Carboxypeptidase E deficiency as seen in the fat/fat mice is associated with reduced antral somatostatin content but tripling of the progastrin product. Thus, fat/fat mice are able to maintain normal tissue concentrations of bioactive cu-amidated gastrin in spite of grossly attenuated progastrin processing. After induction of achlorhydria, however, neither the amount of alpha-amidated gastrin nor the total progastrin product increased in the fat/fat mice. This is contrary to what is seen in wild-type mice. Furthermore, the synthesis of antral somatostatin and fundic chromogranin A is also abnormal. Hence the results suggest a breakdown in the feedback loop that regulates gastric acid secretion.