The insulin signalling pathway

A key aim for future research is to identify the hydrophobic motif kinase that phosphorylates PKB, S6K, SGK and to establish how this protein kinase(s) is regulated by PtdIns(3,4,5)P3. It is also becoming obvious that the information obtained by the overexpression of constitutively active and dominant negative mutants of protein kinases is not providing physiologically reliable results and that new genetic and pharmacological approaches are needed to identify the substrates of each of the individual insulin-regulated protein kinases and to establish their roles in mediating insulin-dependent responses. Another key challenge will be to define the mechanism by which PKB and the activation of TC10 trigger the translocation of GLUT4 from its intracellular stores to the plasma membrane. Although our understanding of the insulin signal transduction pathway is far from being complete, our current knowledge of this pathway provides a framework for the development of novel drugs to treat diabetes. For example a drug that could mimic PtdIns(3,4,5)P3 would be expected to promote glucose uptake, glycogen synthesis and stimulate protein synthesis in tissues of diabetic patients. Recent studies have also demonstrated that inhibitors of GSK3, do indeed mimic the effects of insulin on this enzyme in cell lines and promote the uptake of glucose from the blood and its conversion to glycogen. If drugs that mimic the effect that insulin has on its signalling pathway are orally effective, it is possible that these could be used to treat type 1, as well as type 2 diabetes, and so reduce or replace the need for daily insulin injections.