AM Insulinization of the Liver Is an Important Driver of PM Hepatic Glucose Uptake

Abstract

Glucose tolerance is significantly improved in response to consuming a second, identical meal later in the day. It is known that physiologic (portal vein) exposure to insulin in the morning primes the liver for increased hepatic glucose uptake and glycogen storage in the afternoon. Although this phenomenon has been observed in both healthy and diabetic individuals, it has not yet been established whether or not morning peripheral insulin delivery could bring about the same response. Thus, the aim of this study was to determine how the route of morning insulin delivery impacts the liver’s ability to extract and store glucose later in the day. To explore this aim, we delivered insulin into the portal vein (Po Ins) or a leg vein (Pe Ins) in the morning (AM) and subsequently challenged conscious dogs to a hyperinsulinemic-hyperglycemic (HIHG) clamp in the afternoon (PM). We then assessed the impact that each route of AM insulin delivery had on hepatic glucose uptake (HGU), non-HGU, and glycogen storage in the PM. The insulin infusion rates used in the Po Ins group were selected to mimic the rise in endogenous insulin secretion previously observed during a 4hr AM duodenal glucose infusion (2.1 mU/kg/min [0-30 min], 2.4 mU/kg/min [30-60 min], and 1.5 mU/kg/min [60-240 min]). In efforts to expose both groups to the same amount of insulin in the periphery while creating a difference at the liver, these rates were halved in the Pe Ins group. In the PM clamp, all groups received 4x basal insulin, 2x basal glycemia, and portal glucose infusion to simulate a second meal. During the 2.5hr PM clamp, the mean HGU was 1.8-fold higher in the Po Ins group vs. the Pe Ins group (HGU of 6.28±0.62 vs. 3.49±0.31 mg/kg/min; net AUC of 827±82 vs. 474±40 mg/kg/2.5hr, p<0.002), respectively, with no significant difference in non-HGU (net AUC of 819±118 mg/kg/2.5hr in Po Ins vs. 684±83 mg/kg/2.5hr in Pe Ins). Additionally, mean PM hepatic glycogen content was 47% larger in Po Ins vs. Pe Ins (23.6±1.1 vs. 12.5±1.5 mg/g liver, p<0.001), respectively. When compared to a group from an earlier study that received morning saline and a HIHG clamp in the afternoon (Sal Ctrl), there was no significant difference between Pe Ins and Sal Ctrl for any parameter measured. Therefore, physiologic hepatic insulin exposure in the morning is critical for increased hepatic glucose disposition and glycogen storage later in the day. 5T32DK007563 5R01DK131082-02. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.