Lipid-Derived Mediators in Insulin Action

Abstract

Conclusions

There seems to be little doubt that insulin provokes rapid changes in phospholipid metabolism in many of its target tissues. These changes include apparent hydrolysis of PI-glycan or other glycolipids, activation of de novo phosphatidic acid synthesis, and phosphatidylcholine hydrolysis. Diacylglycerol can derive from each of these three phospholipid effects of insulin, and more recent studies suggest that this diacylglycerol is functionally active and results in the activation of protein kinase C. A pertussis toxin-sensitive G protein appears to also be involved in PI-glycan (or other glycolipid) hydrolysis and de novo phosphatidic acid synthesis: this G protein (Giα) probably serves to couple the insulin receptor to a phospholipase C which hydrolyzes the PI-glycan, and the latter appears to release head group mediators which activate the de novo pathway. On the other hand, the activation of phosphatidylcholine hydrolysis appears to occur by a separate mechanism, which does not involve a pertussis toxin-sensitive G protein. It therefore appears that there are two separable mechanisms whereby insulin activates phospholipid metabolism, and while these parallel effects are separable mechanistically, they appear to be integrated to provide for coordinated hydrolysis and continued resynthesis of a PI-glycan (or other glycolipid) and phosphatidylcholine. Although the role of head group mediators and diacylglycerol-protein kinase C signaling remain to be further defined, preliminary findings suggest that many of the actions of insulin may be accounted for, wholly or in part, through these signaling pathways (Fig. 2). It remains for future studies to test the hypothesis that these signaling pathways are important, not only during insulin action physiologically, but also in clinical states of insulin resistance.