INDOMETHACIN TREATMENT CAUSES LOSS OF INSULIN ACTION IN RATS - INVOLVEMENT OF PROSTAGLANDINS IN THE MECHANISM OF INSULIN ACTION

Glucose tolerance tests in rats showed that after indomethacin treatme nt plasma insulin levels rose fivefold higher than in untreated contro ls. Accordingly, the pancreatic islets of indomethacin-treated rats se creted insulin at a threefold higher rate. Glucose tolerance tests add itionally showed that indomethacin treatment led to a retarded disposa l of the elevated blood glucose, Both effects appear to be caused by a n attenuation of the hormone responsiveness for insulin and noradrenal ine (alpha-adrenoceptor action) by indomethacin, The following observa tions support this view: insulin and adrenaline (alpha-adrenoceptor ac tion) lost their ability to lower cyclic adenosine monophosphate (AMP) levels in hepatocytes; the glycogen content of liver and skeletal mus cle was reduced by 95% and 65%, respectively; in adipocytes the stimul ation of glucose transport by Insulin was reduced by 60%. These effect s of indomethacin can be reversed by the addition of exogenous prostag landin E (PGE), as elevated cyclic AMP synthesis was again sensitive t o alpha-adrenergic inhibition in the liver. These results indicate a r elationship between prostaglandins and insulin action. These effects o f indomethacin could result from reduced synthesis of cyclic PIP (pros taglandylinositol cyclic phosphate), a proposed second messenger for i nsulin and alpha-adrenoceptor action, whose synthesis was decreased by indomethacin treatment and increased by the addition of exogenous PGE . Stimulation of glucose transport by cyclic PIP was unaffected by ind omethacin treatment, in contrast to the stimulation by insulin. Inhibi tion of PGE and cyclic PIP synthesis resulted in a metabolic state com parable to insulin resistance in non-insulin-dependent diabetes mellit us.