Hk. Wasner et al., INDOMETHACIN TREATMENT CAUSES LOSS OF INSULIN ACTION IN RATS - INVOLVEMENT OF PROSTAGLANDINS IN THE MECHANISM OF INSULIN ACTION, Acta diabetologica, 31(4), 1994, pp. 175-182
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.