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Insulin secretion under extracellular acid-base alterations (metabolic acidosis or alkalosis) was studied, by challenging in vitro perfused sodium pentobarbital-anesthetized-rat pancreases with glucose, arginine, and tolbutamide. Under our experimental conditions, the amount of insulin released was lower at pH 7.8 than the amount corresponding to the pH 7.4 control, in spite of the agent used to stimulate the pancreas. The effect of pH 7.0 on insulin secretion, however, depends on the type and concentration of the stimulus used. It enhances the secretion elicited by glucose (6.6 mM) and glucose plus arginine (6.6 and 10 mM, respectively). On the other hand, it reduces the beta cell response to glucose plus tolbutamide (3.3 mM and 400 microgram/ml, respectively), whereas the response to high glucose (16.6 mM) is reduced in the first phase and not affected in the second. According to these results, modifications of the extracellular pH, mainly at high levels, may interfere with a common process involved in insulin secretion, namely beta cell emiocytosis.