Effect of diltiazem on insulin secretion

Abstract

Abstract-Effect of diltiazem on insulin secretion was investigated in the perfused rat pancreas. Experiments were also carried out in anesthetized dogs and conscious rats with and without glucose loading.In the perfused rat pancreas, diltiazem reduced both glucose and tolbutamide-induced insulin secretion and these effects of diltiazem were reversed with removal of the compound. Inhibition of the glucose-induced insulin secretion caused by diltiazem was counteracted by increasing the concentration of calcium ion. In experiments on intact animals, diltiazem at vasoactive doses produced no significant influence on the basal level of plasma insulin or glucose-induced insulin secretion.These data taken together with findings in previously reported work suggest that diltiazem reduces insulin secretion from pancreatic B-cells in vitro possibly by the calcium-antagonistic property, while the compound exhibits practically no inhibitory action on the insulin secretion in vivo.In a preceding paper (1), it was shown that in isolated islets of Langerhans from rats, diltiazem produced a concentration-dependent inhibition of the release of insulin following stimulation with glucose. This inhibitory effect of diltiazem was antagonized with increasing concentrations of extracellular calcium ion. We suggested that diltiazem may suppress the glucose-induced insulin secretion by reducing free calcium ion concentration in B-cells.In the present study, the time course for change in insulin secretion from rat pancreas was followed using a perfusion method and the dynamic aspects of the inhibitory effect by diltiazem were studied. In vivo effects of diltiazem on the insulin secretion were also studied in dogs and rats with and without glucose loading. MATERIALS AND METHODS1. Perfusion of rat pancreas: The perfused rat pancreas was prepared according to the method described by Sussman et al. (2) with slight modification. Male Sprague-Dawley rats (about 450 g) were anesthetized with sodium pentobarbital (50 mg/kg i.p.) and the abdominal cavity was opened. All abdominal vessels except for the superior mesenteric artery and celiac axis were ligated and cut. A portion of the duodenum tightly adhering to the pancreas was left intact. The thoracic aorta was cannulated to a point just superior of the celiac axis and the perfusate was allowed to flow through the pancreas and a portion of the small intestine. The effluent was continuously collected through a cannulated portal vein at one to two min intervals. At the end of the experiments, the perfusion circuit was confirmed to be complete by perfusion with Evans blue. The perfusate was Krebs-bicarbonate

Diltiazem

“…Similar findings with diltiazem were observed subsequently in the perfused rat pancreas preparation (150). In studies on anesthetized dog, diltiazem (20 p,glkg/ min for 20 min) had no effect on glucose-stimulated insulin release (150). Similar findings were obtained in a conscious rat model at a diltiazem dose of 50 mg/kg p.0.…”

“…Similar findings were obtained in a conscious rat model at a diltiazem dose of 50 mg/kg p.0. In both cases, the diltiazem dosage had systemic vasodilator effects, suggesting that the insulin release mechanism is not sensitive to the calcium entry blocker effects of diltiazem at vasodilator dosages (150).…”

Direct diabetogenic effect of diltiazem ?

“…Accordingly, diltiazem may impede insulin secretion by reducing the intracellular concentration of free calcium ions [2]. Diltiazem, however, does not appear to influence the plasma concentration of insulin or glucose-induced insulin secretion significantly in non-diabetic animals [3]. This discrepancy in the results of in vitro and in vivo studies may be due to the activation of mechanisms of counter-regulation in vivo.…”