1565-P: Morning Hyperglucagonemia Disrupts the Priming Action of AM Insulin

The second meal effect describes an improvement in the glycemic response seen following the consumption of a 2nd identical meal. We previously showed that morning (AM) exposure of the liver to hyperinsulinemia can prime the liver so that there is increased hepatic glucose uptake and glycogen storage later in the day, with no effect on non-hepatic glucose uptake (non-HGU). Considering that most individuals consume meals that prompt both insulin and glucagon secretion, we sought to determine if AM hyperglucagonemia can alter the priming effect of AM hyperinsulinemia on PM hepatic glucose metabolism. To explore this aim, canines were exposed to 4h of hyperinsulinemia in the AM in a delivery pattern that mimicked the insulin secretory profile previously observed during a 4h AM duodenal glucose infusion. This 4h period of hyperinsulinemia was accompanied by either basal (INS, n=6) or elevated (I + G, n=8) glucagon. After a 1.5h non-clamp period, the dogs were challenged using a 2.5h afternoon (PM) hyperinsulinemic-hyperglycemic (HIHG) clamp during which the glucose load, insulin and glucagon levels, and the artery to portal vein glucose gradient were identical between the two groups. During the PM clamp, the mean NHGB in I+G was only 54% of that in INS (mean NHGB of -3.3±0.5 vs. -6.2±0.5 mg/kg/min; net AUC of 415±70 vs. 785±73 mg/kg/2.5h, P0.003), respectively. Additionally, glycogen synthesized during the PM clamp was twice as high in INS vs. I+G (mean PM glycogen storage of 23.6±1.3 vs. 12.0±1.9 mg/g liver, P0.001), respectively. There was no significant difference in mean PM non-HGU between the two groups. The mean PM NHGB for a group that received basal insulin and basal glucagon in the AM (No Prime) was -2.7±0.5 mg/kg/min, which is not statistically different from PM NHGB for I+G. In conclusion, exposing the liver to hyperglucagonemia in the morning has the potential to block the priming action of meal-induced AM hyperinsulinemia, preventing enhanced glucose uptake and glycogen storage by the liver later in the day. Disclosure H.L. Waterman: None. M.C. Moore: None. M.S. Smith: None. B. Farmer: None. K. Yankey: None. D.S. Edgerton: None. A.D. Cherrington: Consultant; Abvance Therapeutics. Research Support; Abvance Therapeutics. Advisory Panel; AdipoPharma. Research Support; Cellular Longevity, Inc. dba Loyal. Advisory Panel; Fractyl Health, Inc. Consultant; Fractyl Health, Inc. Research Support; Fractyl Health, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Paratus, Portal Insulin. Advisory Panel; Sekkei Bio, Sensulin Labs, LLC. Consultant; Thetis Pharmaceuticals, LLC. Funding National Institutes of Health (5R01DK131082); National Institutes of Health (5T32DK007563)