分别为2.2±0.3与0.1±0.3毫克/千克/分钟，P<0.005），表明GE和/或PGS增强。PM非HGU无差异（4.5±0.3与4.0±0.3毫克/千克/分钟）。在之前的实验中，当PM中所有三种因素（HI、GE、PGS）都存在时，接受AM胰岛素预充组与基础胰岛素组的净HGU分别为6.3±1.7与2.4±1.1毫克/千克/分钟。因此，AM胰岛素预充使HI、GE和PGS对PM HGU的作用增强了3.9毫克/千克/分钟，而在胰岛素未升高的情况下，它使葡萄糖（GE和PGS）的作用增强了2.1毫克/千克/分钟。综上所述，数据表明AM HI同等程度地增强了PM胰岛素作用和GE（包括PGS）。这表明AM胰岛素预充增强了PM中胰岛素和葡萄糖信号共有的细胞靶点。
