High fat and fructose diets (HFFD) disrupt glucose metabolism. The aim of this study was to determine the effect of HFFD on glucagon (GGN) effectiveness. Dogs were fed either chow or HFFD for one month. After a basal sampling period, somatostatin and basal portal vein infusions of insulin and GGN were given for 4h, with the exception of GGN, which was either maintained at basal or increased 6-fold. Glucose was infused in the basal GGN groups (CHOW+GLC & HFFD+GLC) to match the 3-fold increase in plasma glucose that occurred with 6x-GGN (CHOW+GGN & HFFD+GGN) . There were no differences in plasma insulin or glucose and GGN levels were proportional to GGN infusion rates in all groups. 6x-GGN caused an identical increase in net hepatic glucose balance (NHGB) in the chow and HFFD groups (Fig 1A) after which NHGB declined. During the last hour NHGB was 1.8-fold greater in HFHF+GGN compared to Chow+GGN (A) . However, hyperglycemia per se caused a switch from net hepatic glucose output to uptake in Chow+GLC but not HFHF+GLC (there was a 3.7±0.4 vs. 0.3±0.4 mg/kg/min decrease in NHGB over time in the two groups, respectively) (B) . Thus, when expressed relative to each group’s respective glucose control group, the AUC for GGN stimulated NHGB was 1.9-fold greater in the Chow (C) compared to HFHF (D) groups (P<0.05) .
In summary, HFHF feeding reduced hepatic glucagon action indirectly by impairing hepatic glucose effectiveness.
D.S.Edgerton: None. G.Kraft: None. K.C.Coate: None. B.Farmer: None. M.S.Smith: None. M.Scott: None. J.R.Hastings: None. M.C.Moore: None. A.D.Cherrington: Advisory Panel; Biocon, Diakard, Metavention, Sekkei Bio, Sensulin Labs, LLC, vTv Therapeutics, Consultant; Abvance, Fractyl Health, Inc., Novo Nordisk, Research Support; Bristol-Myers Squibb Company.