Diacylglycerol directly stimulates the insulin receptor tyrosine kinase.

Studies with detergent:lipid mixed micelles reveal that diacylglycerol directly stimulates the intrinsic tyrosine kinase activity of the insulin receptor. Kinetic analyses indicate that diacylglycerol activates the kinase by causing a marked increase in the affinity of the receptor for insulin. In contrast, diacylglycerol has no effect on the insulin receptor's catalytic activity or its affinity for ATP. Stimulation of the insulin receptor is not a result of protein kinase C activation. First, phorbol myristate acetate, a potent activator of protein kinase C, has no effect on insulin receptor activity. Second, the activation by diacylglycerol is not stereospecific, in marked contrast to the specificity for 1,2-diacyl-sn-glycerol in the activation of protein kinase C. Because circulating levels of insulin are below the Kd of the insulin receptor for insulin, the ability of diacylglycerol to modulate the affinity of the receptor for ligand suggests that increases in cellular levels of diacylglycerol directly sensitize the receptor to insulin.