The effect of a sulfonylurea, glibenclamide, on the release of insulin, glucagon, and somatostatin was studied in the isolated perfused rat pancreas. At glucose concentrations of 1.1 mM or less, the drug stimulated somatostatin release, whereas glucagon release, after 2-3 min of increase, was markedly inhibited. Insulin release was moderately stimulated, and maximal release occurred relatively late. A moderate glucose load (6.7 mM) inhibited glibenclamide-induced release of somatostatin, whereas the two in combination exerted an additive action on insulin release. Greater ,ug/ml was added to the infusion medium (Fig. 1). Before the addition of glibenclamide, the amount of insulin and somatostatin in the perfusate increased with increasing glucose concentrations, whereas the amount of glucagon decreased (Fig. 1).The insulin release by glibenclamide was considerably more pronounced at glucose concentrations of 3.3 and 4.4 mM than 0-and 1.1 mM. In contrast, the release of somatostatin after glibenclamide addition was more pronounced at glucose concentrations of 0-3.3 mM than at 4.4 mM.The elevated levels of glucagon appearing at glucose concentrations of 0 and 1.1 mM were markedly inhibited by gli-

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Arginine significantly stimulated the release of insulin, glucagon and somatostatin from the isolated perfused rat pancreas. A sulphonylurea, glibenclamide, markedly enhanced the effect of arginine on somatostatin release and inhibited its effect on glucagon release. Insulin release was not modulated by addition of glibenclamide. These findings support the idea of a paracrine interaction of islets hormones.

The effects of sulfonylurea on glucagon secretion were characterized in the perfused rat pancreas using glibenclamide (1 microgram/ml) or tolazamide (10 micrograms/ml) in the presence of 3.3 mmol/l glucose. Glucagon release, which was unaffected by glibenclamide at 2.75 mmol/l calcium, was suppressed at 1.19 and 0.64 mmol/l but transiently stimulated at 0.25 mmol/l extracellular calcium. The insulinogenic effect of glibenclamide at 0.64 and 0.25 mmol/l calcium was enhanced by 35% and 89%, respectively, compared to the response at 2.75 mmol/l calcium. The stimulatory effect of the compound on somatostatin secretion, however, was lost at the lower calcium levels. The effects of tolazamide at 2.75 and 0.64 mmol/l calcium mimicked those of glibenclamide, thus indicating that our results with the latter compound may be representative for all sulfonylureas. In pancreata from insulin-deficient alloxan-diabetic rats, glibenclamide completely lost its inhibitory effect on glucagon release at 0.64 mmol/l calcium. Inhibition was not restored by adding insulin (25 U/l) to the perfusate. However, when diabetic rats had been treated with insulin for 6-7 days, glibenclamide suppressed glucagon release at low calcium levels in the absence of stimulated insulin and somatostatin release. It is concluded that, at low calcium concentrations, sulfonylureas suppress glucagon secretion by a direct action on the A cell and not through paracrine interactions by insulin and somatostatin. Prolonged insulin deficiency impairs the sulfonylurea action on glucagon secretion.

The extracellular calcium requirements for insulin, glucagon and somatostatin release induced by 1 microgram/ml of glibenclamide have been compared in the perfused, isolated rat pancreas. In the absence of glucose, the drug evoked insulin release equally well at physiological (2.6 mmol/l) and low (0.25 mmol/l) levels of total calcium. In contrast, glibenclamide evoked somatostatin release at 2.6 but not at 0.25 mmol/l of calcium. At 2.6 mmol/l of calcium, glibenclamide evoked bimodal effects (stimulation followed by inhibition) on glucagon secretion. At 0.25 mmol/l of calcium, basal secretory rates of glucagon were elevated and a small stimulatory effect of glibenclamide was seen. Addition of 0.5 mmol/l of EGTA to media with low calcium concentrations uniformly abolished the A, B and D cell secretory responses to glibenclamide. The possible modulation of calcium dependency by a non-stimulatory concentration of glucose was tested by its addition at 3.3 mmol/l to the perfusion media. Glucose enhanced glibenclamide-induced insulin secretion, both at 0.25 and 2.6 mmol/l of calcium. However, at 0.25 mmol/l of calcium, the enhancing effect of glucose was more pronounced than at 2.6 mmol/l. At 2.6 mmol/l of calcium, glucose diminished the somatostatin and abolished the glucagon response to glibenclamide. At 0.25 mmol/l of calcium, glucose did not influence somatostatin release while the presence of the sugar diminished basal and glibenclamide-induced glucagon secretion. The present data confirm the requirement of extracellular calcium for A, B and D cell secretion, demonstrating different calcium dependencies for the cell types and indicate that this dependency can, in part, be modulated by glucose.