1849-P: Importance of Insulin’s Direct and Indirect Effects on Postprandial Hepatic Glucose Uptake

Abstract

In heathy individuals the liver is a primary site of glucose disposal, it is in a state of glucose uptake most of the day, and this process is impaired in diabetes. Insulin stimulates hepatic glucose uptake (HGU) but the importance of its indirect effects (at fat, brain and pancreatic alpha cells) in driving HGU is unclear. Thus, the aim of this study was to determine the impact of insulin’s indirect mechanisms of control of HGU. Postprandial conditions were simulated for 4-hour in conscious dogs (n=7/group) by infusing somatostatin, intraportal insulin (1.8 mU/kg/min) and glucose (4 mg/kg/min), and leg vein glucose (to clamp arterial glucose at 2-fold basal). In one group insulin’s direct and indirect effects on the liver were both present (D+I) while in the other insulin’s indirect effects were blocked (D-only). In D+I the basal intraportal glucagon infusion rate was decreased to create a progressive decline in glucagon over time, FFA levels were allowed to fall, and brain insulin action was allowed to increase. In D-only glucagon and FFA levels were maintained at basal levels by infusions of intraportal glucagon and leg vein lipid emulsion. Hypothalamic insulin action was blocked by 3rd ventricle infusion of an insulin receptor antagonist. In the D+I and D-only groups, respectively, hepatic insulin increased during the experimental period (from 20±3 to 88±8 and 21±3 to 89±8 µU/ml), hepatic glucagon fell or remained basal (39±5 to 24±3 and 40±6 to 41±2 pg/ml) and arterial FFA fell or remained basal (1069±19 to 99±23 and 1195±63 to 998±99 µmol/l). HGU and net hepatic glucose uptake (NHGU) were independently measured using tracer and cold glucose balance techniques. The AUCs for HGU and NHGU (mg/kg/240 min) in D+I were 841±143 and 792±105, respectively, and 738±130 and 698±58 in D-only (P=0.6 and 0.4 between groups, respectively). Thus, in the healthy animal, HGU responds normally to insulin even in the absence of the hormone’s indirect effects. Instead HGU is driven almost exclusively by insulin’s direct effects. Disclosure D.S. Edgerton: Speaker's Bureau; Self; Novo Nordisk A/S. G. Kraft: Consultant; Self; Metavention. B. Farmer: None. M.S. Smith: None. P.E. Williams: None. A.D. Cherrington: Board Member; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Abvance, Boston Scientific Corporation, California Institute for Biomedical Research, Galvani Bioelectronics Limited, MedImmune, Novo Nordisk Inc., Thetis Pharmaceuticals LLC. Research Support; Self; Abvance, Diasome Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; Abvance, Biocon, Fractyl Laboratories, Inc., Metavention, Novo Nordisk Inc., Sensulin, LLC., Thetis Pharmaceuticals LLC, Zafgen, Inc. Funding National Institutes of Health