2484-P: The Clinical Effect of Peripheral Insulin Delivery in Dogs Fed a High Fat and Fructose Diet

Introduction and Objective: Clinical (subcutaneous) insulin delivery abolishes the endogenous portal vein (PV) to arterial insulin gradient, leading to relative hepatic under-insulinization as well as excess insulin exposure of muscle. Our aim was to determine how route of insulin delivery affects liver vs muscle glucose disposal in dogs with high fat and fructose (FF) induced metabolic dysfunction. Methods: Dogs (n=6/group) were fed a chow (C) or FF diet for 4 weeks. Somatostatin was used to disable the pancreas and basal glucagon was infused. Postprandial hyperglycemia was created with PV (4 mg/kg/min) and leg vein (LV) glucose (infused as needed), while insulin was infused (1.2 mU/kg/min) either into the PV or a LV. Results: PV insulin was ~2x greater with PV infusion whereas arterial insulin was ~2x greater with LV infusion. Net hepatic glucose uptake was markedly reduced in FF compared to C-fed dogs. While the diet’s effect on NHGU was not altered by route of insulin delivery (6.2±0.5, 2.4±0.2 and 2.2±2.2 mg/kg/min in the C+PV ins, FF+PV ins and FF+LV ins groups, respectively), MGU was ~2.5x greater in FF+LV ins vs FF+PV ins. Conclusion: While PV nor LV insulin were able to overcome the severe reduction in liver glucose uptake caused by the FF diet, LV insulin delivery, in addition, caused much greater MGU, an effect that increases hypoglycemic risk. Therefore, diet induced impairment of postprandial hepatic glucose uptake cannot be normalized by increasing the dose of peripherally delivered insulin. Disclosure G. Kraft: None. K. Yankey: None. B. Farmer: None. H. Waterman: None. M. Lee: None. J. Hastings: None. D. Edgerton: None. Funding NIH RO1DK018243