1563-P: High Fat and Fructose Feeding Severely Impairs Hepatic Glucose Effectiveness but Not Insulin Action Under Euglycemic Conditions

Diets high in fat and fructose (HFHF) disrupt glucose metabolism. This study compared the effects of a HFHF diet on liver insulin action vs glucose effectiveness. Dogs were fed either a chow or HFHF diet for 1 month. At the start of each study, 3-3H-glucose was infused and after a basal sampling period, somatostatin and basal glucagon were given. During the experimental period (4h) either insulin was infused into the hepatic portal vein at 4 fold basal, while glucose was delivered to maintain euglycemia (CHOW-INS and HFHF-INS), or glucose was infused to increase its level 2.5 fold, while insulin was maintained at basal (CHOW-GLC and HFHF-GLC) (n=6/grp). Plasma insulin, glucagon, glucose, and hepatic glucose load were matched within the respective groups. In response to selective hyperinsulinemia, net hepatic glucose balance (NHGB) was suppressed from output to uptake (basal period to last h; 1.2±0.1 to -1.0±0.2 vs 1.7±0.2 to 0.0±0.1; deltas of 2.2±0.2 vs 1.6±0.3 mg/kg/min in CHOW-INS vs HFHF-INS, respectively; p=0.2). Selective hyperglycemia, on the other hand, caused changes in NHGB of 1.1±0.2 to -2.5±0.4 vs 1.4±0.1 to 1.7±0.6; deltas of 3.6±0.4 vs -0.3±0.6 mg/kg/min in CHOW-GLC vs HFHF-GLC, respectively (p<0.001). Glucose turnover (Ra) was suppressed (basal period to last h) by 1.7±0.3 vs 1.3±0.1 mg/kg/min (p=0.4) in CHOW-INS vs HFHF-INS, and by 1.9±0.2 vs 0.5±0.1 mg/kg/min (p<0.001) in CHOW-GLC vs HFHF-GLC, respectively. Thus, the HFHF diet had a small, non-significant effect on liver insulin action under euglycemic conditions, whereas it severely impaired the effect of hyperglycemia in the presence of basal insulin (i.e. hepatic glucose effectiveness). These data demonstrate that the “gold standard” hyperinsulinemic euglycemic clamp may overlook substantial diet induced liver dysfunction. Furthermore, Ra accounts for glucose production but not liver uptake, thus has the potential to miss critical and substantial changes in liver glucose metabolism. Disclosure D.S. Edgerton: None. G. Kraft: None. H.L. Waterman: None. B. Farmer: None. K. Yankey: None. M.S. Smith: None. J.R. Hastings: None. M. Scott: 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 R01DK18243