Synthetic inositol phosphoglycans related to GPI lack insulin-mimetic activity

Insulin signaling has been suggested, at least in part, to be affected by an insulin-mimetic species of low molecular weight. These inositol phosphoglycans (IPGs) are generated upon growth hormone/cytokine stimulation and control the activity of a multitude of insulin effector enzymes. The minimal structural requirements of IPGs for insulin-mimetic action have been debated. Two types of IPGs were suggested, and the IPG-A type resembles the core glycan of glycosylphosphatidylinositol (GPI)-anchors. In fact, purified GPI-anchors of lower eukaryotic origin have been shown to influence glucose homeostasis. To elucidate active IPGs, a collection of synthetic IPGs designed on the basis of previous reports of activity were tested for their insulin-mimetic activity. In vitro and ex vivo assays in rodent adipose tissue as well as in vivo analyses in mice were employed to test the synthetic IPGs. None of the IPGs we tested mimic insulin actions as determined by PKB/Akt phosphorylation and quantification of glucose transport and lipogenesis. Furthermore, none of the IPGs had any effect in in vivo insulin tolerance assays. In stark contrast to previous claims, we conclude that neither of the compounds tested is insulin-mimetic.