1597-P: High Fat and Fructose Diet Dysregulates Postprandial Gut and Hepatic Metabolism in a Canine Model

Diets high in fat and sugar are associated with the development of metabolic disease, but pathogenic changes in the gut and downstream metabolic organs are not well understood. In the dog, we sought to assess 9 weeks of chow (n=5) versus high-fat, high-fructose diet (HFFD) (n=5) on the gut response and the impact on liver, pancreas fat, and muscle following a mixed meal (26g protein, 67g carbohydrates, 22g lipids). To measure the 6-hour postprandial rate of nutrient absorption and secretion of pancreatic and gut hormones, dogs underwent surgical placement of catheters in the portal vein, hepatic vein, and femoral artery, and flow probes around the portal vein and hepatic artery. Duodenal morphology and L and K cell distribution were evaluated. The meal-induced glucose absorption occurred rapidly with HFFD (peak 13.5±1.1 mg/kg/min at 90 min post-meal v 10.9±1.3 mg/kg/min at 120 min), resulting in a greater rise in glucose (231±25 v. 162±7 mg/dL, p=0.03) compared to chow. Insulin secretion rates for HFFD and chow groups were similar at the 90 min peak (1.6±0.3 v. 1.9±0.6 µU/kg/min) and 6h AUC (237±46 v 243±67 mU/kg). Meal-induced GIP secretion was markedly increased (542±70 v 295±74 pg/kg/min, p=0.05) while GLP-1 was reduced (100±40 v 219±64 pg/kg/min, p=0.16) in HFFD compared to chow. These changes were associated with increased duodenal total mucosal height (1817±133 v 1500±159 µm, p=0.04) but no change in L or K cell distribution. HFFD-induced liver response was markedly altered with a failure to switch from net hepatic glucose output pre-meal to glucose uptake and storage post-meal (output of 1.7±0.2 to output of 3.0±1.4 mg/kg/min) compared to chow (output of 1.6±0.3 to uptake of 3.4±1.1). Given the lack of hepatic uptake, meal glucose was likely taken up by muscle.

In conclusion, HFFD-induced changes in duodenal morphology, gut function, and gut hormone secretion that were associated with abnormal hepatic and pancreatic responses, suggesting a role for the gut in metabolic pathogenesis.