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Indomethacin treatment causes loss of insulin action in rats: involvement of prostaglandins in the mechanisms of insulin action

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Abstract

Glucose tolerance tests in rats showed that after indomethacin treatment plasma insulin levels rose five-fold higher than in untreated controls. Accordingly, the pancreatic islets of indomethacin-treated rats secreted insulin at a threefold higher rate. Glucose tolerance tests additionally showed that indomethacin treatment led to a retarded disposal of the elevated blood glucose. Both effects appear to be caused by an attenuation of the hormone responsiveness for insulin and noradrenaline (α-adrenoceptor action) by indomethacin. The following observations support this view: insulin and adrenaline (α-adrenoceptor action) lost their ability to lower cyclic adenosine monophosphate (AMP) levels in hepatocytes; the glycogen content of liver and skeletal muscle was reduced by 95% and 65%, respectively; in adipocytes the stimulation of glucose transport by insulin was reduced by 60%. These effects of indomethacin can be reversed by the addition of exogenous prostaglandin E (PGE), as elevated cyclic AMP systhesis was again sensitive to α-adrenergic inhibition in the liver: These results indicate a relationship between prostaglandins and insulin action. These effects of indomethacin could result from reduced synthesis of cyclic PIP (prostaglandylinositol cyclic phosphate), a proposed second messenger for insulin and α-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 indomethacin treatment, in contrast to the stimulation by insulin. Inhibition of PGE and cyclic PIP synthesis resulted in a metabolic state comparable to insulin resistance in non-insulin-dependent diabetes mellitus.

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Correspondence to H. K. Wasner.

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Wasner, H.K., Weber, S., Partke, H.J. et al. Indomethacin treatment causes loss of insulin action in rats: involvement of prostaglandins in the mechanisms of insulin action. Acta Diabetol 31, 175–182 (1994). https://doi.org/10.1007/BF00571947

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Key words

  • Insulin release
  • Insulin resistance
  • Glucose transport
  • Prostaglandin E
  • Cyclic AMP
  • Indomethacin