FATPs in hepatic lipid transport and their potential to be regulated by insulin in other tissues we set about looking into the link between insulin and lipid transport and its Axitinib relation to FATP 2 and 5 in the liver. Investigating the hyperinsulinemic state Kerouz et al. have reported that obese ob/ob mice have significantly higher IRS-1 than IRS-2 liver protein. Furthermore, Guo et al. reported that inactivation of IRS-1 leads to improvement in murine hepatic steatosis. Further, Taniguchi et al. found that short term adenovirus mediated inactivation of IRS-2 increased hepatic steatosis. Thus, we conclude from the literature our data that an imbalance of IRS signaling favoring relatively more IRS-1 than IRS-2 occurs in the hyperinsulinemic state. Investigating the hypoinsulinemic state Rojas et al. observed that liver IRS-2 protein increased relative to IRS-1 after a 72-hour fast or with STZ-induced T1DM. Contrary to these findings, Simmgen et al. reported that IRS-2 signaling is not required for hepatic lipid metabolism. However, the authors of these studies did not assess this in either fasting or STZ-induced conditions, where IRS-2 is shown to be increased. We observed in our insulin replacement experiment a dose dependent reduction in liver TG content in STZ treated T1FLD mice receiving insulin. Though we did not measure fatty acid transport directly in our current experiments this is clearly an important path of future research. This decrease in FFA maybe a manifestation of direct insulin mediated reduction in peripheral lipolysis and therefore contribute to the reduction in TG accumulation independent of FATP regulation. We acknowledge that these two in vivo models may not be completely translatable to human conditions such as type 2 and type 1 diabetes, however, further evidence that insulin impacts the FATP levels directly comes from our in vitro studies where targeted gene disruption of IRS-1&2, led to decreased FATP-2&5 expressions. Though all in vitro experiments were not performed under identical conditions unlike in vivo, there is no peripheral lipolysis in vitro, thus we concluded that increased FATP expression at extremes of insulin concentrations is likely mediated via imbalanced IRS signaling. We acknowledge that some of the concentrations of insulin used maybe be supraphysiological but they do provide for proof of concept. Indeed, others have also found that IRS-1 mRNA and protein levels are increased with insulin treatment, and that IRS-2 mRNA is down regulated by insulin. Thus, if a relative increase of IRS-1 signaling is paramount in the pathogenesis of obesity comorbidities, then a pharmacologic means of restoring IRS-2 signaling might prove to be a viable therapeutic option. White et al have reported that finding drugs which stimulate IRS-2 synthesis or promote its signaling might be a useful treatment option for obesity-associated T2DM. Similarly, Gupta et al. have reported that the long-acting glucagon-like peptide 1 agonist, Exendin-4, decreases hepatic steatosis and activates the same pathway as IRS-2.