Insulin resistance is known to cause intestinal dyslipidemia. It is unclear whether the intestine experiences aberrant insulin signaling during the insulin resistant state. To investigate the effect of insulin on intestinal lipid metabolism, in vivo and ex vivo studies were conducted in the fructose fed (FF) hamster model. The normal chow fed hamster model was able to respond to the inhibitory effects of insulin and a decrease in circulating levels of apoB48-containing lipoproteins occurred. However, the FF hamster model was unresponsive to the insulin-induced downregulation of apoB48 synthesis suggesting intestinal insulin insensitivity. The FF hamsters experienced a downregulation of IRS-1 and AKT expression. The p110 subunit of PI3 kinase, PTP-1B and basal levels of phosphorylated ERK were increased. MEK1/2-inhibition led to a decrease in apoB48 synthesis and secretion. The FF hamster displays intestinal insulin insensitivity and aberrant insulin signaling that may be mediated through the activation of the MAPK pathway.