EFFECT OF CHLORPROMAZINE (CPZ) ON INSULIN RELEASE IN VIVO AND IN VITRO IN THE RAT

¹ E.P. Joslin Research Laboratory, Peter Bent Brigham Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts

The diabetogenic action of chlorpromazine (CPZ) is well known. Its mechanism, however, is poorly understood, and do data are available on its action on insulin. We investigated the effect of CPZ on glucose and insulin levels in the rat during a glucose tolerance test as well as on isolated pancreatic islets. For the in vivo studies CPZ was administered intraperitoneally one hour before glucose tolerance testing at a dose of either 3.2 or 32 mg/kg. There were six rats in each of the treatment and control groups. Fasting hyperglycemia (174 vs. 136 mg/100 ml) and a frankly diabetic glucose tolerance test were observed after 32 mg/kg of CPZ; no significant changes in blood glucose took place after 3.2 mg/kg of CPZ. Serum insulin rose 2.5-fold 20 minutes after glucose in control aimimals but failed to respond in either of the CPZ-pretreated group of rats. In isolated pancreatic rat islets, we studied the effect of CPZ in concentrations between 0.001 and 1 mM on glucose-induced insulin release and glucose oxidation. In the absence of CPZ, glucose (3 mg/ml) stimulated insulin release approximately 10-fold. Addition of CPZ (0.005, 0.01 and 0.1 mM) significantly reduced glucose-mediated insulin release by more than half. In contrast, addition of 1 mM CPZ either in the absence or in the presence of glucose caused the release of large amounts of insulin into the medium. In the lesser doses, CPZ did not affect the extractable insulin content of islets. When oxidation of labeled glucose to ¹⁴CO₂ was studied, concentrations of CPZ up to 0.1 mM significantly decreased oxidation of glucose labeled in the carbon 1 position, whereas oxidation of ¹⁴C-6 glucose was not significantly affected. However, 1 mM CPZ decreased ¹⁴CO₂ production from both ¹⁴C-1 and ¹⁴C-6 glucose. It is concluded that CPZ exhibits its main action On the -cell inhibiting glucose-induced insulin release. Base-line insulin levels are not decreased. Very high concentrations of CPZ (1 mM) decrease glucose oxidation in both the pentose phosphate shunt and the Embden-Meyerhof pathway. The paradoxical insulin release into the medium is the result of leakage due to cellular death.

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