Vesiculin is a two-chain peptide derived from IGF-II through the action of enzymatic cleavage [1,2]. We have shown vesiculin to be capable of lowering blood glucose in mice and importantly we have shown this effect is not hindered by insulin resistance [3]. In addition, we have also shown vesiculin to be capable of driving an increase in serum insulin levels in insulin resistant hA-Tg mice that was accompanied by increased islet cell area and islet cell nuclear PCNA expression [4]. We have further explored glucose uptake activity in cell models of both differentiated 3T3-L1 adipocytes an L6 myocytes with and without induction of insulin resistance. The cell models once again revealed IGF-II and vesiculin to be equally capable of driving glucose uptake in adipocytes and myocytes, however IGF-II activity is diminished in both cell lines when insulin resistance was induced in these cells fully ablating insulin action. Vesiculin activity was not diminished. We have also shown differences in binding affinities for these peptides with IGF binding protein 3 (IGFBP3). Taken together with the fact we have shown both peptides to signal via the same family of receptors and through an Akt dependant mechanism (as does insulin), insulin resistance must induce a change in the proportion of different receptor types (IGF1R, IR-A and IR-B) and or may alter tissue specific binding protein expression, both of which have not yet been fully explored. Understanding the mechanism by which vesiculin bypasses insulin resistance will open up potential novel therapeutic approaches.