2471-P: The Effect of Glucagon on Hepatic Insulin Extraction in Obesity with or without Hepatic Steatosis

Introduction and Objective: Insulin is secreted into the portal vein in response to nutrient ingestion. However, a significant proportion is extracted as it traverses the liver prior to reaching the systemic circulation. The effect of glucagon on hepatic extraction is uncertain. This is particularly germane to situations where postprandial suppression of glucagon is impaired, theoretically altering the systemic availability of endogenous insulin. Methods: To study glucagon’s actions on hepatic metabolism, we studied lean (n = 7) and obese subjects (n = 13). In all participants hepatic fat by MRI as Proton Density Fat Fraction (PDFF); 6 obese subjects had PDFF 5%; the remainder PDFF 5%. After an overnight fast, femoral vein, femoral artery, and hepatic vein catheters were placed at 0700 (-180 min). At 1000 (0 min), somatostatin (60ng/kg/min) was infused to inhibit endogenous islet hormone secretion. insulin was infused at 0.8 mU/kg/min (0 - 240 min) alongside glucagon (1.5 ng/kg/min 0 - 120 min; 3.0 ng/kg/min 120 - 240 min). A hyperglycemic clamp maintained glucose at ~9.0 mmol/L. Fasting insulin extraction was calculated from basal C-peptide and insulin concentrations, incorporating age- and body surface area-associated changes in both hormone kinetics, as described by Campioni et al. Fractional extraction of insulin during the clamp was estimated from the arteriovenous differences across the liver. Results: Glucagon concentrations rose from 7 ± 1 to 24 ± 1 and to 46 ± 2 pmol/l (0, 120, 240 min respectively). Hepatic extraction of insulin did not differ across the 3 stages of the experiment (0.28 ± 0.04 vs. 0.32 ± 0.04 vs. 0.32 ± 0.03, p = 0.91). Although BMI, PDFF and insulin action correlated with insulin extraction, there was no interaction with glucagon. Conclusion: Glucagon does not alter hepatic extraction of insulin. In addition, this effect is not modulated by body habitus, hepatic steatosis or insulin action. Disclosure H.E. Christie: None. S. Mohan: None. F. Boscolo: None. A. Egan: None. M. Jensen: Consultant; Current; Dexcom, Inc., Novo Nordisk. Other - support as invited speaker; Current; Lilly. K. Nair: None. C. Dalla Man: Other - Webinar provider; Ended; Sanofi. Other - Joint research project; Current; Sanofi-Aventis Deutschland GmbH. A. Vella: Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Current; Rezolute. Research Support; Current; Dexcom, Inc. Advisory Panel; Current; Neurotronic, Amylx. Funding National Institute of Health (DK116231-06)